Conditions: Plasmodium Falciparum Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 377
Healthy volunteers: no

Brief summary:
Primary Objective:

To determine whether a single dose combination of OZ439 (Artefenomel)/FQ (Ferroquine) was an efficacious treatment for uncomplicated Plasmodium falciparum malaria in adults and children.

Secondary Objectives:

* To evaluate the efficacy of OZ439/FQ:

  * To determine the incidence of recrudescence and re-infection.
  * To determine the time to relief of fever and parasite clearance.
* To evaluate the safety and tolerability of OZ439/FQ in adults and children.
* To characterize the pharmacokinetics of OZ439 in plasma, FQ and its active metabolite SSR97213 in blood.
* To determine the blood/plasma ratio for FQ and SSR97213 in some participants at limited time points in selected sites.

Detailed description:
Total duration was 63 days for each participant.

Arms:
arm 1: On Day 0, based on the body weight (BW), participants received orally a single dose of ferroquine (FQ) capsules or oral suspension (along with matching placebo, as applicable to maintain blinding) and a single dose of artefenomel (OZ439) (maximum dose up to 800 milligrams \[mg\]) oral suspension as follows: BW greater than or equal to (\>=) 35 kilograms (kg): FQ 400 mg + OZ439 800 mg; BW \>=24 kg to less than (\<) 35 kg: FQ 300 mg + OZ439 600 mg; BW \>=15 kg to \<24 kg: FQ 200 mg + OZ439 400 mg; BW \>=10 kg to \<15 kg: FQ 150 mg + OZ439 300 mg; BW \>=7 kg to \<10 kg: FQ 100 mg + OZ439 200 mg; \>=5 kg to \<7kg: FQ 75 mg + OZ439 150 mg. arm 2: On Day 0, based on the BW, participants received orally a single dose of FQ capsules or oral suspension (along with matching placebo, as applicable to maintain blinding) and a single dose of OZ439 (maximum dose up to 800 mg) oral suspension as follows: BW \>= 35 kg: FQ 600 mg + OZ439 800 mg; BW \>=24 kg to \<35 kg: FQ 450 mg + OZ439 600 mg; BW \>=15 kg to \<24 kg: FQ 300 mg + OZ439 400 mg; BW \>=10 kg to \<15 kg: FQ 225 mg + OZ439 300 mg; BW \>=7 kg to \<10 kg: FQ 150 mg + OZ439 200 mg; \>=5 kg to \<7kg: FQ 115 mg + OZ439 150 mg. arm 3: On Day 0, based on the BW, participants received orally a single dose of FQ capsules or oral suspension (along with matching placebo, as applicable to maintain blinding) and a single dose of OZ439 (maximum dose up to 800 mg) oral suspension as follows: BW \>= 35 kg: FQ 900 mg + OZ439 800 mg; BW \>=24 kg to \<35 kg: FQ 675 mg + OZ439 600 mg; BW \>=15 kg to \<24 kg: FQ 450 mg + OZ439 400 mg; BW \>=10 kg to \<15 kg: FQ 335 mg + OZ439 300 mg; BW \>=7 kg to \<10 kg: FQ 225 mg + OZ439 200 mg; \>=5 kg to \<7kg: FQ 170 mg + OZ439 150 mg. arm 4: On Day 0, based on the BW, participants received orally a single dose of FQ capsules or oral suspension (along with matching placebo, as applicable to maintain blinding) and a single dose of OZ439 (maximum dose up to 800 mg) oral suspension as follows: BW \>= 35 kg: FQ 1200 mg + OZ439 800 mg; BW \>=24 kg to \<35 kg: FQ 900 mg + OZ439 600 mg; BW \>=15 kg to \<24 kg: FQ 600 mg + OZ439 400 mg; BW \>=10 kg to \<15 kg: FQ 450 mg + OZ439 300 mg; BW \>=7 kg to \<10 kg: FQ 300 mg + OZ439 200 mg; \>=5 kg to \<7kg: FQ 225 mg + OZ439 150 mg.

Interventions: intervention 1: Ferroquine SSR97193 intervention 2: Artefenomel intervention 3: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form:Capsules Route of administration: oral intervention 2: Pharmaceutical form:Granules for suspension Route of administration: oral intervention 3: Capsules. Placebo capsules were used to keep the same number of capsules in each weight band while keeping the ferroquine dose blinded. No participant received placebo only.

Protocol document:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-003152 VERSION N°3.0 (04-FEB-2016)
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL NO. 03 
Protocol Amendment 03 
Version number: 1 (electronic 2.0) 
Date : 10-Apr-2019 
Amended Clinical Trail Protocol 02 
Version number: 1 (electronic 3.0) 
Date : 11-Jul-2017 
Protocol Amendment 02 
Version number: 1 (electronic 1.0) 
Date : 11-Jul-2017 
Amended Clinical Trial Protocol 01 
Version number: 1 (electronic 2.0) 
Date : 04-Nov-2015 
Protocol Amendment 01 
Version number: 1 (electronic 2.0) 
Date : 04-Nov-2015 
Clinical Trial Protocol 
Version number: 1 (electronic 1.0) 
Date : 20-Nov-2014 
Version Number: 
1 
EudraCT 
Not applicable 
IND Number(s) 
115,244 (SSR97193) 104549 (OZ439) 
WHO universal trial 
number: 
U1111-1155-7960 
Date: 
10-Apr-2019
Total number of pages: 109 
VV-CLIN-0181265 5.0
COMPOUND: SSR97193 / ferroquine in association with artefenomel 
A randomized, double-blind, Phase IIb study to investigate the efficacy, safety, 
tolerability and pharmacokinetics of a single dose regimen of ferroquine (FQ) with 
artefenomel (OZ439) in adults and children with uncomplicated 
Plasmodium falciparum malaria 
STUDY NUMBER: DRI12805 
VERSION DATE / STATUS: 10-Apr-2019 / Approved 
NCT02497612


Amended Clinical Trial Protocol No. 03  
10-Apr-2019 
DRI12805 - ferroquine in association with artefenomel 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 2 
NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
Sanofi-aventis recherche & développement 
1 Avenue Pierre Brossolette 
91385 CHILLY-MAZARIN CEDEX 
France 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
 
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Amended Clinical Trial Protocol No. 03  
10-Apr-2019 
DRI12805 - ferroquine in association with artefenomel 
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Page 3 
CLINICAL TRIAL SUMMARY 
COMPOUND:  
SSR97193 - ferroquine in 
association with artefenomel 
STUDY No: DRI12805  
 
TITLE 
A randomized, double-blind, phase IIb study to investigate the efficacy, safety, 
tolerability and pharmacokinetics of a single dose regimen of ferroquine (FQ) 
with artefenomel (OZ439) in adults and children with uncomplicated 
Plasmodium falciparum malaria  
INVESTIGATOR/TRIAL LOCATION 
Africa and previously in Asia (recruitment in Asia is closed) 
STUDY OBJECTIVES  
 
Primary objective 
 
To determine whether a single dose combination of OZ439/FQ is an 
efficacious treatment for uncomplicated Plasmodium falciparum 
(P. falciparum) malaria in adults and children 
Secondary objectives 
 
To evaluate the efficacy of OZ439/FQ: 
- 
To determine the incidence of recrudescence and re-infection 
- 
To determine the time to relief of fever and parasite clearance 
 
To evaluate the safety and tolerability of OZ439/FQ  
 
To evaluate the pharmacokinetics of OZ439/FQ: 
- 
To characterize the pharmacokinetics of OZ439 in plasma, FQ 
and its active metabolite SSR97213 in blood  
- 
To determine the blood/plasma ratio for FQ and SSR97213 in 
some patients at limited time points in selected sites. 
 
To further explore efficacy of OZ439/FQ: 
- 
To evaluate the proportion of patients with gametocytes at each 
parasitological assessment 
- 
To characterize gametocyte carriage 
- 
To evaluate the relationship between Adequate Clinical & 
Parasitological Response (ACPR) and exposure to OZ439/FQ  
- 
To explore the relationship between Kelch-13 genotype and 
parasite clearance kinetics 
 
To explore in vitro drug resistance of P. falciparum infecting patients 
>14 years old in Vietnamese sites. 
STUDY DESIGN 
A randomized, double-blind single-dose treatment, 3 to 4 dose-regimen study in 
patients with uncomplicated Plasmodium falciparum malaria. Adults and children 
will be included sequentially in four cohorts through a progressive age step-
down procedure and FQ dose step-up procedure (pre-defined data of patients 
>14 years and body weight ≥35 kg exposed to the 3 first lowest doses in parallel 
will be reviewed before testing 1200 mg FQ dose in association with 800 mg 
OZ439).  
At the end of each cohort (or sub-Cohort 1a and 1b), a safety review of adverse 
events, potentially clinically significant abnormalities (PCSAs) for clinical 
laboratory test results, vital signs, and 12-lead ECGs will be performed. For 
patients >14 years (Cohort 1), FQ/active metabolite (SSR97213) blood 
concentration/QTc effect modelling will be done by a Sponsor’s independent 
unblinded statistician and reviewed by an independent Data Monitoring 
Committee (DMC). This PK/QTc analyses may or may not be reviewed by the 
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Page 4 
DMC at the same time as the safety data review and therefore may or may not 
be considered by DMC for DMC decision rule to proceed to the 1200 mg FQ 
dose in association with 800 mg OZ439 in that age category. The DMC will 
further determine if the range of 3 or 4 FQ doses in association with 800 mg 
OZ439 can be assessed in the lower age cohorts. 
The DMC could also decide to enroll additional patients in a same age cohort for 
collecting more safety data. 
In addition, interim futility analyses on polymerase chain reaction (PCR)-
adjusted ACPR at Day 28 will be performed using Bayesian methodology when 
approximately 50 patients per treatment arm and thereafter every time another 
25 patients per treatment arm have completed Day 28 assessment.  
The decision to step down with age cohorts will be based on safety. 
STUDY POPULATION  
Main selection criteria: 
Inclusion criteria 
 
Male or female patient aged >6 months old and <70 years old: 
- 
Cohort 1 = 14 years <age <70 years and body weight ≥35 kg,  
- 
Cohort 2 = 5 years <age ≤14 years; 
- 
Cohort 3 = 2 years <age ≤5 years; 
- 
Cohort 4 = 6 months <age ≤2 years. 
 
Body weight ≥5 kg and ≤90 kg. 
 
Presence of mono-infection by P. falciparum with: Fever, as defined 
by axillary temperature ≥37.5°C or oral/rectal/tympanic temperature 
≥38°C, or history of fever in the previous 24 hours (history of fever 
must be documented) and, microscopically (blood smear) confirmed 
parasite infection, ranging from 1000 to 100 000 asexual parasites/µL 
of blood. 
 
Informed Consent Form signed by the patient or parent or legally 
acceptable representative of the minor patient. 
Main exclusion criteria  
 
Presence of severe malaria (according to WHO definition).  
 
Anti-malarial treatment:  
- 
With piperaquine -based compound, mefloquine, naphthoquine 
or sulphadoxine/pyrimethamine (SP) within the previous 6 weeks 
(after their inhibition of new infections has fallen below 50%). 
- 
With amodiaquine or chloroquine within the previous 4 weeks. 
- 
With quinine, halofantrine, lumefantrine-based compounds and 
any other anti-malarial treatment or antibiotics with antimalarial 
activity (including cotrimoxazole, tetracyclines, quinolones and 
fluoroquinolones, and azithromycin) within the past 14 days. 
- 
With any herbal products or traditional medicines, within the past 
7 days.  
 
Known history or evidence of clinically significant disorders. 
 
Previous treatment within 5 times the half-life or within the last 
14 days, whichever the longest which are: P-gp substrates, CYP2D6 
main substrates and/or strong CYP2C or CYP3A inhibitors and/or 
moderate inhibitors but inhibiting both CYP2C and CYP3A and/or CYP 
inducers. 
 
Mixed Plasmodium infection. 
 
Severe vomiting. 
 
Severe malnutrition. 
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 
Laboratory parameters with clinical significant abnormalities and/or 
reaching critical values. For Liver Function Test: (LFT) aspartate 
transferase [AST >2 upper limit of normal (ULN)], or alanine 
transferase [ALT >2 ULN] or total bilirubin [>1.5 ULN]. 
 
Presence of Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen 
(HBs Ag) or Hepatitis C antibody (HCV Ab). 
 
Previous participation in any malaria vaccine study or received malaria 
vaccine in any other circumstance. 
 
Female patient of child bearing potential or male patient having a 
partner of child bearing potential not willing to use an effective 
contraceptive(s) method(s) for the duration of the study. 
 
Positive pregnancy test at study screening for female participants of 
childbearing potential. 
 
Known history of hypersensitivity, allergic or anaphylactoid reactions 
to ferroquine or other - aminoquinolines or to OZ439 or OZ277 or to 
any of the excipients. 
 
Family history of sudden death or of congenital prolongation of the 
QTc interval or known congenital prolongation of the QTc-interval or 
any clinical condition known to prolong the QTc interval eg, patients 
with a history of symptomatic cardiac arrhythmias or with clinically 
relevant bradycardia. 
 
QTcF >450 ms at screening or pre-dose. 
 
Hypokalemia (<3.5 mmol/L), hypocalcemia (<2.0 mmol/L) or 
hypomagnesemia (<0.5 mmol/L) at screening or pre-dose. 
 
Any treatment known to induce a lengthening of QT interval. 
Total expected number of patients: 
Approximately 495 (in case of 3 treatment arms, scenario A) or 662 (in case of 
4 treatment arms, scenario B) African patients (approximately 165 per treatment 
arm), plus 21 Asian patients. 
Expected number of sites: 
Approximately 18 sites in Africa and Asia 
STUDY TREATMENTS 
 
Investigational Products 
Formulation 
Ferroquine (FQ): Capsules of 5, 30, 100 and 200 mg and matching placebo 
Artefenomel (OZ439): Individual sachets containing 150, 200, 300, 400, 600 and 
800 mg OZ439 + TPGS granules for oral suspension.  
Route of administration: 
Oral route, fasted conditions (3 hours) 
Dose regimen: 
 
 
 
 
 
 
 
3 to 4 treatment arms for the combination of FQ and OZ439. 
For patients ≥35 kg, 3 to 4 treatment arms of FQ will be assessed along with a 
fixed dose of OZ439: 
- 
Treatment arm #1: OZ439 800 mg and FQ 400 mg in single dose; 
- 
Treatment arm #2: OZ439 800 mg and FQ 600 mg in single dose; 
- 
Treatment arm #3: OZ439 800 mg and FQ 900 mg in single dose; 
- 
Treatment arm #4: OZ439 800 mg and FQ 1200 mg in single dose will 
be assessed, if the DMC gives green light to proceed with this dose.  
Patients <35 kg will receive weight-adjusted doses for OZ439 predicted to 
achieve exposure (based on AUC) not exceeding 1.5-fold that of a 60 kg adult 
and not exceeding that of the lightest adult (35 kg) for the lightest patient in each 
weight band. 
Patients <35 kg will receive weight adjusted doses for FQ, predicted to achieve 
FQ and SSR97213 exposure (based on mean Cmax and AUC) not exceeding 
1.3-fold that of a lightest adult (35 kg) for the lightest patient in each weight 
band. 
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Page 6 
PRIMARY AND SECONDARY 
ENDPOINTS  
 
Primary endpoint: 
PCR-adjusted Adequate Clinical and Parasitological Response (ACPR) at 
Day 28  
Secondary endpoints 
Efficacy endpoints 
 
PCR - adjusted ACPR at Day 42 and 63. 
 
PCR - crude ACPR at Day 28, 42 and 63. 
 
Kaplan Meier analysis for: 
- 
Time to re-emergence; 
- 
Time to recrudescence; 
- 
Time to re-infection.  
 
Parasite clearance time (PCT).  
 
Fever clearance time (FCT).  
 
Parasite reduction rate (PRR). 
Safety endpoints 
 
Adverse events, including Serious Adverse Events (SAE), Adverse 
Event of Special Interest (AESI) and Treatment Emergent Adverse 
Event (TEAE). 
 
Clinical laboratory tests, vital signs and ECG, including:  
- 
Liver Function test (LFT); 
- 
QTc assessment. 
 
Physical examination and clinical signs and symptoms related to 
uncomplicated P. falciparum malaria (fever, dizziness, headache, 
nausea, anorexia, vomiting, diarrhea, itching, urticaria, skin rash, 
abdominal pain, joint pain, muscle pain, palpitations, sleep problems, 
confusion, hearing problems, vision problems, and fatigue). 
Pharmacokinetic (PK) endpoints 
 
Pharmacokinetic parameters (mainly CL/F, Vss/F, Cmax, AUC as 
relevant) of OZ439 in plasma, FQ and SSR97213 in blood and plasma 
 
Blood/plasma ratio for FQ and SSR97213 (some patients in selected 
sites).  
Exploratory endpoints 
 
Time to clearance of gametocytemia on blood smear for patients with 
gametocytes at baseline. 
 
Time to appearance of gametocytemia on blood smear for patients 
with no gametocytes at baseline and time to clearance. 
 
RT-PCR to measure gametocyte maturation stage (expression of 
Pfs25 mRNA) in patients >5 years. 
 
Correlation between Kelch-13 genotype status and parasite clearance 
kinetics. 
 
Define phenotypic and genotypic resistance pattern to conventional 
ACT of P. falciparum infecting patients aged >14 years old in 
Vietnamese sites. 
 
In vitro susceptibility testing of P. falciparum infecting patients aged 
>14 years old in Vietnamese sites to OZ439, FQ and both drugs.  
ASSESSMENT SCHEDULE 
Refer to study flow chart  
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Page 7 
STATISTICAL CONSIDERATIONS 
 
Analysis population: 
The primary efficacy analysis population will be the Per-Protocol (PP) population 
defined as “lower" naturally acquired immunity (NAI) population”, children 
≤5 years in Africa.  
Sample size determination: 
This protocol is adaptive allowing futility at pre-specified interim points during the 
conduct of the study. At each interim time point, tests for futility will be 
performed. Recruitment will cease to a particular treatment arm if the pre-
specified criterion for futility is reached. Interim assessment of futility will occur 
after recruitment of approximately 50 evaluable patients per treatment arm for 
the 1st futility analysis and every 25 patients per treatment arm thereafter for the 
3 other interim analyses (including 75, 100 and 125 evaluable patients per 
treatment arm, respectively). Recruitment continues until each treatment arm is 
deemed to be futile or until 150 evaluable patients per treatment arm for the final 
analysis is reached. 
Given the adaptive nature of the study design, the total number of patients to be 
recruited can only be estimated. Simulations for different PCR-adjusted ACPR 
responses at Day 28 showed that a sample size of 150 evaluable patients per 
treatment arm will provide ≥80% probability to reject the null hypothesis 
(H0: probability of PCR-adjusted ACPR at Day 28 ≤0.90) at the final analysis, 
for the true rate ≥96.4%. 
In addition, a minimum of 15 African patients older than 5 years per treatment 
arm (likely to have higher NAI and therefore not included in the efficacy 
analyses) will be included for the DMC safety review. 
Primary analysis: 
Within each treatment arm, the following null hypothesis will be tested: 
 
H0: p ≤0.90 
Against the one sided alternative: 
 
H1: p >0.90 
where p is the probability of PCR-adjusted ACPR at Day 28. 
The study will follow a group sequential design with up to 4 interim futility 
analyses, the first one when approximately 50 evaluable patients per 
treatment arm have reached Day 28 and thereafter every time another 
25 evaluable patients per treatment arm (until the final analysis including 
150 evaluable patients) have reached Day 28. 
At each interim analysis, one of the following potential decisions is to be made: 
 
The treatment arm is stopped for futility if the posterior probability of 
H0 (that is, response rate is below 90%) given the data accumulated 
at the look for the treatment arm in question is too large, that is,  
 
Pr(H0|data) ≥0.30. 
 
The treatment arm advances to the next stage if the above conditions 
is not met (even if the observed response rate is 95% or greater). 
A Beta (9.5, 0.5) distribution will be used as prior distribution for the response 
rate and combined with a binomial likelihood to get a Beta posterior distribution 
and calculate the posterior probability. 
At the final analysis, providing the treatment arm has not been stopped for 
futility, the null hypothesis will be rejected and efficacy of the treatment arm 
demonstrated if the lower limit of the exact 95% confidence interval using 
Clopper-Pearson method is >90%.  
 
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Analysis of secondary endpoints 
Secondary efficacy variables will be summarized descriptively with incidence 
rates or standard descriptive methods, including 95% confidence intervals, as 
appropriate and using PCSAs criteria for relevant safety parameters. Time to 
event variables will be summarized with Kaplan-Meier estimates of the survival 
function. 
The relationship between QTc and FQ & SSR97213, respectively and OZ439 
concentrations will be explored graphically and by mixed effect modeling. 
Prediction (estimate and 90% CI) at the observed geometric mean of Cmax will 
be presented for each treatment arm. Three PK/QTc analyses are planned 
(one for Cohort 1a and a second based on the pool of Cohort 1a & 1b for DMC 
review, the last one will take into account all cohorts for the final analysis). 
Standard descriptive statistics on OZ439, FQ and SSR97213 concentration data 
and PK parameters, blood/plasma ratio for FQ and SSR97213. 
Relationship between PCR-adjusted ACPR and dose, concentration or 
exposure to OZ439/FQ will be explored through logistic regression. 
Safety: 
The on-treatment phase will be defined as the start time of investigational 
medicinal product (IMP) administration up to end of study (EOS). All TEAEs will 
be summarized (counts and percent) by primary system organ class, preferred 
term and treatment group. 
Potentially Clinically Significant Abnormalities (PCSAs) for clinical laboratory test 
results, vital signs, and 12-lead ECGs (manual readings, mean values of the 
3 replicates) will be listed, flagged and summarized for treatment group. 
In addition, raw data and changes from baseline for some relevant parameters 
(ECGs, vital signs and laboratory parameters) will be summarized in descriptive 
statistics and summary plots if relevant. 
DURATION OF STUDY (per patient) 
Screening or predose on Day -1. 
Treatment with OZ439/FQ single dose on Day 0. 
Hospitalization at minimum for 48 hours post-dose (African patients greater than 
5 years) or 72 hours post -dose (all Asian patients and African patients 
≤5 years) or for a maximum of 7 days, depending on age, parasite and fever 
clearance, clinical judgment and patient convenience. 
Note: those patients discharged at 48 or 72 hours or later but prior to D7 will 
need to return to the investigational site for scheduled assessments up to Day 7. 
In case the patient is discharged after Day 3, patient has to perform the Day 3 
discharge examinations.  
Following discharge, patients will return for further assessment up to Day 63. 
Total duration will be up to 67 days for each patient. 
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1 
FLOW CHARTS 
1.1 
STUDY FLOW CHART 
Table 1 - Schedule of assessments: screening to Day 63 (Times are post-dose) 
Evaluation 
Screen/ 
Predose 
Treatment Period and post-treatment surveillance 
Follow-Up (FU) 
Visits (V) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
(EOS) 
Daya 
-1 
0 
1 
2 
3 
5 
7 
10 
14 
15-
18g 
21 
+/- 2 
24-
25g 
28  
+/- 2 
42 
+/- 3 
63  
+/- 3  
Hours  
 
0 
0.5 
1 
2 
4 
6 
8 
12 
18 
24 
30 
36 
48 
72 
 
 
 
 
 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography, 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IVRS/IWRS call 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalizationb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit at clinical 
site 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
(X) 
X 
(X) 
X 
X 
X 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OZ439c 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FQc  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and 
concomitant 
medication 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Evaluation 
Screen/ 
Predose 
Treatment Period and post-treatment surveillance 
Follow-Up (FU) 
Visits (V) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
(EOS) 
Daya 
-1 
0 
1 
2 
3 
5 
7 
10 
14 
15-
18g 
21 
+/- 2 
24-
25g 
28  
+/- 2 
42 
+/- 3 
63  
+/- 3  
Hours  
 
0 
0.5 
1 
2 
4 
6 
8 
12 
18 
24 
30 
36 
48 
72 
 
 
 
 
 
 
 
 
 
 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
& malaria signs 
& symptoms 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
 
 
 
 
X 
X 
X 
Weightj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
(X) 
 
 
 
 
 
 
 
 
 
X 
Temperature 
(single)d  
X  
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Asexual & 
sexual count 
(thick & thin 
blood films) 
>14 y and ≥35 
kg (Cohort 1)d 
Xe 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
(X) 
X 
X 
X 
Asexual & 
sexual count 
(thick & thin 
blood films) ≤14 
years (Cohorts 
2 to 4)d 
Xe 
 
 
 
 
 
X 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
(X) 
X 
X 
X 
qPCR, parasite 
genotyping & 
RT-PCR 
gametocyte 
detection 
sampling >14 y 
and ≥35 kg  
(Cohort 1)f  
Xe 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
(X) 
X 
X 
X 
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Evaluation 
Screen/ 
Predose 
Treatment Period and post-treatment surveillance 
Follow-Up (FU) 
Visits (V) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
(EOS) 
Daya 
-1 
0 
1 
2 
3 
5 
7 
10 
14 
15-
18g 
21 
+/- 2 
24-
25g 
28  
+/- 2 
42 
+/- 3 
63  
+/- 3  
Hours  
 
0 
0.5 
1 
2 
4 
6 
8 
12 
18 
24 
30 
36 
48 
72 
 
 
 
 
 
 
 
 
 
 
Parasite 
genotyping 
sampling >6M & 
≤14 y (Cohorts 
2 to 4)f  
Xe 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
(X) 
X 
X 
X 
qPCR & RT-
PCR 
gametocyte 
detection 
sampling >5 y & 
≤14 y (Cohort 
2)f 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
Malaria RDT 
(taken 'in field') 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
 
(X) 
 
 
 
Kelch-13 
analysisf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Susceptibility 
testing in 
patients >14 y 
in Vietnamese 
sitesf 
X 
 
 
 
 
 
 
 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECGi 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
(X) 
(X) 
 
X 
 
 
 
 
 
 
 
 
Vital signsi 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
(X) 
(X) 
 
X 
X 
X 
 
X 
 
X 
X 
X 
AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory 
testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
laboratory 
safety >5 yj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
(X) 
 
X 
 
X 
 
X 
 
X 
 
 
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Evaluation 
Screen/ 
Predose 
Treatment Period and post-treatment surveillance 
Follow-Up (FU) 
Visits (V) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
(EOS) 
Daya 
-1 
0 
1 
2 
3 
5 
7 
10 
14 
15-
18g 
21 
+/- 2 
24-
25g 
28  
+/- 2 
42 
+/- 3 
63  
+/- 3  
Hours  
 
0 
0.5 
1 
2 
4 
6 
8 
12 
18 
24 
30 
36 
48 
72 
 
 
 
 
 
 
 
 
 
 
Clinical 
laboratory 
safety ≤5 yj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
(X) 
 
X 
 
X 
 
 
 
X 
 
 
Hepatitis 
Serologyk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testl  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
OZ PK >14 ym 
 
 
 
 
P00 
P01 
P02 
 
P03 
 
P04 
 
 
P05 
P06 
P07 
 P08 
P09 
 P10 
 
 
 
 
 
 
OZ PK  
>2 y to ≤14 ym 
 
 
 
 
P00 
 
 P02 
 
 
 
P04 
 
 
 
 
 
P08 
 
P10 
 
 
 
 
 
 
OZ PK  
>6 m to ≤2 ym 
 
 
 
 
P00 
 
 P02 
 
 
 
P04 
 
 
 
 
 
P08 
 
 
 
 
 
 
 
 
FQ PK >14 ym 
 
 
BP00 
 
 
BP01, 
PP00 
BP02 
 
BP03 
 
BP04 
 
BP05 
 
 
BP06 
 
 
 
BP07 
 
 
BP08, 
PP01 
 
BP09 
 
 
 
 
BP10, 
PP02 
 
BP11 
BP12 
FQ PK  
>5 y to ≤14 ym 
 
 
 
 
BP01, 
PP00 
 
BP03 
 
 
 
BP06 
 
 
 
 
 
 BP08 
 
BP09 
 
 
 
 
BP10, 
PP02 
 
BP11 
 
FQ PK Group 1 
>2y to ≤5 ym 
 
 
 
 
BP01, 
PP00 
 
BP03 
 
 
 
 
BP06 
 
 
 
 
 
 BP08 
 
BP09 
 
 
 
 
 
 
FQ PK Group 1 
>6 m to ≤2 ym 
 
 
 
 
BP01 
 
BP03 
 
 
 
BP06 
 
 
 
 
 
BP08 
 
BP09 
 
 
 
 
 
 
FQ PK Group 2 
>2 y to ≤5 ym 
 
 
 
 
BP01 
 
BP03 
 
 
 
BP06 
 
 
 
 
 
 BP08 
 
 
 
 
 
BP10, 
PP02 
 
 
FQ PK Group 2 
>6 m to ≤2 ym 
 
 
 
 
BP01 
 
BP03 
 
 
 
BP06 
 
 
 
 
 
BP08 
 
 
 
 
 
BP10 
 
 
FQ PK Group 3 
>2 y to ≤5 ym 
 
 
 
 
BP01 
 
BP03 
 
 
 
BP06 
 
 
 
 
 
BP08, 
PP01 
 
 
 
 
 
 
 
BP11 
 
FQ PK Group 3 
>6 m to ≤2 ym 
 
 
 
 
BP01 
 
BP03 
 
 
 
BP06 
 
 
 
 
 
BP08 
 
 
 
 
 
 
BP11 
 
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a At each patient visit/contact post dose, antimalarial rescue therapy conditions will be assessed and rescue therapy may be given accordingly. 
b Discharge at 48 hours (African patients > 5 years) or 72 hours (all other patients) (or up to Day 7) depending on age, parasite and fever clearance, clinical judgment and patient convenience. If discharged prior to 
Day 7, will return to Investigational site for further assessment on all scheduled times up to Day 7. 
c Patients should have fasted from food and milk for 3 hours before administration. Neither food nor milk should be taken within 2 hour after the end of IMP dosing.  
d Blood films (thick and thin, performed locally) and temperature measurements need to be confirmed as follows: when 1st parasite clearance or 1st temperature <37.5 °C, measurements need to be confirmed with 
second reading 6 to 12 hours after the 1st measurement (ie, to determine Parasite Clearance or Fever Clearance). The first measurement (if confirmed) will be considered the 'Clearance Time'. Only asexual count 
will be used as parasitemia for evaluation of study endpoints. If parasites have not cleared by 72 hours after IMP administration and criteria for rescue medication are not met at 72 h, blood films should continue to 
be taken according to site standard practice (or at minimum every 8 hours) until parasite clearance is shown or until criteria for rescue medication are met (see Section 8.9). If these additional blood smears are 
taken they should be recorded as unscheduled visits in the CRF. 
Note: Axillary temperature should be recorded. If the axillary method is not possible, an alternative route (tympanic, oral, rectal) may be used. Within an individual patient the same method of temperature measure 
should be used throughout the study. 
e Measurement required within 4 hours prior to dosing. Local thick and thin blood films performed at the site, before Informed Consent signature, according to local standard procedures, can be used as screening / 
Pre-dose parasitaemia assessments (Section 9.3.1.1) provided that a standard procedure is in place at site and blood films stainings are performed according to Study Parasitology Procedures Manual. 
f 
Blood spots or blood sample for qPCR (patients >5 y only), blood spot for parasite genotyping and Kelch-13 analysis; blood sample for RT-PCR gametocyte detection (patients >5 y only). To be collected, 
according to the schedule and the instructions reported in the Study Laboratory Procedures Manual. Parasite genotyping analysis will be performed on previously collected blood spot sample only in case of a 
positive blood film after initial parasite clearance: one pre-dose sample and one sample at 18 or 24 hours post dosing. A further sample will be analyzed at the time point at which recrudescence/re-infection occurs 
(if applicable). Sample for Kelch-13 analysis at baseline only. All of these tests will be performed in central lab. During the intervening periods between V10 and V12, blood for RT-PCR gametocyte detection and 
qPCR (patients >14 years and ≥35kg only) will only be taken if the patient returns to the site for assessment. (see g ). An additional blood sample (susceptibility testing) will be taken in patients >14 years old in 
Vietnamese sites at screening (6 mL) and when criteria for rescue treatment for malaria is met (6 mL). These samples will be used for in vitro research of drug resistance (see Section 9.4.2). 
g Patients will have one additional safety check at V10 and V12. Patients may either return to the Investigational site or tests can be performed in the field by trained persons. If returning to the Investigational site, a 
blood film (thick and thin), a genotyping sample and temperature should be taken. Sample for qPCR and, RT-PCR should be taken for patients >14 years and ≥35 kg only. For patients remaining in the field, a 
malaria RDT and temperature should be taken. Patients feeling unwell, with increased temperature (axillary temperature ≥37.5 °C) and/or a positive RDT should return to the Investigational site for assessment 
including blood films, parasite genotyping.  
h Deleted. 
i 
Patients should rest supine prior to measurement for a minimum of 10 minutes (or at least 5 minutes for blood pressure measurement).  
Single ECG will be taken at screening. Triplicate ECGs will be taken at T0 (before IMP administration) and at all time-points thereafter. Depending on discharge date, triplicate ECG to be performed at D2 or D3. 
For all African patients of Cohort 1, triplicate ECG to be performed at D2 (PK/QTc purpose). For all patients discharged after D3, triplicate ECG should be performed at D3. 
Body weight at screening, discharge (D2 or D3) and EOS. For all patients discharged after D3, body weight and vital signs should be performed at D3. Height at screening for BMI calculation. 
j 
Laboratory safety: hematology (local), clinical chemistry (screening: one local lab sample for inclusion criteria and one central lab sample for baseline values; central lab samples at all time-points thereafter), and 
urinary dipstick (performed locally; if any parameter on the dipstick is abnormal, a urine sample should be sent to the central lab for microscopic analysis) (See Table 4 for details). Depending on discharge date, 
laboratory safety at D2 or D3. For all patients discharged after D3, sample should be taken at D3. No sample will be taken at V11 (D21+/-2) for children ≤ 5 years. 
k Serology: Test for hepatitis by rapid spot test: HAV IgM, HBs Ag and HCV Ab. 
l 
Urine HCG is the minimum acceptable test. It will be performed locally. Result must be confirmed negative prior to dosing and must be consistent with menstrual history. 
m Where time points coincide, PK sampling should be performed after vital signs, temperature and ECG measurement. Blood samples will be collected within ± 15 minutes of nominal time until 48 h after 
administration. The exact date and time should be recorded at all PK sampling time points. 
For FQ PK samplings, blood will be collected by venipuncture for Dried Blood Spot (DBS) assay (all sites). In selected sites, plasma (Dried Plasma Spot, DPS) assay will also be performed in a sub-set of patients. 
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Note: For FQ PK samplings, “BPXX” indicate DBS sample, “PPXX” indicate DPS sample. For OZ PK samplings, "PYY" indicates a plasma OZ PK sample. 
For patients > 6 months and ≤5 years, FQ PK sampling will consist of 3 different sampling schedules (Group 1, Group 2, Group 3) attributed at random by the IVRS/IWRS. PP00, PP01 and PP02 only for children 
>2 years. In addition, for all patients where possible, a PK (OZ and FQ) sample should be obtained when a rescue treatment for malaria is given or when QTcF>500 ms or QTcF prolongation >60 ms from baseline 
or when ALT increase (see Section 10.4.1.4). Those additional samples will be identified as “BPA01” for DBS of FQ and as “PA01” for plasma sample of OZ. 
Note: Visit 1 & Visit 2 can occur on the same day, provided that all baseline assessments and biology (including parasitemia and laboratory safety) results are obtained, before patient randomization. Visits or 
examinations presented in brackets have to be performed when applicable.
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1.2 
STEP-DOWN AND STEP-UP PROCEDURES  
Figure 1 - DMC safety review for age step-down & FQ dose step-up procedures 
 
Scenario A: design with 3 treatment arms (OZ439/FQ 800/400 mg, 800/600 mg and 800/900 mg) 
if 4th treatment arm (OZ439/FQ 800/1200 mg) not started after DMC review at the end of 
Cohort 1a or stopped after DMC review at the end of Cohort 1b. 
Scenario B: design with 4 treatment arms (OZ439/FQ 800/400 mg, 800/600 mg, 800/900 mg and 
800/1200 mg) if 4th treatment arm (OZ439/FQ 800/1200 mg) started and continued after DMC 
reviews at the end of Cohorts 1a & 1b respectively. 
 
Patients ≥35 kg: 
- 
Treatment arm 1 = OZ439 800 mg - FQ 400 mg,  
- 
Treatment arm 2 = OZ439 800 mg - FQ 600 mg,  
- 
Treatment arm 3 = OZ439 800 mg - FQ 900 mg,  
- 
Treatment arm 4 = OZ439 800 mg - FQ 1200 mg 
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 
Patients <35 kg will receive  
- 
Weight-adjusted doses for OZ439 predicted to achieve exposure (based on AUC) not 
exceeding 1.5-fold that of a 60 kg adult and not exceeding that of the lightest adult 
(35 kg) for the lightest patient in each weight band. 
- 
Weight adjusted doses for FQ predicted to achieve FQ and SSR97213 exposure (based 
on mean Cmax and AUC) not exceeding 1.3-fold that of a lightest adult (35 kg) for the 
lightest patient in each weight band. 
*: 
 A minimum number of 10 patients (Cohort 1) per treatment arm for DMC safety & PK/QTc evaluation 
**:  
A minimum number of 5 patients (Cohort 2) per treatment arm for DMC review  
***:  
A minimum number of 8 patients (Cohorts 3 & 4) per treatment arm for DMC review  
 
After all these age step-down stages, the recruitment will be fully open. Approximately 62 patients will be recruited in 
Cohorts 1 and 2 for Scenario B. The remaining patients will comprise Cohorts 3 and 4. At least 10% of the lower NAI 
population will come from African patients of Cohort 4. 
****:  
DMC review before starting Cohort 2 recruitment will be made on pooled data (Cohorts 1a & 1b) with a total number of 
patients N ≥42. 
Notes: 
 
Patients likely to have higher NAI (African patients >5 years old to <70 years old) 
and Asian patients will only be considered for safety review. 
 
African patients likely to have lower NAI (children 5 years) will be considered for 
safety review, and also futility and efficacy analyses. 
For DMC safety review, no predefined ratio between African and Asian patients is requested to 
move forward from one group of age to the next one. Patients will be included following a 
“competitive recruitment” process. 
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Figure 2 - Futility interim analysis 
 
 
 
 
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2 
TABLE OF CONTENTS 
 
AMENDED CLINICAL TRIAL PROTOCOL NO. 03 ....................................................................................... 1 
1 
FLOW CHARTS ............................................................................................................................... 9 
1.1 
STUDY FLOW CHART .................................................................................................................... 9 
1.2 
STEP-DOWN AND STEP-UP PROCEDURES ............................................................................. 15 
2 
TABLE OF CONTENTS ................................................................................................................ 18 
LIST OF TABLES ......................................................................................................................................... 23 
LIST OF FIGURES ........................................................................................................................................ 23 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 24 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 27 
4.1 
INTRODUCTION ............................................................................................................................ 27 
4.2 
RATIONALE ................................................................................................................................... 28 
4.2.1 
Study Rationale .............................................................................................................................. 28 
4.2.2 
Dose Rationale ............................................................................................................................... 28 
5 
STUDY OBJECTIVES ................................................................................................................... 33 
5.1 
PRIMARY OBJECTIVE .................................................................................................................. 33 
5.2 
SECONDARY OBJECTIVES ......................................................................................................... 33 
5.3 
EXPLORATORY OBJECTIVES ..................................................................................................... 33 
6 
STUDY DESIGN ............................................................................................................................ 34 
6.1 
DESCRIPTION OF THE PROTOCOL ........................................................................................... 34 
6.2 
DURATION OF STUDY PARTICIPATION .................................................................................... 35 
6.2.1 
Duration of study participation for each patient ............................................................................. 35 
6.2.2 
Determination of end of clinical trial (all patients) .......................................................................... 35 
6.3 
INTERIM ANALYSIS ...................................................................................................................... 35 
6.4 
STUDY COMMITTEES .................................................................................................................. 36 
7 
SELECTION OF PATIENTS .......................................................................................................... 37 
7.1 
NUMBER OF PATIENTS ............................................................................................................... 37 
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7.2 
INCLUSION CRITERIA .................................................................................................................. 37 
7.3 
EXCLUSION CRITERIA ................................................................................................................ 38 
7.3.1 
Exclusion criteria related to study methodology ............................................................................ 38 
7.3.2 
Exclusion criteria related to the current knowledge of Sanofi compound ...................................... 39 
7.4 
PATIENT POPULATION ................................................................................................................ 40 
7.4.1 
Patient sub-populations ................................................................................................................. 40 
7.4.1.1 
Higher naturally acquired immunity population .............................................................................. 40 
7.4.1.2 
Lower naturally acquired immunity population ............................................................................... 40 
7.4.2 
Age range step-down and FQ dose step-up procedures ............................................................... 40 
8 
STUDY TREATMENTS ................................................................................................................. 42 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS ............................................................................. 42 
8.1.1 
Ferroquine (FQ) ............................................................................................................................. 42 
8.1.2 
Artefenomel (OZ439) ..................................................................................................................... 42 
8.1.3 
Treatment arms .............................................................................................................................. 43 
8.1.4 
Re-dosing in the event of vomiting after OZ439 administration ..................................................... 44 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT ....................................................................... 44 
8.3 
BLINDING PROCEDURES ............................................................................................................ 44 
8.3.1 
Methods of blinding ........................................................................................................................ 44 
8.3.2 
Randomization code breaking during the study ............................................................................. 45 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP .............................................. 45 
8.5 
PACKAGING AND LABELING ...................................................................................................... 46 
8.6 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 46 
8.7 
RESPONSIBILITIES ...................................................................................................................... 47 
8.7.1 
Treatment accountability and compliance...................................................................................... 47 
8.7.2 
Return and/or destruction of treatments ........................................................................................ 47 
8.8 
CONCOMITANT MEDICATION ..................................................................................................... 48 
8.8.1 
LIST OF FORBIDDEN CONCOMITANT MEDICATION ................................................................ 48 
8.9 
RESCUE TREATMENT FOR MALARIA........................................................................................ 48 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 49 
9.1 
PRIMARY ENDPOINT ................................................................................................................... 49 
9.1.1 
Primary efficacy endpoint ............................................................................................................... 49 
9.2 
SECONDARY ENDPOINTS .......................................................................................................... 49 
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9.2.1 
Secondary efficacy endpoints ........................................................................................................ 49 
9.2.2 
Safety endpoints ............................................................................................................................ 49 
9.2.2.1 
Adverse events .............................................................................................................................. 50 
9.2.2.2 
Laboratory safety variables ............................................................................................................ 50 
9.2.2.3 
Vital signs ....................................................................................................................................... 52 
9.2.2.4 
Electrocardiogram variables .......................................................................................................... 52 
9.2.2.5 
Physical examination and malaria signs and symptoms ............................................................... 52 
9.3 
MEASUREMENT OF PARASITEMIA ............................................................................................ 52 
9.3.1 
Parasitemia (Thick and thin blood films) ........................................................................................ 52 
9.3.1.1 
Screening and pre-dose blood films .............................................................................................. 53 
9.3.1.2 
Post-dose blood films ..................................................................................................................... 53 
9.3.1.3 
Definition of parasite clearance (by microscopy) ........................................................................... 53 
9.3.2 
Quantitative PCR, parasite genotyping and Kelch-13 analysis ..................................................... 54 
9.3.3 
Gametocyte detection (RT-PCR) ................................................................................................... 54 
9.4 
OTHER ENDPOINTS..................................................................................................................... 55 
9.4.1 
Pharmacokinetics ........................................................................................................................... 55 
9.4.1.1 
Sampling time ................................................................................................................................ 55 
9.4.1.2 
Number of pharmacokinetic samples ............................................................................................. 55 
9.4.1.3 
Pharmacokinetics handling procedure ........................................................................................... 55 
9.4.1.4 
Bioanalytical method ...................................................................................................................... 56 
9.4.1.5 
Pharmacokinetics parameters ....................................................................................................... 57 
9.4.2 
Exploratory efficacy endpoints ....................................................................................................... 57 
9.4.3 
Pharmacogenetic assessment ....................................................................................................... 58 
9.5 
FUTURE USE OF SAMPLES ........................................................................................................ 58 
9.6 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 58 
10 
STUDY PROCEDURES ................................................................................................................ 59 
10.1 
VISIT SCHEDULE .......................................................................................................................... 59 
10.1.1 
Visit 1; Day-1: Screening / Predose Visit ....................................................................................... 59 
10.1.2 
Visit 2; Day 0 (may be on the same calendar day than Day-1) ..................................................... 60 
10.1.3 
Visit 3; Day 1 .................................................................................................................................. 60 
10.1.4 
Visit 4; Day 2 .................................................................................................................................. 61 
10.1.5 
Visit 5; Day 3 .................................................................................................................................. 61 
10.1.6 
Follow-up: V6 to V15 at Day 5, 7, 10, 14, 15-18, 21+/-2, 24-25, 28+/-2, 42+/-3 and 63+/-3 ......... 62 
10.2 
DEFINITION OF SOURCE DATA .................................................................................................. 63 
10.3 
HANDLING OF PATIENT STUDY DISCONTINUATION .............................................................. 63 
10.3.1 
Temporary treatment discontinuation with investigational medicinal products .............................. 63 
10.3.2 
Permanent treatment discontinuation with investigational medicinal products ............................. 64 
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10.3.3 
List of criteria for permanent treatment discontinuation ................................................................. 64 
10.3.4 
Handling of patients after permanent treatment discontinuation ................................................... 64 
10.3.5 
Procedure and consequence for patient withdrawal from study .................................................... 64 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING .......................... 64 
10.4.1 
Definitions of adverse events ......................................................................................................... 64 
10.4.1.1 Adverse event ................................................................................................................................ 64 
10.4.1.2 Serious adverse event ................................................................................................................... 65 
10.4.1.3 Adverse event of special interest ................................................................................................... 66 
10.4.1.4 Project specific AESIs .................................................................................................................... 66 
10.4.2 
General guidelines for reporting adverse events ........................................................................... 67 
10.4.3 
Instructions for reporting serious adverse events .......................................................................... 68 
10.4.4 
Guidelines for reporting adverse events of special interest ........................................................... 68 
10.4.5 
Guidelines for management of specific laboratory abnormalities .................................................. 68 
10.5 
OBLIGATIONS OF THE SPONSOR ............................................................................................. 69 
10.6 
SAFETY INSTRUCTIONS ............................................................................................................. 70 
10.6.1 
Development of complicated malaria ............................................................................................. 70 
10.6.2 
PK sampling in case of QTcF >=500 ms or QTcF prolongation >60 ms and/or 
ALT >=3xULN ................................................................................................................................ 70 
11 
STATISTICAL CONSIDERATIONS .............................................................................................. 71 
11.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 71 
11.2 
DISPOSITION OF PATIENTS ....................................................................................................... 71 
11.3 
ANALYSIS POPULATIONS ........................................................................................................... 72 
11.3.1 
Randomized population ................................................................................................................. 72 
11.3.2 
Efficacy populations ....................................................................................................................... 72 
11.3.2.1 Modified intent-to-treat population ................................................................................................. 73 
11.3.2.2 Per-protocol (PP) population .......................................................................................................... 73 
11.3.3 
Safety population ........................................................................................................................... 73 
11.3.4 
Pharmacokinetic population ........................................................................................................... 73 
11.3.5 
Pharmacokinetic/pharmacodynamic population ............................................................................ 73 
11.4 
STATISTICAL METHODS ............................................................................................................. 74 
11.4.1 
Demographics and baseline characteristics .................................................................................. 74 
11.4.2 
Extent of study treatment exposure and compliance ..................................................................... 74 
11.4.2.1 Extent of investigational medicinal product exposure .................................................................... 74 
11.4.2.2 Compliance .................................................................................................................................... 74 
11.4.3 
Analyses of efficacy endpoints ....................................................................................................... 74 
11.4.3.1 Analysis of primary efficacy endpoint............................................................................................. 75 
11.4.3.2 Analyses of secondary efficacy endpoints ..................................................................................... 76 
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11.4.3.3 Multiplicity considerations .............................................................................................................. 76 
11.4.3.4 Analyses of exploratory endpoints ................................................................................................. 77 
11.4.4 
Analyses of safety data .................................................................................................................. 77 
11.4.4.1 Analyses of adverse events ........................................................................................................... 79 
11.4.4.2 Laboratory variables analyses ....................................................................................................... 80 
11.4.4.3 Analyses of vital sign variables ...................................................................................................... 82 
11.4.4.4 ECG parameters analyses ............................................................................................................. 83 
11.4.5 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 84 
11.4.5.1 Analysis of pharmacokinetic data .................................................................................................. 84 
11.4.5.2 Analysis of pharmacodynamic data ............................................................................................... 84 
11.4.5.3 Analysis of pharmacokinetic/pharmacodynamic data .................................................................... 84 
11.4.6 
Analyses of quality of life/health economics variables ................................................................... 86 
11.5 
INTERIM ANALYSIS ...................................................................................................................... 87 
12 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 88 
12.1 
ETHICAL AND REGULATORY STANDARDS .............................................................................. 88 
12.2 
INFORMED CONSENT ................................................................................................................. 88 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) .............. 89 
13 
STUDY MONITORING................................................................................................................... 90 
13.1 
RESPONSIBILITIES OF THE INVESTIGATORS ......................................................................... 90 
13.2 
RECORD RETENTION IN STUDY SITES .................................................................................... 90 
13.3 
RESPONSIBILITIES OF THE SPONSOR ..................................................................................... 90 
13.4 
SOURCE DOCUMENT REQUIREMENTS .................................................................................... 91 
13.5 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST ...................................................................................................................................... 91 
13.6 
USE OF COMPUTERIZED SYSTEMS .......................................................................................... 91 
14 
ADDITIONAL REQUIREMENTS ................................................................................................... 92 
14.1 
CURRICULUM VITAE.................................................................................................................... 92 
14.2 
CONFIDENTIALITY ....................................................................................................................... 92 
14.3 
PROPERTY RIGHTS ..................................................................................................................... 92 
14.4 
DATA PROTECTION ..................................................................................................................... 93 
14.5 
INSURANCE COMPENSATION .................................................................................................... 93 
14.6 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ................................. 93 
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14.7 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE ............................................................................................................................................ 94 
14.7.1 
By the Sponsor ............................................................................................................................... 94 
14.7.2 
By the Investigator ......................................................................................................................... 94 
14.8 
CLINICAL TRIAL RESULTS .......................................................................................................... 94 
14.9 
PUBLICATIONS AND COMMUNICATIONS ................................................................................. 95 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS .......................................................................... 96 
16 
BIBLIOGRAPHIC REFERENCES ................................................................................................. 97 
17 
APPENDICES ................................................................................................................................ 98 
APPENDIX A 
SEVERE P. FALCIPARUM MALARIA DEFINITION ........................................................... 99 
APPENDIX B 
CYPS INDUCER/INHIBITOR/SUBSTRATE, P-GP SUBSTRATE (NON-
EXHAUSTIVE LIST)..................................................................................................................... 100 
APPENDIX C 
DRUGS KNOWN TO MODIFY QT INTERVAL (NON EXHAUSTIVE LIST) ..................... 102 
APPENDIX D 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI .................................................................................................... 105 
 
LIST OF TABLES 
Table 1 - Schedule of assessments: screening to Day 63 (Times are post-dose).......................................... 9 
Table 2 - Weight bands and pediatric doses for OZ439 (OZ) and FQ .......................................................... 32 
Table 3 - Treatment kits................................................................................................................................. 43 
Table 4 - Clinical laboratory blood tests ........................................................................................................ 51 
Table 5 - Number of PK samples .................................................................................................................. 55 
Table 6 - Summary of handling procedures for FQ and its active metabolite SSR97213 assessment in 
blood and in plasma ...................................................................................................................................... 56 
Table 7 - Summary of handling procedures for OZ439 assessment ............................................................ 56 
Table 8 - Summary of bioanalytical method for FQ and its active metabolite SSR97213 ............................ 56 
Table 9 - Summary of bioanalytical method for OZ439 ................................................................................. 56 
Table 10 - Summary of adverse event reporting instructions........................................................................ 69 
 
LIST OF FIGURES 
Figure 1 - DMC safety review for age step-down & FQ dose step-up procedures ....................................... 15 
Figure 2 - Futility interim analysis .................................................................................................................. 17 
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3 
LIST OF ABBREVIATIONS 
 
°C: 
degrees Celsius 
ACPR: 
adequate clinical and parasitological response 
ACT: 
artemisinin-based combined therapy 
AESI: 
adverse event of special interest 
AS: 
artesunate 
BP: 
blood pressure 
CRF: 
case report form 
DBS: 
dry blood sample 
DMC: 
data monitoring committee 
DPS: 
dry plasma sample 
DRF: 
discrepancies resolution form 
e-CRF: 
electronic case report form 
ETF: 
early treatment failure 
FCT: 
fever clearance time 
FQ: 
ferroquine 
GCP: 
good clinical practices 
HR: 
heart rate 
IA: 
interim analysis 
ICH: 
International Conference of Harmonization 
IMP: 
investigational medicinal product 
IRB/IEC: 
institutional review board/independent ethics committee 
LCF: 
late clinical failure 
LFT: 
liver function test 
LOQ: 
limit of quantification 
LPF: 
late parasitological failure 
MMV: 
Medicines for Malaria Venture 
MPC: 
minimum parasiticidal concentration 
ms: 
millisecond 
NAI: 
naturally acquired immunity 
OZ439: 
artefenomel 
P. falciparum: 
Plasmodium falciparum 
PCR: 
polymerase chain reaction 
PCT: 
parasite clearance time 
PK: 
pharmacokinetic 
PRR: 
parasite reduction rate 
RDT: 
rapid diagnostic test 
SAE: 
serious adverse event 
SUSAR: 
suspected unexpected serious adverse reaction 
TEAE: 
treatment emergent adverse event 
TPGS: 
alpha tocopherol polyethylene glycol 1000 succinate 
WHO: 
World Health Organization 
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GLOSSARY OF TERMS 
qPCR (quantitative polymerase chain reaction) 
A polymerase chain reaction procedure is used to quantify the amount of Plasmodium falciparum 
(P. falciparum)-specific DNA present and is transformed into number of parasites/µL.  
RT-PCR (reverse transcriptase polymerase chain reaction) 
Gametocytes are differentiated from asexual forms by targeting RNA transcripts of gametocyte-
specifically expressed genes (Pfs25).  
Recrudescence 
Recrudescence is defined as the 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 microscopy (positive blood smear) and polymerase chain reaction (PCR) analysis. 
Re-infection 
Re-infection is defined as the appearance of asexual parasites after clearance of initial infection 
with a genotype that differs from that of parasites present at baseline. Re-infection must be 
confirmed by microscopy (positive blood smear) and PCR analysis. Confirmed new infection will 
not be regarded as treatment failure or recrudescence. 
Re-emergence/Recurrence  
Re-emergence (recrudescence and re-infection) is defined as the appearance of asexual parasites 
after clearance of initial infection irrespective of genotype.  
PCR crude 
PCR-crude adequate clinical and parasitological response (ACPR) does not distinguish between 
re-infection (by a new clone of parasite) and recrudescence (re-emergence of the original clone of 
parasite that is present at baseline). 
PCR-adjusted 
PCR-adjusted ACPR applies only to recrudescence (re-emergence of the original clone of parasite 
that is present at baseline). Recrudescence is distinguished from re-infection by genotyping the 
parasite clone. 
SSR97213 
N-demethyl derivative, active metabolite of ferroquine (FQ) 
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CLASSIFICATION OF TREATMENT OUTCOMES (ADAPTED FROM WHO, 2009) (1) 
Parasitemia will be evaluated locally with blood smear. 
Early treatment failure (one the following) 
 
Danger signs or severe malaria on Day 1, 2 or 3 in the presence of parasitemia; 
 
Parasite count on Day 2 higher than on Day 0, irrespective of axillary temperature; 
 
Parasitemia on Day 3 with axillary temperature ≥37.5°C; 
 
Parasite count on Day 3 ≥25% on Day 0. 
Late clinical failure 
 
Danger signs or severe malaria on any day between Day 4 and Day 63 in the presence of 
parasitemia, without previously meeting any of the criteria of early treatment failure; 
 
Presence of parasitemia and axillary temperature ≥37.5 degrees Celsius (°C) (or history of 
fever) on any day between Day 4 and Day 63, without previously meeting any of the 
criteria of early treatment failure. 
Late parasitological failure 
 
Presence of parasitemia on any day between Day 7 and Day 63 and axillary temperature 
<37.5°C, without previously meeting any of the criteria of early treatment failure or late 
clinical failure. 
Adequate clinical and parasitological response (ACPR) 
 
Absence of parasitemia on Day 28 (or Day 42 or Day 63), irrespective of axillary 
temperature, without previously meeting any of the criteria of early treatment failure or 
late clinical failure or late parasitological failure. 
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4 
INTRODUCTION AND RATIONALE 
4.1 
INTRODUCTION 
Plasmodium falciparum (P. falciparum) malaria is a parasitic disease that kills over 
600 000 people and results in up to 200 million cases annually affecting mainly young children in 
Sub Saharan Africa (2). The economic consequences of malaria are enormous in endemic regions 
including gross domestic product loss and productive life loss due to deaths and disability (3). 
Malaria is curable and preventable: principal control strategies including rapid diagnosis, effective 
treatment and personal protection with bed nets. 
World Health Organization guidelines (WHO 2015) recommend the use of artemisinin-based 
combination therapies (ACT) to treat uncomplicated P. falciparum malaria (1, 4) 
Artemisinin (AS) produces a rapid parasitemia clearance with resolution of malaria symptoms.  
A 7-day course was reduced to 3 days when given in combination with long half-life anti-malarial 
drugs such as 4-aminoquinoline drugs (5). Evidence suggests that compliance to a 3-day treatment 
course is low, reducing the effectiveness of the treatment. In addition, evidence of emergence of 
potential plasmodial resistance to artemisinin may become an issue in the coming years (1, 6, 7). 
Thus new drug combinations are required, and effective single exposure combination treatments 
in particular are likely to lead to significant improvement in treatment efficacy.  
Sanofi and Medicines for Malaria Venture (MMV), are co-developing a fixed dose combination 
of Ferroquine (FQ;IND 115 244) and Artefenomel (OZ439;IND 104 549) for a single day-single 
dose treatment of uncomplicated malaria in adults and children with the objective of limit the risk 
for selecting organisms resistant to either or the two partner drugs. Currently OZ439/FQ is 
intended to be used for investigational purpose. 
Detailed information for both products are described in the related Investigator’s brochures, 
reference document of each product updated regularly or at any time, as needed. 
Artefenomel 
Artefenomel (OZ439) is a novel, synthetic trioxolane that shows promise as a peroxidic anti-
malarial agent. Trioxolanes are closely related to artemisinin in that their chemical structure 
contains the peroxidic pharmacophore that leads to the potent anti-malarial activity of these 
agents. 
Based upon evidence to date, OZ439 demonstrates an acceptable safety profile, with continued 
close monitoring for hepatic and cardiac conduction effects recommended in the further clinical 
development.  
OZ439 is studied in combination with FQ in the present Phase IIb DRI12805 FALCI study. 
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Ferroquine 
Ferroquine (FQ) is a new 4-aminoquinoline analogue active against chloroquine-resistant and 
sensitive P. falciparum strains with a promising antimalarial therapeutic potential in humans.  
FQ is a ferrocenyl derivative of chloroquine. Incorporation of a ferrocene core in the lateral side 
chain of chloroquine confers lipophilicity, rigidity, and redox potential to the molecule. A 
multifactorial mechanism of action of FQ has been proposed: inhibition of hemozoin formation, 
improved compared to chloroquine, and probably due to preferential location of FQ at the lipid-
water interface, and generation of reactive oxygen species. 
Ferroquine is a racemic compound with both enantiomers showing an antimalarial activity similar 
to that of the parent compound, in vitro and in vivo. Ferroquine is metabolized into 1 major 
metabolite (N-demethyl derivative, SSR97213), equally active in vitro.  
Additional information can be found in FQ and OZ latest versions investigator's brochure. 
The risk assessment of FQ alone and in combination with OZ439 is based on current available 
results from nonclinical data and clinical data (12 completed Phase I and Phase 2 studies), 
including an additional human challenge study (Q3CP14) with FQ alone in healthy subjects. The 
primary adverse events reported were mainly gastrointestinal (nausea, vomiting) and nervous 
system (headache, dizziness) events. Hepatic effect (elevated liver enzymes) and pro-arrhythmic 
effect (QTc prolongation) are the identified risks for the individual components FQ and OZ439 
given alone or in combination. 
4.2 
RATIONALE 
4.2.1 Study Rationale 
The aim of the phase 2b DRI12805 is to investigate the efficacy, safety, tolerability and 
pharmacokinetics of a single dose regimen of FQ with OZ439 in adults and children with 
uncomplicated P. falciparum malaria. Based on predicted efficacy and safety data, this study will 
determine which single dose combination of OZ439 /FQ once daily is an efficacious and safe 
treatment for uncomplicated P. falciparum malaria in adults and children. The primary endpoint 
being evaluated is PCR adjusted ACPR at Day 28. A dose effect of FQ when combined with a 
defined dose of OZ439 may be demonstrated. 
4.2.2 Dose Rationale 
Doses for DRI12805 were selected based on clinical data obtained in Human Challenge Model 
studies for OZ439, Phase IIa data for OZ439 (MMV_OZ439_10_002), Phase IIb FQ/AS 
(DRI10382 results) and predicted QTc prolongation for FQ as discussed below. 
Based on modeling and simulation of the parasite clearance kinetics of OZ439, the MPC 
(minimum parasiticidal concentration) for OZ439 was estimated to be 3-6 ng/mL. Time above 
MPC for 800 mg OZ was estimated to be approximately 200 h.  
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This was confirmed in a Phase IIa study of the acute efficacy (up to 36 hours post-dose) of 
OZ439 against P. falciparum and P. vivax malaria in a PoC study in Asian adult patients 
(MMV_OZ439_10_002) leading to a 97.9% reduction in parasite concentration by 36 hours for 
P. falciparum for all doses investigated (200 to 1200 mg). 
Assuming an 11-fold reduction in log10 parasitemia is sufficient for effective therapy of patients 
(malaria patient parasitemia is between 1011 and 1012 parasites) PK/PD modeling suggests that a 
single dose of OZ439 at 800 mg can be considered as effective therapy when administered alone 
with around 11-fold decrease in log 10 parasitemia.  
In DRI10382, PCR-adjusted Day 28 cure rate was 93.3, 97.1 and 96.8% after 100, 200 & 300 mg 
(2, 4 & 6 mg/kg) of FQ respectively when given in combination with AS over 3 days in children. 
A dose effect was observed for secondary criteria (uncorrected Day 28 cure rate) with values of 
50.0%, 60.0% and 74.2% after 2, 4 and 6 mg/kg x 3 days respectively, in pediatric population (8, 9). 
After simulations using POP PK model in children and 55 kg adults, FQ and SSR97213 Day 28 
concentrations obtained after 600 mg single dose (or equivalent dose in children, see Table 2) are 
similar as compared to Day 28 concentration obtained in children after 4 mg/kg x 3 days 
(corresponding to 200 mg x 3 days). Thus assuming that OZ439 800 mg single dose performs at 
least as well as AS 200 mg x 3 days (internal MMV data show that OZ439 800 single dose 
performs better than 150 mg x 3 days di-hydro artemisinin) efficacy expected after 600 mg 
FQ /800 mg OZ (expressed in adult dose) single dose should be similar in children and in 55 kg 
adults to efficacy after 200 mg FQ/ 200 AS x 3 days (expressed in adult dose) with PCR-adjusted 
Day 28 cure rate of 97% in pediatrics.  
Considering both corrected and uncorrected Day 28 cure rate from DRI10382, it was deemed 
relevant to test also doses higher than 600 mg and target the highest possible dose that is 
considered safe (see below). 
The choice of the maximal FQ dose of 900 mg as the high dose (first intention) in adult cohort 
derives from the predictive QTc effect in the TDU12511 study in the time interval T0h30 – T48h. 
The predicted mean ΔΔQTcF at FQ maximum peak observed concentration (Cmax) Day 1 
(284 and 618 ng/mL after 900 and 1200 mg, respectively) of 1.3 ms with a 90% upper bound of 
3.7 ms and 2.9 ms with a 90% upper bound of 8.0 ms for FQ doses of 900 and 1200 mg in healthy 
subjects, respectively. Maximum Peak Observed Concentration (Cmax) is expected to be higher 
in patients (estimated around 1.4-fold higher) with FQ mean values estimated at 388 and 
670 ng/mL at 900 mg in 64 kg and 35 kg patients, respectively, thus corresponding to predicted 
mean ∆∆QTcF of 1.8 ms with a 90% upper bound of 5.0 ms and 3.1 ms with a 90% upper bound 
of 8.6 ms, respectively (predicted values from the PK/PD ECG model using TDU12511 data in 
the time interval T0h30 – T48h). Greater than dose proportional increases in ferroquine exposure 
(Cmax and AUC) were observed between 900 and 1200 mg in the phase I OZ439/ferroquine 
combination study when ferroquine was administered with milk. Based on preliminary 
investigations using Physiologically-Based Pharmacokinetic modeling,(10) the current hypothesis 
for this non-linearity is an increase in absorbed fraction (estimated at 100%) at high doses in 
presence of milk. In fasting conditions (as it is recommended for the current DRI12805 study) the 
PK is believed to be linear between 900 and 1200 mg. In this respect, FQ 900 mg once daily is the 
highest recommended dose in the Cohort 1a in DRI12805 study (see Section 9.4.1.5). 
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The expected outcome of this phase 2b study is to document the contribution of FQ to the parasite 
clearance and long term prevention of recrudescence/re infection, and to select a safe and 
efficacious dose that will be tested in a large scale Phase 3 trial. It is therefore important to 
consider increasing level of FQ dose and correctly frame the selected dose.  
 
The upper limit will most likely be defined on safety aspect and could reasonably be  
900 mg or 1200 mg.  
 
The lower limit should be assessed on efficacy by defining the lowest efficacious dose and 
the highest non efficacious dose.  
Ultimately, we should be able to demonstrate a dose effect of FQ when combined with a defined 
dose of OZ439, the primary endpoint being evaluated on PCR adjusted ACPR.  
Regarding the step-down procedure, the 3 treatment arms (OZ439/FQ 800/400 mg, 800/600 mg 
and 800/900 mg) will be administered as a single dose in 4 successive cohorts corresponding to 
4 age categories evaluated in the following order: 
 
Cohort 1: adults patients (>14 years and <70 years and body weight ≥35 kg) including, 
two sub cohorts 1a (highest FQ dose of 900 mg) & 1b (highest FQ dose of 1200 mg),  
 
Cohort 2: adolescent and toddlers (>5 to ≤14 years),  
 
Cohort 3: children (>2 years to ≤5 years) and  
 
Cohort 4: infants and young children (>6 months to ≤2 years).  
At the end of the Cohort 1a (OZ439/FQ 800/400 mg, 800/600 mg and 800/900 mg), an interim 
safety analysis, which may include PK/QTc change analysis will be performed by a Sponsor’s 
unblinded statistician (independent from the study) and reviewed by the Data Monitoring 
Committee (DMC). This PK/QTc analyses may or may not be reviewed by the DMC at the same 
time as the safety data review and therefore may or may not be considered by DMC for DMC 
decision rule. If the 3 treatments up to 800/900 mg OZ439/FQ dose show good tolerability, 
a 4th treatment arm consisting of OZ439/FQ at 800/1200 mg (Cohort 1b with 2 additional patients 
receiving OZ439/FQ 800/900 mg for keeping the blinded conditions) will be recruited in the study 
for assessing the safety of highest FQ dose. A Final PK/QTc change analysis using data from 
Cohorts 1a and 1b will be performed (details of PK/QTc analysis in Section 11.4.5.3). OZ439/FQ 
at 800/1200 mg will be first evaluated in adult patients (>14 years and <70 years and body weight 
≥35 kg, Cohort 1b) vs OZ439/FQ 800/900 mg in a 5:1 randomization ratio to keep the study 
blinded. 
The transition from one cohort to another will be made upon an interim review of clinical and 
biological safety data by the DMC (which may include PK/QTc change analysis on pooled 
Cohorts 1a & 1b) which will continuously monitor safety aspects throughout the study (refer to 
DMC charter). 
For patient <35 kg, the pediatric doses for FQ were weight-adjusted through simulation using 
POP PK model. The body weight band limits and associated pediatric doses for FQ for treatment 
arm 2 (600 mg in patient ≥35 kg) were selected in order that D28 concentration of FQ/SSR97213 
after single dose of treatment arm 2 are close to corresponding D28 concentration obtained after 
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3-day treatment of FQ at 4 mg/kg (DRI10382) (as in adult), in order that the lightest subject of a 
given weight band would not have exposures (based on mean Cmax and AUC) higher than 1.3-fold 
the lightest adult (35 kg), and in order to maintain a fixed OZ439/FQ dose ratio across the weight 
continuum. Pediatric doses for other Treatment groups were selected similarly as regards 
predicted exposure in pediatrics as compared to the lightest adult and with a fixed OZ439/FQ dose 
ratio over the weight continuum in each Treatment group. In addition for the first 3 treatment 
arms (OZ439/FQ 800/400 mg, 800/600 mg and 800/900 mg) mean FQ and SSR97213 exposure 
are predicted not to exceed the mean exposures achieved in previous studies for any weight band 
except for FQ Cmax. For the 900 mg equivalent adult dose, the highest mean FQ Cmax in pediatric 
patients is estimated at 756 ng/mL (for a 10 kg child in the 10-15kg weight band); for this Cmax 
value, the predicted ΔΔQTcF (change from baseline corrected from placebo) is of 3.52 ms with a 
90% upper bound of 9.74 ms.  
Up to date, OZ439 has not been studied in a pediatric population. Therefore, in absence of any 
evidence to the contrary it was assumed that clearance (mainly hepatic) and volume of distribution 
are related to body weight using the theoretic allometric exponents (0.75 and 1, respectively).  
The pediatric doses for OZ439 were selected such that the heaviest patient in each weight band 
would achieve similar exposures to a 60 kg adult subject in the same treatment arm, and the 
lightest subject would not have exposures higher than the lightest adult (35 kg) in the same 
treatment arm. The aim was to ensure adequate efficacious exposures for each body weight band. 
The lightest patient in each weight band would achieve exposures up to 1.5 times that of a 60 kg 
adult and not exceeding that of the lightest adult (35 kg).  
OZ439 exposures in this study are predicted not to exceed the approximate exposures achieved in 
previous studies ie, an approximate mean Cmax of 2000 ng/mL and mean AUCinf of 
29000ng.h/mL. These exposures have been demonstrated to have an acceptable safety and 
tolerability profile (see OZ439 investigator’s brochure). 
The weight bands and pediatric doses for OZ439 and FQ are detailed in Table 2: 
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Table 2 - Weight bands and pediatric doses for OZ439 (OZ) and FQ 
FQ_400 mg group 
≥ kg 
< kg 
FQ 
OZ 
FQ/OZ 
pediatric 
35 
 
400 
800 
0.5 
dosing 
24 
35 
300 
600 
0.5 
 
15 
24 
200 
400 
0.5 
 
10 
15 
150 
300 
0.5 
 
7 
10 
100 
200 
0.5 
 
5 
7 
75 
150 
0.5 
 
FQ_600 mg group 
≥ kg 
< kg 
FQ 
OZ 
FQ/OZ 
pediatric 
35 
 
600 
800 
0.8 
dosing 
24 
35 
450 
600 
0.8 
 
15 
24 
300 
400 
0.8 
 
10 
15 
225 
300 
0.8 
 
7 
10 
150 
200 
0.8 
 
5 
7 
115 
150 
0.8 
 
FQ_900 mg group 
≥ kg 
< kg 
FQ 
OZ 
FQ/OZ 
pediatric 
35 
 
900 
800 
1.1 
dosing 
24 
35 
675 
600 
1.1 
 
15 
24 
450 
400 
1.1 
 
10 
15 
335 
300 
1.1 
 
7 
10 
225 
200 
1.1 
 
5 
7 
170 
150 
1.1 
 
FQ_1200 mg group 
≥ kg 
< kg 
FQ 
OZ 
FQ/OZ 
pediatric 
35 
 
1200 
800 
1.5 
dosing 
24 
35 
900 
600 
1.5 
 
15 
24 
600 
400 
1.5 
 
10 
15 
450 
300 
1.5 
 
7 
10 
300 
200 
1.5 
 
5 
7 
225 
150 
1.5 
FQ: ferroquine, OZ: artefenomel 
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5 
STUDY OBJECTIVES 
This study will investigate the efficacy exposure-response of OZ439/FQ combination in the target 
populations and if it meets its efficacy objectives, will inform dose selection for Phase III studies. 
5.1 
PRIMARY OBJECTIVE 
To determine whether a single dose combination of OZ439/FQ is an efficacious treatment for 
uncomplicated P. falciparum malaria in adults and children 
5.2 
SECONDARY OBJECTIVES 
To evaluate the efficacy of OZ439/FQ: 
 
To determine the incidence of recrudescence and re-infection. 
 
To determine the time to relief of fever and parasite clearance. 
To evaluate the safety and tolerability of OZ439/FQ in adults and children.  
To evaluate the pharmacokinetics of OZ439/FQ: 
 
To characterize the pharmacokinetics of OZ439 in plasma, FQ and its active metabolite 
SSR97213 in blood. 
 
To determine the blood/plasma ratio for FQ and SSR97213 in some patients at limited 
time points in selected sites. 
5.3 
EXPLORATORY OBJECTIVES 
To further explore efficacy of OZ439/FQ: 
 
To evaluate the proportion of patients with gametocytes at each parasitological 
assessment. 
 
To characterize gametocyte carriage. 
 
To evaluate the relationship between ACPR and exposure to OZ439/FQ.  
 
To explore the relationship between Kelch-13 genotype and parasite clearance kinetics. 
 
To explore in vitro drug resistance of P. falciparum infecting patients >14 years old in 
Vietnamese sites. 
 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
This is a randomized, double-blind single-dose (loose combination) study in patients spanning the 
age range greater than to 6 months to less than 70 years, with uncomplicated P. falciparum 
malaria.  
Adults and children will be included sequentially in four cohorts through a progressive age step-
down procedure and FQ dose step-up procedure (pre-defined data of patients >14 years and  
<70 years and body weight ≥35 kg exposed to the 3 first lowest doses will be reviewed before 
testing 1200 mg FQ dose in association with 800 mg OZ439).  
For patient ≥35 kg, 3 to 4 treatment arms of FQ (depending of DMC safety review of Cohorts 1a 
& 1b) will be assessed along with a fixed dose of OZ439: 
 
Treatment arm #1: OZ439 800 mg and FQ 400 mg in single dose. 
 
Treatment arm #2: OZ439 800 mg and FQ 600 mg in single dose. 
 
Treatment arm #3: OZ439 800 mg and FQ 900 mg in single dose. 
 
Treatment arm #4: OZ439 800 mg and FQ 1200 mg in single dose will be assessed, if the 
DMC gives green light to proceed with this dose.  
Patients <35 kg will receive weight-adjusted doses for OZ439, predicted to achieve exposure 
(based on AUC) not exceeding 1.5-fold that of a 60 kg adult and not exceeding that of the lightest 
adult (35 kg) for the lightest patient in each weight band.  
Patients <35 kg will receive weight adjusted doses for FQ, predicted to achieve FQ and SSR97213 
exposure (based on mean Cmax and AUC) not exceeding 1.3-fold that of a lightest adult (35 kg) for 
the lightest patient in each weight band. 
For each age cohort, once a pre-defined minimal number of patients per treatment arm have been 
enrolled and completed Day 28 visit, a safety review will be done by an independent Data 
Monitoring Committee (DMC) who will recommend or not to proceed to the 1200 mg FQ dose in 
association with 800 mg OZ439 and then to the lower age cohorts. The safety review will be 
based on adverse event, potentially clinically significant abnormalities (PCSAs) for clinical 
laboratory test results, vital signs, and 12-lead ECGs; it may also include FQ/SSR97213 blood 
concentration/QTc effect modelling for Cohort 1a & 1b only. 
The DMC could also decide to enroll additional patients in a cohort for collecting more safety 
data in that cohort. 
In addition, a first interim futility analysis on PCR-adjusted ACPR will be performed at Day 28 
using Bayesian methodology when approximately 50 patients per treatment arm and thereafter 
every time another 25 patients per treatment arm have completed Day 28 assessment 
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(ie, 75 patients/treatment arm for the 2nd interim analysis (IA), 100 patients/treatment arm for the 
3rd IA, 125 patients/treatment arm for the 3rd IA until 150 patients/treatment arm for the final 
analysis). Of note, there will be no treatment arm dropped for efficacy, only for futility.  
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
Screening / predose Day -1. 
Treatment with OZ439/FQ single dose on Day 0. 
Hospitalization at minimum for 48 hours post-dose (African patients greater than 5 years) or 
72 hours post -dose (all Asian patients and African patients ≤5 years) or for a maximum of 7 days, 
depending on age, parasite and fever clearance, clinical judgment and patient convenience. 
After discharge patients will return to the investigational site for further assessment up to Day 63. 
Note: those patients discharged at 48 or 72 hours will need to return for scheduled assessment up 
to Day 7. 
Total duration will be up to 67 days for each patient. 
6.2.2 Determination of end of clinical trial (all patients) 
The end of the clinical trial is defined as the day the last patient completes his/her last visit 
planned in the protocol (ie, EOS visit). 
6.3 
INTERIM ANALYSIS 
Safety review 
Unblinded safety data of each cohort (N = 10 patients/arm for Cohort 1, 5 patients/arm for 
Cohort 2 and 8 patients/arm for Cohort 3 & 4) will be analyzed by the DMC independent 
statistician and reviewed by the DMC. Refer to Section 11.5 for details. 
Interim futility analysis 
Up to 4 interim futility analyses may be planned and will be performed by the Sponsor’s 
unblinded independent statistician and reviewed by DMC: for details, please refer to  
Section 11.5. 
 
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6.4 
STUDY COMMITTEES 
Data Monitoring Committee (DMC): The Data Monitoring Committee is composed of 
clinicians and methodologists who are experienced with clinical trials –drug safety and malaria-
and can be relied upon to exercise good judgment in weighing the potential risks and benefits to 
patients as data accumulate in this trial. They will be responsible for monitoring the safety of the 
patients exposed to study medication on a regular basis as well as reviewing the results of each 
interim futility analysis. DMC members are listed in the DMC charter. 
Using clinical and laboratory safety data and PK/QTc evaluations (the latter may or may not be 
considered for decision rule), the DMC will provide guidance on inclusion of a 1200 mg FQ 
group (associated with OZ439-800 mg), moving to lower age cohort or stopping a study group for 
safety reason or if futility rules are met. Stopping rules are provided in the DMC charter. 
The DMC, which includes an associated statistician, will receive safety, laboratory and efficacy 
data from the Sponsor’s unblinded statistician for the safety and futility assessment. The data will 
be blinded per treatment arm and unblinded review of treatment arms will be done upon DMC 
members' request to the Sponsor's unblinded statistician. The DMC is independent from 
pharmaceutical companies, including Sanofi and competitor companies, from other study 
committees, and from the study investigators. 
The chairman of the DMC, in conjunction with the other members, will communicate their 
recommendations to the Sponsor after each meeting. A DMC charter is displayed in a separate 
document prepared under the responsibility of the DMC chairman. The procedures used to protect 
the blind within the Sponsor and the age step-down and FQ dose step-up procedures are described 
in the DMC charter.  
All safety data will be collected throughout the entire duration of the study, in timely fashion. 
Tabular summaries of these will be provided on a regular basis to the DMC chair who may decide 
at any time to convene a DMC meeting and analyze safety data and endpoints. On the basis of the 
totality of these results the DMC may recommend to the Sponsor changes in the protocol or 
stopping the trial. 
 
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7 
SELECTION OF PATIENTS 
7.1 
NUMBER OF PATIENTS 
The study will be performed using interim assessments of futility. The number of African patients 
that will be required for the ‘lower' naturally acquired immunity (NAI) per protocol population is 
150 patients per treatment arm. However to allow for potentially higher variability, the target 
number of patients recruited will be 165 per treatment arm consisting of: 
 
15 African patients per treatment arm greater than 5 years (ie, considered to have “higher" 
NAI) who will be evaluated within Cohort 1 & 2 and will not be included in the interim 
analyses for futility (of note,17 patients should be included in treatment arm #3 since, in 
scenario B, 2 additional African patients would be added to Cohort 1b to maintain the 
blind); these patients will not be part of the per protocol efficacy population, 
 
Up to 150 patients per treatment arm from the 'lower’ NAI population (ie, African patients 
≤5 years old) who will be included in the interim analyses for futility. 
Overall, this will give a total maximum number of 495 African patients (scenario A with 
3 treatment arms) or 662 African patients (scenario B with 4 treatment arms) assuming no 
treatment arm is dropped 'early' for futility, ie, up to 165 African patients/treatment arm (except 
treatment arm #3 in which 167 patients should be included regarding scenario B) (see Section 1.2, 
Figure 1). Twenty-one Asian patients will also be recruited. 
7.2 
INCLUSION CRITERIA 
I 01. Male or female patient aged >6 months old and <70 years old: 
- 
Cohort 1 = 14 years < age <70 years and body weight ≥35 kg, 
- 
Cohort 2 = 5 years < age ≤14 years, 
- 
Cohort 3 = 2 years < age ≤5 years, 
- 
Cohort 4 = 6 months < age ≤2 years. 
I 02. Body weight ≥5 kg and ≤90 kg. 
I 03. Presence of mono-infection by P. falciparum with:  
a) Fever, as defined by axillary temperature ≥37.5°C or oral/rectal/tympanic temperature 
≥38°C, or history of fever in the previous 24 hours (history of fever must be 
documented) and, 
b) Microscopically (blood smear) confirmed parasite infection, ranging from 1000 to 
100 000 asexual parasites/µL of blood. 
 
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I 04. Informed Consent Form signed by the patient (if the patient is ≥ age defining majority) or 
parent or by the legally acceptable representative of the minor patient (<18 years of age or 
< other age locally defining majority). In addition, in accordance with local regulation, 
minor participants with capacity for writing could sign off on an Assent Form. For those 
who are able to understand but with no capacity for writing the Assent Form would be 
read. In that case, an impartial witness could certify the document was read to the child.  
7.3 
EXCLUSION CRITERIA 
Patients who have met all the inclusion criteria listed in Section 7.2 will be screened for the 
following exclusion criteria which are sorted and numbered in the following three sub-sections: 
7.3.1 Exclusion criteria related to study methodology 
E 01. Presence of severe malaria (according to WHO definition) (see Appendix A). 
E 02. Any anti-malarial treatment: 
 
With piperaquine -based compound, mefloquine, naphthoquine or 
sulphadoxine/pyrimethamine (SP) within the previous 6 weeks (after their inhibition of 
new infections has fallen below 50%). 
 
With amodiaquine or chloroquine within the previous 4 weeks. 
 
With quinine, halofantrine, lumefantrine-based compounds and any other anti-malarial 
treatment or antibiotics with antimalarial activity (including cotrimoxazole, tetracyclines, 
quinolones and fluoroquinolones, and azithromycin) within the past 14 days. 
 
With any herbal products or traditional medicines, within the past 7 days.  
E 03. Known history or evidence of clinically significant disorders such as, respiratory 
(including active tuberculosis), hepatic, renal, gastrointestinal, immunological, 
neurological (including auditory), endocrine, infectious, malignancy, psychiatric, history of 
convulsions or other abnormality (including head trauma).  
E 04. Previous treatment within 5 times the half-life or within the last 14 days, whichever the 
longest which are: P-gp substrates, CYP2D6 main substrates and/or strong CYP2C or 
CYP3A inhibitors and/or moderate inhibitors but inhibiting both CYP2C and CYP3A 
and/or CYP inducers (see Appendix B). 
E 05. Mixed Plasmodium infection (ie, presence of another Plasmodium species in addition to 
P. falciparum). 
E 06. Severe vomiting, defined as more than three times in the 24 hours prior to enrollment in 
the study or inability to tolerate oral treatment, or severe diarrhea defined as 3 or more 
watery stools per day. 
E 07. Severe malnutrition (defined for patients aged ten years or less as the weight-for-height 
being below -3 standard deviation or less than 70% of median of the National Center for 
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Health Statistics/World Health Organization (NCHS/WHO) normalized reference values, 
and for patients aged greater than ten years, a body mass index (BMI) of less than 16 (11) 
E 08. Laboratory parameters with clinical significant abnormalities and/or reaching critical 
values. For Liver Function Test: aspartate transferase (AST) >2 ULN, or alanine 
transferase (ALT) >2 ULN or total bilirubin >1.5 ULN. 
E 09. Presence of Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or 
Hepatitis C antibody (HCV Ab). 
E 10. Have received an investigational drug within the past 4 weeks. 
E 11. Previous participation in any malaria vaccine study or received malaria vaccine in any 
other circumstance. 
E 12. Measles and yellow fever vaccine injection within the last 15 days or planned for the 
28 days after randomization. 
E 13. Female patient of child bearing potential not willing to use an effective contraceptive(s) 
method(s) for the duration of the study (eg, implants, oral contraceptives, some intra-
uterine devices or a double barrier method). The need for an efficient method will be 
reminded to the patient and the patient’s legal guardian(s) by the investigator. 
E 14. Positive serum or urine beta-human chorionic gonadotropin (ß-HCG) pregnancy test at 
study screening for female participants of childbearing potential. 
E 15. Breastfeeding women. 
E 16. Male patient having a partner of child bearing potential not willing to use an effective 
method of birth control for the duration of the study, or male patient wishing to father a 
child during study period. 
E 17. Splenectomized patients or presence of surgical scar on left hypochondrium. 
E 18. Patient unable to drink. 
7.3.2 Exclusion criteria related to the current knowledge of Sanofi compound 
E 19. Known history of hypersensitivity, allergic or anaphylactoid reactions to ferroquine or 
other - aminoquinolines or to OZ439 or OZ277 or to any of the excipients.  
E 20. Family history of sudden death or of congenital prolongation of the QTc interval or known 
congenital prolongation of the QTc-interval or any clinical condition known to prolong the 
QTc interval eg, patients with a history of symptomatic cardiac arrhythmias or with 
clinically relevant bradycardia. 
E 21. QTcF >450 ms at screening or pre-dose. 
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E 22. Hypokalemia (<3.5 mmol/L), hypocalcemia (<2.0 mmol/L) or hypomagnesemia 
(<0.5 mmol/L) at screening or pre-dose. 
E 23. Any treatment known to induce a lengthening of QT interval (see Appendix C). 
7.4 
PATIENT POPULATION 
7.4.1 Patient sub-populations 
7.4.1.1 Higher naturally acquired immunity population 
Patients with higher probability of having developed NAI will be recruited (African patients 
>5 years old to <70 years old). Patients from this population will only be considered for DMC 
safety review. 
 
Cohort 1: African Patients >14 years and body weight ≥35 kg (for safety & PK/QTc 
evaluation only) *:  
- 
A minimum of 10 patients/arm (30 patients minimum if 3 treatment arms and 
42 patients minimum if 4 treatment arms) 
 
Cohort 2: African Patients of >5 years and ≤14 years old (for safety evaluation only) *: 
- 
A minimum of 5 patients/arm (15 patients minimum if 3 treatment arms and 
20 patients minimum if 4 treatment arms) 
* If requested by DMC, additional patients may be included and evaluated for PK/QTc and/or safety. 
7.4.1.2 Lower naturally acquired immunity population 
This is the target population of interest. The study aims to recruit predominantly patients with 
lower probability of having developed NAI defined as: 
- 
children >6 months to ≤5 years in Africa  
Only patients from this population will be included in the interim futility analyses and final 
efficacy analysis.  
 
Cohort 3: African Patients >2 years and ≤5 years old 
 
Cohort 4: African Patients >6 months and ≤2 years old: 
- 
A targeted minimum of 10% of the total number of patients recruited in the lower NAI 
population ie, approximately 15 patients per treatment arm (if total numbers per arm 
are 150 for the efficacy analysis). 
7.4.2 Age range step-down and FQ dose step-up procedures 
Safety (up to Day 28 assessments) in the older age cohort will be assessed before proceeding 
down to the younger age range (see Section 1.2 and Section 8.4). 
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Note: For DMC safety review, patients from both higher and lower NAI population will be 
considered. However, no predefined ratio between Africa and Asia patients are requested to move 
forward from one cohort of age to the next one. If requested by DMC, additional patients may be 
included and evaluated for safety. 
1. For Cohort 1 (>14 years and <70 years and body weight ≥35 kg), a minimum of 
10 patients per treatment arm receiving OZ439/FQ at 800/400 mg, 800/600 mg & 
800/900 mg (Cohort 1a, ratio 1:1:1) will be assessed for safety up to Day 28.  
The PK/QTc modeling results will estimate the QT effect of highest FQ plasma 
concentration before starting the Cohort 1b and may or may not be considered for decision 
rule. Within the Cohort 1b, the treatment arm OZ439/FQ at 800/1200 mg would be 
evaluated in a minimum of 10 patients versus 2 patients receiving OZ439/FQ at 
800/900 mg (ratio 5:1) to maintain the study blinded. The two highest doses combinations 
will be assessed for safety up to Day 28 using Cohort 1b data for OZ439/FQ 800/1200 mg 
and pooled data from Cohorts 1a & 1b for OZ439/FQ 800/900 mg. The PK/QTc modeling 
results will estimate the QT effect of highest FQ plasma concentration before opening 
recruitment of the Cohort 2 and may or may not be considered for decision rule. 
2. In the Cohort 2 (>5 and ≤14 years), a minimum of 5 patients/arm will be assessed for 
safety up to Day 28 (ratio 1:1:1 for Scenario A or 1:1:1:1 for Scenario B, see Section 1.2, 
depending of the safety profile of OZ439/FQ 800/1200 mg) before opening recruitment in 
the Cohort 3. 
3. In the Cohort 3 (>2 and ≤5 year), a minimum of 8 patients/treatment arm will be assessed 
for safety up to Day 28 before fully opening recruitment. 
4. In the Cohort 4 (>6 month to ≤2 year), a minimum of 8 patients/treatment arm will be 
assessed for safety up to Day 28. 
The safety evaluation will be performed by the DMC throughout the study with a frequency 
defined in the DMC charter. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS 
The investigational medicinal products (IMPs) will be administered in the following order: FQ 
then OZ439.  
All details regarding the preparation of IMPs, including suspension of FQ and OZ439, will be 
described in a separate pharmacy manual. 
8.1.1 Ferroquine (FQ) 
A combination of the following capsules will be used to compose the 4 doses; individual sachets 
containing sucrose granules are provided: 
 
5 mg, 30 mg, 100 mg and 200 mg FQ or matching placebo. 
 
Placebo capsules are used to keep the same number of capsules in each weight band while 
keeping the FQ dose blinded. No patient will receive placebo only. 
 
For young children, capsules will be opened and their content will be diluted in water with 
sucrose granules in order to make it palatable and given as suspension. 
 
Oral route.  
 
Patients should have fasted from food and milk for 3 hours before administration. Neither 
food nor milk should be taken within 2 hour after the end of IMP dosing. 
 
Treatment duration: single dose at V2 Day 0.  
8.1.2 Artefenomel (OZ439) 
Individual sachets containing OZ439 (dose strengths from 150 mg to 800 mg + alpha tocopherol 
polyethylene glycol 1000 succinate [TPGS]) granules for oral suspension) and individual sachets 
containing sucrose granules.  
 
Oral route. 
 
The sucrose, adjusted to OZ439 dose, is added to the aqueous oral suspension prepared 
from OZ439 + TPGS granules for oral suspension in order to make it palatable. 
 
Patients should have fasted from food and milk for 3 hours before administration. Neither 
food nor milk should be taken within 2 hour after the end of IMP dosing. 
 
Once prepared, the suspension will have to be drunk within 2 hours and 20 minutes of the 
start of its preparation. 
 
The oral suspension should be drunk as quickly as possible and over a maximum of  
30-minute period. 
 
Treatment duration: single dose at V2 Day 0. 
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8.1.3 Treatment arms 
Individual patient treatment kit will be packed according to the weight band. The content of these 
kits are detailed below: 
Table 3 - Treatment kits 
Weight band 
Compound 
Treatment arm 1 
Treatment arm 2 
Treatment arm 3 
Treatment arm 4 
 ≥35 kg 
FQ dosage (mg) 
400 
600 
900 
1200 
OZ439 dosage (mg) 
800 
800 
800 
800 
Sucrose for OZ oral 
suspension dosage (g) 
15 
15 
15 
15 
 ≥24 and <35 kg 
FQ dosage (mg) 
300 
450 
675 
900 
Sucrose for FQ oral 
suspension dosage (g) 
2.813 
2.813 
2.813 
2.813 
OZ439 dosage (mg) 
600 
600 
600 
600 
Sucrose for OZ oral 
suspension dosage (g) 
11,25 
11,25 
11,25 
11,25 
≥15 and <24 kg 
FQ dosage (mg) 
200 
300 
450 
600 
Sucrose for FQ oral 
suspension dosage (g) 
2.813 
2.813 
2.813 
2.813 
OZ439 dosage (mg) 
400 
400 
400 
400 
Sucrose for OZ oral 
suspension dosage (g) 
7,5 
7,5 
7,5 
7,5 
≥10 and <15 kg 
FQ dosage (mg) 
150 
225 
335 
450 
Sucrose for FQ oral 
suspension dosage (g) 
2.813 
2.813 
2.813 
2.813 
OZ439 dosage (mg) 
300 
300 
300 
300 
Sucrose for OZ oral 
suspension dosage (g) 
5.625 
 
5.625 
 
5.625 
 
5.625 
≥7 and <10 kg 
FQ dosage (mg) 
100 
150 
225 
300 
Sucrose for FQ oral 
suspension dosage (g) 
2.813 
2.813 
2.813 
2.813 
OZ439 dosage (mg) 
200 
200 
200 
200 
Sucrose for OZ oral 
suspension dosage (g) 
3,75 
3,75 
3,75 
3,75 
≥5 and <7 kg 
FQ dosage (mg) 
75 
115 
170 
225 
Sucrose for FQ oral 
suspension dosage (g)  
2.813 
2.813 
2.813 
2.813 
OZ439 dosage (mg) 
150 
150 
150 
150 
Sucrose for OZ oral 
suspension dosage (g) 
2.813 
2.813 
2.813 
2.813 
FQ: ferroquine, OZ439: artefenomel, OZ: artefenomel 
The appropriate volume of water needed for the preparation of each specific oral suspension will 
be mentioned in the Pharmacy Manual. 
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8.1.4 Re-dosing in the event of vomiting after OZ439 administration 
 
If a patient vomits within 5 minutes of the start of dosing with OZ439, they can be re-
dosed with a freshly prepared new suspension from a new individual patient treatment kit 
assigned via IVRS/IWRS. No re-dosing of FQ will be performed. 
 
If vomiting occurs from 5 minutes to 35 minutes post start of OZ439, they should continue 
to take the OZ439 dose (if any left), but should not be re-dosed. 
 
If a patient vomits after 35 minutes from the start of OZ439 dosing, they should not be re-
dosed. 
 
No re-dosing of FQ will be performed if a patient vomits during or after FQ administration 
but before OZ439 administration. In that case, OZ439 will not be administered and the 
patient will receive a rescue therapy as per Section 8.9. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT 
Not applicable. 
8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
For FQ, a double blind design has been set up. Therefore, in each weight band, each patient will 
receive the same number of capsules, see Section 8.1.1. 
Each treatment kit is labeled with a number, which is generated by a computer program from the 
Sponsor. Investigators do not have access to the randomization (treatment) code except under 
circumstances described in Section 8.3.2. 
 
Consequently, the double blinded will be maintained. 
For young children, FQ can be administered as an oral suspension (see Section 8.1). The 
oral suspension will be prepared by opening the capsules and mixing their content with 
sweetened water. Depending on the capsules strengths, the color of the content of capsules 
varies from white to orange. So the oral suspension will be prepared by an unblinded 
pharmacist. Once ready, there is no difference in color of the oral suspensions within each 
weight band which can then be administered to the patient by a caregiver (investigator or 
nurse) maintained blinded 
 
Study site procedures will be implemented to describe this process and ensure that only 
well identified and limited personnel will prepare FQ solution. 
OZ439 is under open label design, but it will be included in the FQ treatment kit as 
described in Section 8.5. 
Refer to Section 10.5 for suspected unexpected adverse drug reaction unblinding by the Sponsor. 
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8.3.2 Randomization code breaking during the study 
Please see also Section 8.3. 
In case of an adverse event (AE), the code should only be broken in circumstances when 
knowledge of the IMP is required for treating the patient. If possible, a contact should be initiated 
with the Monitoring Team before breaking the code. 
Code breaking can be performed at any time by using the proper module of the interactive voice 
response system (IVRS) and/or by calling any other phone number provided by the Sponsor for 
that purpose. If the blind is broken, the Investigator should document the date, time of day and 
reason for code breaking. As much as possible, patient will continue to be followed up to the End 
of Study according to study flow-chart (see Table 1). 
The DMC will receive blinded by treatment group or unblinded (if necessary) confidential reports 
from an independent statistician for review, which have to be handled strictly confidentially. None 
of these reports can be delivered to unauthorized persons. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
Centralized randomization and IVRS/IWRS related procedures will be detailed separately 
(IVRS/IWRS specifications manual). 
 
A total of 6 randomized treatment kit number lists will be generated centrally by Sanofi 
corresponding to the weight bands [> 35 kg, 24-35 kg, 15-24 kg, 10-15 kg, 7-10 kg and  
5-7 kg]. 
 
Patients will be randomized to one of the treatment arms via a centralized randomization 
system using an IVRS/IWRS. A patient will be considered randomized when the treatment 
number has been provided by the IVRS/IWRS, as documented from the IVRS/IWRS log 
file. 
 
At the screening visit, Visit 1, the site will contact the IVRS/IWRS to obtain a patient 
number for each patient for whom an informed consent has been obtained. Each patient 
will be allocated a patient number associated with the center and allocated in chronological 
order in each center. 
IVRS will manage 3 patient randomization lists (one for Cohort 1a, a second for Cohort 1b 
and the third including all 4 cohorts) and allocates the treatment number and the 
corresponding treatment kit to the patient as follow: 
- 
In Cohort 1a 30 patients will be randomized to one of the 3 treatment arms of 
OZ439/FQ. The randomization ratio is 1:1:1 (OZ439/FQ 800/400 mg: OZ439/FQ 
800/600 mg: OZ439/FQ 800/900 mg). 
- 
In Cohort 1b, if DMC has given the green light for proceeding with the 1200 mg dose 
of FQ, 12 patients will be randomized to one of the 2 treatment arms of OZ439/FQ. 
The randomization ratio is 1:5 (OZ439/FQ 800/900 mg: OZ439/FQ 800/1200 mg). 
- 
After Cohorts 1a & 1b DMC review  
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- 
if DMC has given the green light for proceeding with the 1200 mg dose of FQ in 
younger patients according to the age step-down procedure, 155 patients (150 patients 
for the lower NAI population + 5 patients of Cohort 2 for the higher NAI population) 
will be randomized to one of the 4 treatment arms of OZ439/FQ according to the 
randomization ratio of 1:1:1:1 (treatment arm 1, treatment arm 2, treatment arm 3, 
treatment arm 4). 
- 
if DMC does not give the green light for proceeding with the 1200 mg dose of FQ in 
younger patients according to the age step-down procedure, 155 patients (150 patients 
for the lower NAI population + 5 patients of Cohort 2 for the higher NAI population) 
will be randomized to one of the 3 treatment arms of OZ439/FQ according to the 
randomization ratio of 1:1:1 (treatment arm 1, treatment arm 2, treatment arm 3).  
 
The third randomization list will be stratified by region, and within Africa, age class 
(>14 years and <70 years/Asia; 5-14 years/Africa; 2-5 years/Africa; and  
6 months-2 years/Africa). Details will be specified in the IVRS/IWRS specifications 
manual. 
 
A patient can be randomized only once. 
8.5 
PACKAGING AND LABELING 
The randomized labelled treatment box will contain:  
 
1 randomized blinded labelled wallet with 6 or 8 capsules of FQ (5, 30, 100 or/and 200 mg 
or placebo) depending on the treatment arm and the weight band, 
 
An open label individual sachet containing sucrose granules for FQ oral suspension only 
in kits of weight band <35 kg, 
 
An open label individual sachet containing OZ439 + TPGS granules for oral suspension 
(150, 200, 300, 400, 600 or 800 mg) depending on the treatment arm and the weight band, 
 
An open label individual sachet containing sucrose granule for OZ439 oral suspension. 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the IMP in a 
secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures.  
Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the Sanofi compound should be 
managed according to the rules provided by the Sponsor. 
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8.7 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMPs will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator’s responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.7.1 Treatment accountability and compliance 
Measures taken to ensure and document treatment compliance and IMP accountability include: 
 
Proper recording of treatment kit number or packaging number as required on appropriate 
electronic case report form (e-CRF) page for accounting purposes. 
 
The unblinded pharmacist or designee will prepare the kit assigned by IVRS/IWRS, will 
complete the corresponding treatment log form, and will perform reconciliation by 
checking the consistency of the treatment number between IVRS/IWRS assignment 
notification, the treatment number printed on the kit boxes and the treatment log forms.  
 
IMP will also be recorded and tracked on the site IMP inventory forms. 
 
The monitor in charge of the study checks the data entered on the e-CRF by comparing 
them with the IMP that has been retrieved and the treatment log form. 
8.7.2 Return and/or destruction of treatments 
All partially-used or unused treatment boxes will be destroyed at study site or returned to the 
Sponsor for destruction according to local regulations.  
A detailed treatment log of the destroyed IMP will be established with the Investigator (or the 
pharmacist) and countersigned by the Investigator and the monitoring team. The Investigator will 
not destroy the unused IMP unless the Sponsor provides written authorization.  
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8.8 
CONCOMITANT MEDICATION 
8.8.1 LIST OF FORBIDDEN CONCOMITANT MEDICATION 
All drugs other than oral contraceptives, paracetamol (acetaminophen) at the maximum dose of 
40 mg/kg/day, metoclopramide if repeated vomiting and beta-lactams for any infection needing an 
antibiotic treatment are prohibited over the entire study period unless medically justified. The 
dosage and number of dose(s) will be recorded. The use of other contraceptive methods may be 
discussed.  
Traditional and herbal remedies are not permitted during the study. 
8.9 
RESCUE TREATMENT FOR MALARIA 
The use of a rescue therapy is recommended in the following cases:  
 
Vomiting during or after FQ dosing or vomiting within 35 minutes after OZ439 re-dosing 
 
Treatment failure as-per protocol section “Classification of Treatment Outcomes”  
The use of established anti-malarial drug combination per WHO recommendations (1) or local 
guidelines is to be considered as a rescue therapy and the choice of the best therapeutic option is 
left at Investigator’s decision.  
In case of rescue therapy is given, where possible, a PK (OZ439 and FQ) sample should be taken 
before giving rescue therapy. 
Before giving established ACT:  
 
Blood films and parasite genotyping must be taken for all patients. 
 
RT-PCR and qPCR for patients >5 years only. 
Following administration of established ACT, patients should be managed according to local 
standard of care practices. Safety data should continue to be collected in the e-CRF, according to 
the study schedule, and up to the end of the study even if re-emergence is confirmed. 
Patients who will have received a rescue treatment after the OZ439/FQ has failed will be part of 
the Per-Protocol Population (see Section 11.3.2.2) whereas patients who will have received a 
rescue treatment because of vomiting during IMP administration will be part of the safety 
analyses only. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
PRIMARY ENDPOINT 
9.1.1 Primary efficacy endpoint 
 
PCR-adjusted ACPR at Day 28. 
- 
The ACPR is defined as a negative parasitemia (blood films) at Day 28, irrespective of 
axillary temperature, without previously meeting any criteria of early treatment failure 
(ETF) or late clinical failure (LCF) or late parasitological failure (LPF) or having 
received a rescue treatment for malaria in the conditions defined in Section 8.9. 
- 
The PCR-adjusted ACPR applies only to recrudescence (re-emergence of the original 
clone of parasite that is present at baseline). Recrudescence is distinguished from re-
infection by genotyping the parasite clone. 
9.2 
SECONDARY ENDPOINTS 
9.2.1 Secondary efficacy endpoints 
 
PCR - adjusted ACPR at Day 42 and 63. 
 
PCR - crude ACPR at Day 28, 42 and 63. 
 
Kaplan Meier for: 
- 
Time to re-emergence  
- 
Time to recrudescence  
- 
Time to re-infection  
 
Parasite clearance time (PCT).  
 
Fever clearance time (FCT).  
 
Parasite reduction rate (PRR): the PRR is calculated as the slope of the linear portion of 
the regression fit of logarithm parasitemia (per mL) versus time (in hours). 
9.2.2 Safety endpoints 
 
Adverse events, including Serious Adverse Events (SAE), Adverse Event of Special 
Interest (AESI) and Treatment Emergent Adverse Event (TEAE). 
 
Clinical laboratory tests, vital signs and ECG, including:  
- 
Liver Function test (LFT) 
- 
QTc assessment 
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Physical examination and clinical signs and symptoms related to uncomplicated 
P. falciparum malaria (Fever, Dizziness, Headache, Nausea, Anorexia, Vomiting, 
Diarrhea, Itching, Urticaria, Skin Rash, Abdominal Pain, Joint Pain, Muscle Pain, 
Palpitations, Sleep Problems, Confusion, Hearing Problems, Vision Problems, and 
Fatigue). 
9.2.2.1 Adverse events 
Refer to Section 10.4 to Section 10.6 for details. 
9.2.2.2 Laboratory safety variables  
(see Study Flow-Chart in Section 1.1 for detailed time schedule) 
The clinical laboratory data consist of blood analysis (including hematology, clinical chemistry 
and urinalysis). Clinical laboratory values will be analyzed after conversion into standard 
international units. International units will be used in all listings and tables. 
Clinical laboratory at screening: 
 
Hematology: performed in local laboratory. 
 
Clinical chemistry: performed in local laboratory for screening purpose and an additional 
sample to be sent to central laboratory for baseline assessment. 
 
Urinary dipstick: performed locally; if abnormal: urine sample to be sent to central 
laboratory for microscopy analysis. 
Clinical laboratory at all other visits: 
 
Hematology: performed in local laboratory. 
 
Clinical chemistry: sample to be sent to central laboratory. 
 
Urinary dipstick: performed locally; if abnormal: urine sample to be sent to central 
laboratory for microscopy analysis. 
Details will be provided in Laboratory Manual.  
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Table 4 - Clinical laboratory blood tests 
Clinical Chemistry  
Total bilirubin (also Direct, when total bilirubin is ≥ULN) 
Albumin 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Haptoglobin  
Lactate Dehydrogenase (LDH) 
Creatine kinase 
Alkaline phosphatase (ALP) 
Urea 
Creatinine and creatinine clearancea 
Sodium 
Potassium 
Magnesium (screening) 
Calcium (screening) 
Glucose 
Hematology  
Haematocrit 
Haemoglobin 
Absolute reticulocytes 
Erythrocyte count (RBC) 
Platelet count 
Leukocytes (WBC) with differential count including eosinophils 
Urinalysis Dipstick  
Specific gravity, pH, glucose, protein, bilirubin, ketones, leukocytes and blood 
Pregnancy test (urine β-HCG) for females of childbearing potential 
Urinalysis Microscopy (if urinalysis dipstick abnormal) 
WBC, RBC and casts (if required) 
a For patients >18 years old, the creatinine clearance (CrCl) will be calculated from Cockroft and Gault formula: CrCl (mL/min) = 
1.23 (for male) or 1.04 (for female) x weight (kg) x (140 - Age) / serum creatinine (µmol/L) with age in years. For patients 
≤18 years old, the GFR Bedside Schwartz Formula should be used: eGFR (mL/min/1.73 m²) = 0.413 x height (cm) / serum 
creatinine (mg/dL) 
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9.2.2.3 Vital signs  
(see Study Flow-Chart in Section 1.1 for detailed time schedule) 
Vital signs include:  
 
Heart rate (HR) and systolic & diastolic blood pressure (BP) measured after at least 
5 minutes in supine resting position and prior to any blood sampling. 
 
Axillary temperature should be recorded in °C and to an accuracy of one decimal place. If 
the axillary method is not possible, an alternative route (tympanic, oral or rectal) may be 
used. The alternative route shall be recorded in the e-CRF. Within an individual patient the 
same method of temperature measurement (axillary, tympanic, oral or rectal) should be 
used throughout the entire study period.  
All vital signs will be assessed according to local procedures. 
9.2.2.4 Electrocardiogram variables  
(see Study Flow-Chart in Section 1.1 for detailed time schedule). 
Heart rate, QRS duration, PR interval, QT interval, ST deviation and T-wave morphology and 
also U-wave presence or absence are determined using centralized readings of all ECGs. The 
screening visit ECG will be read by the Investigator and the automatic QTcF calculation will 
serve as the reference for exclusion criterion E21. All ECG recordings (triplicate) will be centrally 
read by independent experts. Refer to central ECG reading manual for more details. 
9.2.2.5 Physical examination and malaria signs and symptoms 
The Physical Examination will include: general appearance, head and eyes, ears, nose and throat, 
chest and lungs, cardiovascular, abdomen, neurological, lymphatic and musculoskeletal and any 
additional body system considered of relevance by the Investigator. 
A full assessment of malaria signs and symptoms will be made alongside the physical 
examination.  
9.3 
MEASUREMENT OF PARASITEMIA 
9.3.1 Parasitemia (Thick and thin blood films) 
Blood sampling for parasitology can be done usually by means of finger prick except when the 
timing for parasitology assessments coincide with time for clinical laboratory tests, in which case, 
blood films can be done using the venous blood collected for clinical laboratory analyses. Blood 
spot samples will also be prepared for qPCR, genotyping and Kelch-13 analysis and for RT-PCR 
gametocyte detection (see Section 9.3.2 and Section 9.3.3). 
For full details of slide preparation, determination of parasitemia and quality control, refer to the 
Study Laboratory Procedures Manual. 
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9.3.1.1 Screening and pre-dose blood films 
For parasitology, Screening and pre-dose are to be considered as one time point. Three slides 
(two thick films and one thin film) should be prepared in this period for this time point and should 
be prepared using samples taken within 4 hours of dosing. Local thick and thin blood films 
performed at the site, before Informed Consent signature, according to local standard procedures 
and within 4 hours prior to dosing, can be used for screening / Pre-dose parasitemia assessment, 
provided that a standard procedure is in place at site and blood films staining is performed 
according to Study Parasitology Procedures Manual. 
The first thick film slide must be rapidly stained with 10% Giemsa stain for a period of 10 to 
15 minutes. The parasite count from this slide will be used to calculate the Screening parasitemia 
value. 
The second thick film slide must be used only if the patient meets all entry criteria and is being 
recruited into the study. This second thick film slide should be stained with 2.5 to 3% Giemsa 
stain for a period of 45 to 60 minutes. The slide from this slower but more accurate staining 
technique should be used to calculate a more accurate pre-dose parasitemia counts (asexual). 
The thin film slide is used specifically for parasite speciation. Only patients with P. falciparum 
mono-infection should be recruited in the study. 
9.3.1.2 Post-dose blood films 
Three slides (two thick films and one thin film) should be prepared at each planned time point 
(see Study Flow-Chart in Section 1.1 for detailed time schedule). The first thick film slide should 
be stained with 2.5 to 3% Giemsa stain for a period of 45 to 60 minutes and used to determine 
parasite counts. The second thick film slide should be kept as contingency and be stained only if 
the first thick film slide become damaged prior to reading it. The thin film slide is used 
specifically for parasite speciation which should be recorded at each time point. 
Additional unscheduled films may be prepared to confirm Parasite clearance as described below. 
Details of slide preparation, staining, examination, calculation methods and quality control are 
given in the Study Laboratory Procedures Manual. No deviation from the Sponsor guidelines will 
be accepted. 
9.3.1.3 Definition of parasite clearance (by microscopy) 
A blood film will be considered 'negative' when the examination of 1000 white blood cells reveals 
no asexual parasites (see Study Laboratory Procedures Manual for more detail). Parasite clearance 
time is defined as the time of the first negative film. This negative film must be confirmed by a 
second negative film, prepared within 6 to 12 hours of the first. Parasite clearance will be 
concluded following confirmation of the second negative film. Parasite density, expressed as the 
number of parasites per microliter of blood, for asexual parasite and for gametocyte counts will be 
recorded separately throughout the study. 
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If parasites have not cleared by 72 hours after IMP administration and criteria for rescue 
medication are not met at 72 h, blood films should continue to be taken according to site standard 
practice (or at minimum every 8 hours) until parasite clearance is shown or until criteria for rescue 
medication are met (see Section 8.9). 
Two qualified microscopists should independently read the stained thick and thin films. Parasite 
densities will be calculated by averaging the two counts. Blood smears with non-concordant 
results (differences between the two microscopists in species diagnosis, or differences in parasite 
density of >50%) will be re-examined by a third, independent microscopist: if discordance relates 
to parasite density, it will be calculated by averaging the two most concordant counts; if 
discordance relates to species diagnosis, it will be determined by the third microscopist. 
9.3.2 Quantitative PCR, parasite genotyping and Kelch-13 analysis 
Blood samples to measure parasitemia by qPCR will be taken according to study flow-chart 
(see Table 1 in Section 1.1), in patients >5 years only, qPCR analysis will be performed by the 
central laboratory at all scheduled time points. 
For patients >14 years and ≥35 kg only, during the intervening periods between Day 15 and 
Day 18 (ie, V10) and Day 24 and Day 25 (ie, V12), blood for qPCR will be only taken if the 
patient returns to the Clinical Unit for assessment (no qPCR sample when the patient has a rapid 
diagnosis test (RDT) “in the field”)  
Blood samplings for genotyping will be collected according to the study flowchart (see Table 1 
in Section 1.1) and at the time-points when recrudescence or re-infection after initial parasite 
clearance was shown on the blood slide. Parasite genotyping analysis will be performed on 
previously collected blood spot sample only in case of a positive blood film after initial parasite 
clearance: one pre-dose sample and one sample at 18 or 24 hours post dosing. A further sample 
will be analyzed at the time point at which recrudescence/re-infection occurs. 
An analysis of the Kelch-13 genotype will be performed at screening on blood samples (pre-
dose). 
All details concerning processing and technique will be provided separately in the Study 
Laboratory Procedures Manual. 
9.3.3 Gametocyte detection (RT-PCR) 
Blood samples for RT-PCR gametocyte detection will be taken according to Study Flow-Chart 
(see Table 1 in Section 1.1) in patients >5 years only. RT-PCR analysis will be performed by the 
central laboratory at all scheduled time points to detect submicroscopic gametocytemia and 
characterize gametocyte maturation stage. 
For patients >14 years and ≥35 kg only, during the intervening periods between Day 15 and 18 
(ie, V10) and Day 24 and 25 (ie, V12), blood for RT-PCR gametocyte detection will only be taken 
if the patient returns to the Investigational site for assessment (no RT-PCR sample when the 
patient has a RDT “in the field”). 
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All details concerning processing and technique will be provided in the Study Laboratory 
Procedures Manual. 
9.4 
OTHER ENDPOINTS 
9.4.1 Pharmacokinetics 
Plasma levels of OZ439 and blood level of FQ and its metabolite SSR97213 will be measured. 
To evaluate blood/plasma ratio for FQ and SSR97213, plasma level of FQ and SSR97213 will be 
measured at limited time points in selected sites. About 20 to 25 patients per cohort will have this 
measurement, excluding children ≤2 years for whom no plasma sample will be collected for FQ.  
In Cohort 1a and Cohort 1b, FQ PK samples collected during the first 48h should match with 
ECG time points (except for T0.5h [no ECG at that time point]) for the purpose of the PK/QTc 
analyses performed at the end of these cohorts. 
9.4.1.1 Sampling time 
The sampling times for blood collection can be found in the study flow chart (see Table 1 in 
Section 1.1). 
9.4.1.2 Number of pharmacokinetic samples 
Table 5 - Number of PK samples 
 
Blood sample for FQ 
and OZ439 
Total 
sample volume  
Patient >14 years and body weight ≥35 kg 
16 x 1 mL 
16 mL 
Patient >5 to ≤14 years  
7 x 1 mL 
7 mL 
Patient >2 to ≤5 years 
5 or 6 x 1 mL 
5 or 6 mL 
Patient >6 months to ≤2 years 
5 x 0.5 mL 
2.5 mL 
PK: pharmacokinetics, FQ: ferroquine, OZ439: artefenomel 
9.4.1.3 Pharmacokinetics handling procedure 
The sample handling procedures are summarized in a table (Table 6 and Table 7). 
Special procedures for collection, storage, and shipment will be provided in a separate Laboratory 
Manual. 
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Table 6 - Summary of handling procedures for FQ and its active metabolite SSR97213 assessment 
in blood and in plasma 
Anticoagulant 
K3-EDTA 
Handling procedures 
Refer to Laboratory Manual 
Blood aliquot split 
5 spots of 10 µL per card for DBS  
3 spots of 20 µL per card for DPS 
Blood storage conditions 
Room temperature into a Ziploc bag* with desiccant 
Blood shipment conditions 
Room temperature 
FQ: ferroquine, DBS: dry blood sample, DPS: dry plasma sample  
*: the Amber Ziploc bag should be used for DPS (about 20 patients per cohort in selected sites) 
Table 7 - Summary of handling procedures for OZ439 assessment 
Anticoagulant 
Potassium K3-EDTA 
Handling procedures 
Refer to Laboratory Manual 
Plasma aliquot split 
No (1 aliquot) 
Plasma storage conditions 
-20°C 
Plasma shipment conditions 
Dry ice 
OZ439: artefenomel 
 
9.4.1.4 Bioanalytical method 
Table 8 - Summary of bioanalytical method for FQ and its active metabolite SSR97213 
Analyte 
Ferroquine and SSR97213 
Matrix 
Blood (DBS) and plasma (DPS)*  
Analytical technique 
LC-MS/MS 
Lower limit of quantification 
5 ng/mL 
Assay volume 
A punch of whole spot for DBS samples and a punch of 6 mm 
diameter for DPS samples 
Site of bioanalysis 
Covance  
Method reference 
Refer to Laboratory Manual 
FQ: ferroquine, DBS: dry blood sample, DPS: dry plasma sample, LC-MS/MS: Liquid chromatography coupled to tandem mass spectrometry 
*: A plasma sample will be prepared after blood collection by venipuncture for DPS (about 20 patients per cohort in selected sites). 
Table 9 - Summary of bioanalytical method for OZ439 
Analyte 
OZ439 
Matrix 
Plasma 
Analytical technique 
LC-MS/MS 
Lower limit of quantification 
1 ng/mL 
Assay volume 
50 µL 
Site of bioanalysis 
Swissbioquant, Reinach (BL), Switzerland 
Method reference 
Refer to Laboratory Manual 
OZ439: artefenomel, LC-MS/MS: Liquid chromatography coupled to tandem mass spectrometry 
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Incurred sample reproducibility analysis will be performed on selected samples in order to assess 
the reliability of all sample concentration data. These analyses will be reported in addition to the 
final concentration data. 
9.4.1.5 Pharmacokinetics parameters 
A pharmacokinetic analysis for OZ439 in plasma, FQ and SSR97213 in blood will be performed 
using nonlinear mixed effect modelling in separate models for OZ439 and for FQ and SSR97213. 
Data from previously conducted studies might be added for model development. The analysis will 
involve an estimation of inter-patient PK variability, the population pharmacokinetic parameters 
estimates and the assessments of patho-physiologic covariate effects on CL and possibly on 
volume if warranted. Estimation of individual parameters and of individual exposure (AUC) will 
also be performed. The pharmacokinetic analysis will be described more precisely in the 
pharmacokinetic analysis plan. 
PK parameters: 
 
PK parameters (mainly CL/F, Vss/F, Cmax, AUC as relevant) of OZ439 in plasma, FQ and 
SSR97213 in blood, in addition, Concentration at Day 7, Day 14, Day 21 and Day 28 for 
FQ and SSR97213. 
 
Blood/plasma ratio for FQ and SSR97213 (some patients in selected sites). 
 
Interim analysis: 
 
In Cohort 1a and Cohort 1b, a pharmacokinetic analysis for FQ and SSR97213 in 
blood will be performed using linear mixed effect modelling to predict 1200 mg 
(Treatment arm 4) Cmax and AUC in patient >14 y (after the Cohort 1a) and to predict 
Cmax and AUC for Treatment #4 over the weight continuum (after the Cohort 1b). Cmax 
and AUC at 400 mg, 600 mg and 900 mg as secondly predicted parameters will be 
estimated. This PK analysis will be performed by a Sponsor’s unblinded 
pharmacokineticist independent from the study. 
9.4.2 Exploratory efficacy endpoints 
 
Time to clearance of gametocytes on blood smear for patients with gametocytes at 
baseline. 
 
Time to appearance of gametocytes on blood smear for patients with no gametocytes at 
baseline. 
 
Detection of Pfs25 mRNA by RT-PCR in patients >5 years. 
 
Correlation between Kelch-13 genotype status at baseline and parasite clearance kinetics. 
 
Define phenotypic and genotypic resistance pattern to conventional ACT of P. falciparum 
infecting patients aged >14 years old in Vietnamese sites (blood sample taken at 
screening). 
 
In vitro susceptibility testing of P. falciparum infecting patients aged >14 years old in 
Vietnamese sites to OZ439, FQ and both drugs (blood sample taken in case criteria for 
rescue treatment is met). 
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9.4.3 Pharmacogenetic assessment 
Not applicable. 
9.5 
FUTURE USE OF SAMPLES 
Residual or leftover serum, plasma or blood samples may be used for additional research purposes 
on malaria, after the patient will have consented to it. 
9.6 
APPROPRIATENESS OF MEASUREMENTS  
The assessments used in this study follow the recommendations from the WHO. 
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
10.1.1 Visit 1; Day-1: Screening / Predose Visit 
 
Informed consent/Assent. 
 
Demography/Previous medical/surgical history/prior and concomitant medication. 
 
Inclusion/exclusion criteria. 
 
Temperature. 
 
Physical examination, height and body weight measurement, malaria signs & symptoms. 
 
IVRS/IWRS call for screening. 
 
Asexual and sexual count (thick & thin blood films) and parasite genotyping for all 
patients. 
Note: Local thick and thin blood films performed at the site, before Informed Consent 
signature, according to local standard procedures and within 4 hours prior to dosing, can 
be used for screening / Pre-dose parasitemia assessment, provided that a standard 
procedure is in place at site and blood films staining is performed according to Study 
Parasitology Procedures Manual. 
 
RT-PCR and qPCR for patients >5 years only.  
 
Kelch-13 analysis sampling (blood spot). 
 
In Vietnamese sites and for patients >14 years old only: sample for in vitro research of 
drug resistance. 
 
A standard 12-lead ECG. 
 
Vital signs including BP, HR. 
 
Inquire about AEs. 
 
Standardized laboratory exam: local hematology, local biochemistry (including LFTs). For 
biochemistry, a second sample will be drawn and sent to the central laboratory allowing 
pre-treatment baseline measurement. 
 
Urinalysis dipstick: specific gravity, pH, glucose, hemoglobin, protein, nitrates, leukocyte 
esterase, bilirubin. If any parameter on the dipstick is abnormal, an urine sample should be 
sent to the central laboratory for microscopic analysis. 
 
HAV IgM, HBs Ag, and HCV Ab. 
 
Urine pregnancy test (for women of childbearing potential). If negative, discussion as to 
the most appropriate contraceptive method for the duration of the study. 
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10.1.2 Visit 2; Day 0 (may be on the same calendar day than Day-1) 
 
Hospitalization. 
 
IVRS/IWRS call for randomization and IMP kit allocation at T0. 
 
Standard 12-lead ECG at T0 (before IMP administration), T2, T4, T6, T8 and T12. 
 
IMP administration at T0. 
 
Temperature at T1, T2, T6, T12 and T18. 
 
Physical examination/malaria signs & symptoms at T12. 
 
Inquire about AEs at all time-points. 
 
Report concomitant medication at T0. 
 
Asexual and sexual count (thick & thin blood films).  
- 
at T6, T12 and T18, if >14 years and ≥35 kg,  
- 
at T6 and T18, if ≤14 years. 
 
qPCR and RT-PCR gametocyte detection at T6, T12 and T18 for patients >14 years and 
≥35 kg only. 
 
Parasite genotyping (blood spot) at T6, T12, T18 for patients >14 years and >35 kg.  
 
Parasite genotyping (blood spot) at T18 for patients ≤ 14 years. 
 
Vital signs including BP and HR at T6 and T12. 
 
OZ439 PK sampling (see Table 1). 
 
FQ/SSR97213 PK sampling (see Table 1). 
10.1.3 Visit 3; Day 1 
 
Temperature at T24, T30 and T36. 
 
Physical examination/malaria signs & symptoms at T24 and T36. 
 
Inquire about AEs at all time-points. 
 
Report concomitant medication at T24. 
 
Asexual and sexual count (thick & thin blood films), parasite genotyping (blood spot). 
- 
at T24, T30, and T36 if >14 years and ≥35 kg, 
- 
at T24 and T36 only if ≤14 years. 
 
qPCR and RT-PCR gametocyte detection at T24, T30 and T36 for patients >14 years and 
≥35 kg only. 
 
In Vietnamese sites and for patients >14 years old only and only in case criteria for the use 
of rescue therapy is met: sample for in vitro research of drug resistance. 
 
A standard 12-lead ECG. 
 
Vital signs including BP and HR at T24. 
 
OZ439 PK sampling (see Table 1). 
 
FQ/SSR97213 PK sampling (see Table 1). 
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10.1.4 Visit 4; Day 2 
 
Temperature at T48. 
 
Physical examination/malaria signs & symptoms at T48. 
 
Inquire about AEs and report concomitant medication. 
 
Asexual and sexual count (thick & thin blood films) and parasite genotyping (blood spot) 
for all patients. 
 
At T48, qPCR and RT-PCR gametocyte detection for patients >14 years and ≥35 kg only. 
 
In Vietnamese sites and for patients >14 years old only and only in case criteria for the use 
of rescue therapy is met: sample for in vitro research of drug resistance. 
 
Parasite genotyping sampling at first recurrence of parasitemia after first initial parasite 
clearance. 
 
If discharge: 
- 
Standard 12-lead ECG at T48, 
- 
Vital signs including BP and HR at T48,  
- 
Weight, 
- 
Clinical laboratory safety: 
- 
Local hematology, 
- 
Central lab biochemistry (including LFTs), 
- 
Urinalysis dipstick: specific gravity, pH, glucose, hemoglobin, protein, nitrates, 
leukocyte esterase, bilirubin. If any parameter on the dipstick is abnormal, a urine 
sample should be sent to the central laboratory for microscopic analysis. 
 
If African patient from Cohort 1: 
- 
Standard 12-lead ECG at T48. 
 
OZ439 PK sampling (see Table 1). 
 
FQ/SSR97213 PK sampling (see Table 1). 
 
Discharge from hospital (from T48 to T72). 
10.1.5 Visit 5; Day 3  
 
Temperature at T72.  
 
Physical examination/malaria signs & symptoms at T72. 
 
Inquire about AEs and concomitant medication. 
 
Asexual and sexual count (thick & thin blood films), parasite genotyping (blood spot) for 
all patients. 
 
At T72, qPCR , RT-PCR gametocyte detection (for patients >5 years). 
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 
In Vietnamese sites and for patients >14 years old only and only in case criteria for the use 
of rescue therapy is met : sample for in vitro research of drug resistance. 
 
Parasite genotyping sampling at first recurrence of parasitemia after first initial parasite 
clearance. 
 
If discharge at D3 or if the patient is still hospitalized at Day 3, discharge procedures 
should be performed at Day 3: 
- 
Standard 12-lead ECG at T72,  
- 
Vital signs including BP and HR at T72,  
- 
Weight, 
- 
Clinical laboratory safety, 
- 
Local hematology, 
- 
Central lab biochemistry (including LFTs), 
 
Urinalysis dipstick: specific gravity, pH, glucose, hemoglobin, protein, nitrates, leukocyte 
esterase, bilirubin. If any parameter on the dipstick is abnormal, a urine sample should be 
sent to the central laboratory for microscopic analysis. 
 
OZ439 PK sampling (see Table 1). 
10.1.6 Follow-up: V6 to V15 at Day 5, 7, 10, 14, 15-18, 21+/-2, 24-25, 28+/-2, 42+/-3 
and 63+/-3 
 
Temperature at each visit. 
 
Physical examination/malaria signs & symptoms at V7-D7, V13-D28, V14-D42 and  
V15-D63. 
 
Inquire about AEs and concomitant medication at each visit. 
 
Asexual and sexual count (thick & thin blood films) and parasite genotyping (blood spot) 
sampling at each visit for all patients.  
 
qPCR and RT-PCR gametocyte detection:  
- 
at each visit for patients >14 years and ≥35 kg,  
- 
at V7-D7, V13-D28, V14-D42 & V15-D63 for patients >5 years and ≤14 years.  
 
If visits V10 (D15-18) and V12 (D24-25) are performed "in the field" a RDT will be 
performed. During those visits, patients feeling unwell, with increased temperature 
(axillary temperature ≥37.5 °C) and/or a positive RDT should return to the Investigational 
site for assessment including blood films and parasite genotyping. In addition, if patients 
belong to Cohort 1 (>14 years and ≥35kg), qPCR and RT-PCR will be taken. 
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 
In Vietnamese sites and for patients >14 years old only and only in case criteria for the use 
of rescue therapy is met: sample for in vitro research of drug resistance. 
 
Parasite genotyping sampling at first recurrence of parasitemia after first initial parasite 
clearance. 
 
Standard 12-lead ECG at V7-D7. 
 
Vital signs including BP and HR at each visit from V7-D7 to V15-D63 (except V10 and 
V12). 
 
Weight at V15-D63 only. 
 
Clinical laboratory safety: at V7-D7, V9-D14, V11-D21 and V13-D28 for patients 
>5 years (Cohorts 1 & 2). 
 
Clinical laboratory safety: at V7-D7, V9-D14 and V13-D28 for patients ≤5 years 
(Cohorts 3&4). 
 
Pregnancy test (for women of childbearing potential) at V13-D28 and V15-D63. 
 
IVRS/IWRS call for end of study (EOS). 
 
OZ439 PK sampling (see Table 1. 
 
FQ/SSR97213 PK sampling (see Table 1). 
 
PK samples for measuring FQ and SSR97213 concentrations at Post D7 first recurrence of 
parasitemia. 
10.2 
DEFINITION OF SOURCE DATA 
The results of certain examinations or evaluations recorded in the e-CRF may be considered 
source data:  
 
Patient's medical record, 
 
Local laboratory results including blood smear results. 
10.3 
HANDLING OF PATIENT STUDY DISCONTINUATION  
Due to the mode of administration of IMP (FQ [capsules or suspension] followed by OZ439 
suspension) and the dose regimen (single dose), the following may not apply (see Section 8.1 for 
IMP administration). 
10.3.1 Temporary treatment discontinuation with investigational medicinal products 
Temporary treatment discontinuation after incomplete treatment (suspension ingestion) may be 
considered by the Investigator because of suspected AEs. Re-initiation of treatment with the IMP 
will be done under close and appropriate clinical/and or laboratory monitoring once the 
Investigator will have considered according to his/her best medical judgment that the 
responsibility of the IMP(s) in the occurrence of the concerned event was unlikely. 
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10.3.2 Permanent treatment discontinuation with investigational medicinal products 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time after incomplete treatment (suspension ingestion). 
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reasons for treatment discontinuation.  
10.3.4 Handling of patients after permanent treatment discontinuation 
Patients will be followed-up according to the study procedures as specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
10.3.5 Procedure and consequence for patient withdrawal from study 
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason: 
If possible, the patients are assessed using the procedure normally planned for the end-of-study 
visit including a pharmacokinetics sample. 
For patients who fail to return to the site, the Investigator should make the best effort to recontact 
the patient (eg, contacting patient’s family or private physician, reviewing available registries or 
health care databases), and to determine his/her health status, including at least his/her vital status 
at the planned D63 date. Attempts to contact such patients must be documented in the patient’s 
records (eg, times and dates of attempted telephone contact, receipt for sending a registered letter). 
The statistical analysis plan will specify how these patients lost to follow-up for their primary 
endpoints will be considered. 
Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
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10.4.1.2 Serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 
Results in death, or 
 
Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization, or 
 
Results in persistent or significant disability/incapacity, or 
 
Is a congenital anomaly/birth defect 
 
Is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered as a medically important event. The list is 
not intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm  
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
- 
Development of drug dependence or drug abuse 
- 
ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN 
- 
Suicide attempt or any event suggestive of suicidality 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
- 
Bullous cutaneous eruptions 
- 
Cancers diagnosed during the study or aggravated during the study (only if judged 
unusual/significant by the Investigators in oncology studies) 
- 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
(only if judged unusual/significant by the Investigators in studies assessing specifically 
the effect of a study drug on these diseases). 
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10.4.1.3 Adverse event of special interest 
Adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added or removed during a study by protocol amendment. 
 
Pregnancy occurring in a female patient entered in the clinical trial or in a female partner 
of a male patient entered in the clinical trial. It will be qualified as an SAE only if it fulfills 
one of the seriousness criteria (see Section 10.4.1.2). 
 Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined. 
 
Symptomatic overdose (serious or non-serious) with IMP 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the patient (not based on systematic pills 
count) and defined as at least twice the intended dose within the intended therapeutic 
interval, adjusted according to the tested drug.  
Of note, asymptomatic overdose has to be reported as a standard AE. 
10.4.1.4 Project specific AESIs 
Owing to safety findings for FQ and OZ439 on ECG and hepatic parameters, an appropriate ECG 
and hepatic monitoring is proposed (see study flowchart, Table 1). 
 
Increase in alanine transaminase (ALT): ALT ≥3 ULN (if baseline ALT <ULN) or, 
ALT ≥2 times the baseline value (if baseline ALT ≥ULN) will be reported as AESI.  
Cases of ALT >3 ULN will be monitored according to the procedures indicated in 
Appendix D. 
Patients with abnormal ALT values at D63 will be followed-up until ALT returns to 
normal values. A PK sample will be made at time of event for OZ439 and FQ 
(& SSR97213) concentration measurement. 
An ALT increase >3ULN is reportable as an SAE in any of the following situation: 
- 
Possible Hy’s law (ALT or AST >3x upper limit of normal (ULN) and bilirubin 
>2x ULN and (>35% direct bilirubin) in the absence of a serum alkaline phosphatase 
level >2x ULN. [If fractionation is unavailable, record presence of detectable urinary 
bilirubin on dipstick indicating direct bilirubin elevations and suggesting liver injury] 
or 
- 
When ALT >10 x ULN, 
- 
When associated with jaundice or, 
- 
When associated with coagulation disorder (PT<50%) or, 
- 
In presence of signs of hepatic encephalopathy. 
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 
QTcF ≥500 ms or QTcF prolongation >60 ms from baseline 
In the event of QTcF interval ≥500 ms (automatic measurement) or a QTcF prolongation 
>60 ms (automatic measurement) from baseline, the patient should be placed under 
supervision in a specialized setting.  
Subsequent ECG monitoring of the patient should then be performed on a regular and 
clinically responsible basis until the QTc interval returns to their baseline QTcF value. 
In case of QTcF ≥500 ms (automatic measurement) or QTcF prolongation >60 ms from 
baseline, patient will have blood drawn for measurement of OZ439 and FQ (& SSR97213) 
concentration.  
The Investigator will report an AESI only if QTcF ≥500 ms or QTcF prolongation >60 ms 
from baseline is confirmed by central reading. 
10.4.2 General guidelines for reporting adverse events 
 
All AEs, regardless of seriousness or relationship to IMP, spanning from the signature of 
the informed consent form until the end of the study as defined by the protocol for that 
patient, are to be recorded on the corresponding page(s) or screen(s) of the e-CRF. 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s). The causal relationship will be assessed either to 
FQ or OZ439 which are considered as distinct entities. 
 
The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor.  
 
When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient. 
 
Laboratory, vital signs or ECG abnormalities are to be recorded as AEs only if:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
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10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator must immediately: 
 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay. 
 
SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient’s 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
 
All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life threatening within a week (7 days) of the 
initial notification. 
 
A back-up plan (using a paper CRF process) is available and should be used when the 
e-CRF system does not work. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.4.4 Guidelines for reporting adverse events of special interest  
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding screens in the e-CRF. Instructions for AE reporting are summarized in 
Table 10. 
10.4.5 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix D.  
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices.  
 
Neutropenia 
 
Thrombocytopenia 
 
Increase in ALT 
 
Acute renal failure 
 
Suspicion of rhabdomyolysis 
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NOTE: Increase in ALT is considered as AESI (see Section 10.4.1.4) 
Table 10 - Summary of adverse event reporting instructions 
Event category 
Reporting 
timeframe 
Specific events in this 
category 
Case Report Form completion 
AE 
form 
Safety 
Complementary 
Form 
Other 
specific 
forms 
Adverse Event (non-
SAE, non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious Adverse Event 
(non-AESI or AESI) 
Expedited (within 
24 hours) 
Any AE meeting seriousness 
criterion per Section 10.4.1.2 
Yes 
Yes 
No 
Adverse Event of 
Special Interest  
Expedited (within 
24 hours) 
Pregnancy 
Yes 
Yes 
Yes 
 
 
Symptomatic overdose 
Yes 
Yes 
No 
 
 
ALT≥3 ULN (if baseline 
ALT<ULN)  
and ALT≥2 x baseline 
 (if baseline ALT ≥ULN) 
Yes 
Yes 
Yes 
 
 
QTcF ≥500 ms or 
ΔQTcF >60 ms from baseline 
Yes 
Yes 
No  
SAE: Serious AE, AESI: AE of special interest, ALT: alanine transferase, ULN: upper limit of normal, QTcF: QT interval corrected with Fridericia 
method, ms: millisecond 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
 
All SAEs that are both unexpected and at least reasonably related to the IMP (Suspected 
unexpected serious adverse reaction [SUSAR]), to the regulatory authorities, IECs/IRBs as 
appropriate and to the Investigators.  
 
All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol 
will be considered unexpected. 
In case of a SUSAR, Sanofi Global Pharmacovigilance and Epidemiology will utilize XGRID to 
reveal medication assignment for regulatory reporting requirements for the particular case. 
The Sponsor will report in the clinical study report all safety observations made during the 
conduct of the trial. 
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10.6 
SAFETY INSTRUCTIONS 
10.6.1 Development of complicated malaria  
The development of symptoms suggestive of severe (also defined as complicated) malaria will be 
investigated throughout the study. Severe malaria is considered in case of clinical features and/or 
laboratory and other findings as defined in Appendix A. 
Any symptom suggestive of severe malaria will be considered life-threatening and reported as 
unexpected SAE. 
The patient will be treated according the local recommendations for severe malaria. 
10.6.2 PK sampling in case of QTcF >=500 ms or QTcF prolongation >60 ms and/or 
ALT >=3xULN 
Patients having experienced a QTcF ≥500 ms or QTcF prolongation >60 ms from baseline and/or 
with ALT ≥3 ULN will be measured for circulating levels for OZ439, FQ and SSR97213 
immediately after a QTcF ≥500 ms and/or ALT ≥3xULN is reported to the investigator.  
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11 
STATISTICAL CONSIDERATIONS 
The material of Section 11 of the Clinical Trial Protocol is the basis for the Statistical Analysis 
Plan for the study. This plan may be revised during the study to accommodate Clinical Trial 
Protocol amendments and to make changes to adapt to unexpected issues in study execution and 
data that affect planned analyses. These revisions will be based on blinded review of the study and 
data, and a final plan will be issued at the latest 6 to 8 weeks before final database lock. 
11.1 
DETERMINATION OF SAMPLE SIZE 
This protocol is adaptive allowing futility at pre-specified interim points during the conduct of the 
study. At each interim time point, tests for futility will be performed. Recruitment will cease to a 
particular treatment arm if the pre-specified criterion for futility is reached. Interim assessment of 
futility will occur after recruitment of approximately 50 evaluable patients per treatment arm for 
the 1st futility analysis and every 25 evaluable patients per treatment arm thereafter for the 3 other 
interim analyses (including 75, 100 and 125 evaluable patients per treatment arm, respectively). 
Recruitment continues until each treatment arm is deemed to be futile or until 150 evaluable 
patients per treatment arm for the final analysis is reached. In case of high recruitment rate (ie, fast 
recruitment), not all the futility analyses may be performed. 
Given the adaptive nature of the study design, the total number of patients to be recruited can only 
be estimated. Simulations for different PCR-adjusted ACPR responses at Day 28 showed that a 
sample size of 150 evaluable patients per treatment arm will provide ≥80% probability to reject 
the null hypothesis (H0: probability of PCR-adjusted ACPR at Day 28 ≤0.90) at the final analysis, 
for the true rate of 96.4%. Recruitment will therefore continue until each treatment arm is deemed 
to be futile or until 150 evaluable patients per treatment arm is reached. 
In addition, a minimum of 15 African patients older than 5 years per treatment arm (likely to have 
higher NAI and therefore not included in the efficacy analyses) will be included for the DMC 
safety review. 
Lower numbers of patients per treatment arm may be recruited in the event of a poorly efficacious 
dose or doses (ie, futility). 
Thus the targeted number of African patients recruited to this study will be approximately 495 (in 
case of 3 treatment arms, scenario A, approximately 165 patients/arm) or approximately 662 (in 
case of 4 treatment arms, scenario B, approximately 165 patients/arm). 
11.2 
DISPOSITION OF PATIENTS 
Screened patients (counts and percentages) defined as any patient who signed the informed 
consent and met the inclusion criteria, screen failures and reason of screened failures will be 
provided for all patients and separately for each cohort. 
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Randomized patients consist of all patients with a treatment kit number allocated and recorded in 
IVRS/IWRS database at visit 2 (Day 0), and regardless of whether the treatment kit was used or 
not.  
Patients treated without being randomized by IVRS will not be considered as randomized and will 
not be included in any population. 
In the unlikely event of any patient being randomized more than once, only the data associated 
with the first randomization will be used in any analysis population. The safety experience 
associated with any later randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
In addition, a summary table (count and percentage) will be provided on the randomized 
population by treatment arm, country and center. Same summary will be provided also for each 
cohort (one table per cohort). 
Percentages will be calculated using the number of patients randomized as the denominator. 
11.3 
ANALYSIS POPULATIONS 
The analysis populations described below will be summarized by treatment group in a table given 
numbers and percentages based on randomized population. Same summary tables will be 
provided by treatment group and by cohort (one table per cohort). Within Cohort 1, data may also 
be summarized separately for Asian and African patients. 
11.3.1 Randomized population 
The randomized population is defined as all patients who have given their informed consent and 
who have been allocated to a randomized treatment regardless of whether the treatment kit was 
used or not. 
11.3.2 Efficacy populations 
Two efficacy analysis populations will be considered ie, Modified intent-to-treat (mITT) and  
Per-protocol (PP) populations focused on the “lower” NAI African population.  
For the Asian patients and for the higher NAI population defined as all randomized patients 
>5 years in Africa (Cohort 1 & 2), with parasitologically confirmed malaria at baseline, who 
received at least the single administration OZ439/FQ, separate statistical reporting on all efficacy 
endpoints will be provided as secondary analyses.  
The primary efficacy analysis population will be the per-protocol (PP) population defined as 
African patients of lower NAI; children ≤5 years in Africa (see Section 11.3.2.2). 
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11.3.2.1 Modified intent-to-treat population 
Modified intent-to-treat (mITT) population is defined as all randomized African patients of 
“lower” NAI population (ie defined as children ≤5 years in Africa) with parasitologically 
confirmed malaria at baseline, who received at least the single administration OZ439/FQ , ie, who 
did not need rescue therapy due to vomiting during IMP administration (see Section 8.9). 
African patients with age >5 years old, and Asian patients will not belong to the mITT. 
Patients in the mITT population will be analyzed according to the treatment arm allocated by 
randomization. 
11.3.2.2 Per-protocol (PP) population 
Per-protocol (PP) population is defined as mITT patients who do not qualify for a major 
deviation, as defined in the statistical analysis plan.  
11.3.3 Safety population 
The Safety population considered for safety analyses will be the randomized population including 
lower and higher NAI population who did actually receive at least one dose or part of a dose of 
the single administration OZ439 800 mg & FQ. Patients will be analyzed according to the 
treatment actually received (OZ439/FQ). 
In addition, randomized patients for whom it is unclear whether they took the study medication 
will be included in the safety population as randomized. 
11.3.4 Pharmacokinetic population  
The PK analysis will be performed on all treated patients (safety population) with at least 
one evaluable blood sample for PK post double-blind IMP administration and with adequate 
documentation of date of dosing and date of sampling. 
11.3.5 Pharmacokinetic/pharmacodynamic population 
PK/PD analyses using PCR-adjusted ACPR efficacy endpoint will be performed on all patients 
included in both the pharmacokinetic and the Per-Protocol (PP) populations. 
All patients included in the pharmacokinetic population and having at least one post-baseline 
assessment in QTc evaluation regarding the three PK/QTc analyses (one for Cohort 1a a 
second polling Cohorts 1a & 1b and final analysis including all cohorts) will be the 
pharmacokinetic/pharmacodynamic population. 
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11.4 
STATISTICAL METHODS 
11.4.1 Demographics and baseline characteristics 
Continuous variables (age, weight) and qualitative variables (gender, race and BMI [<30 or 
≥30 kg/m2]) will be summarized in descriptive statistics by treatment arm and for all patients, and 
separately for each cohort (one table per cohort) for the randomized population. Within Cohort 1, 
demographics and baseline characteristics will also be summarized separately for Asian and 
African patients. 
Other baseline characteristics like general medical history, previous medications defined as those 
started before the first intake of study drug and concomitant medications defined as those taken 
concomitantly to the study drug will be summarized by treatment arm and for all patients, and 
separately for each cohort (one table per cohort) for the randomized population: 
 
Summary of all medical history (number and percentage of patients) by primary system 
organ class (SOC) and high Level Term (HLT). 
 
Summary of Prior medications taken prior to first IMP intake (number and percentage of 
patients) by anatomic class and therapeutic class. 
 
Summary of concomitant medications (number and percentage of patients) by anatomic 
class and therapeutic class. 
11.4.2 Extent of study treatment exposure and compliance 
The listing of patients receiving IMP from specified batch will also be provided by cohort, 
treatment arm and patient. Besides, a listing sorted by site and cohort will be provided to display 
the randomization scheme (block number, sequence order with block, treatment arm, date and 
time of treatment allocation) of the study. 
11.4.2.1 Extent of investigational medicinal product exposure 
Since this is a single dose administration, duration of IMP exposure will not be calculated. 
11.4.2.2 Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data. Since this is a single dose administration, treatment compliance, 
above-planned and under-planned dosing percentages will not be calculated. 
11.4.3 Analyses of efficacy endpoints 
The primary final analysis will be carried out on the per-protocol (PP) population. Major protocol 
deviations disqualifying patients for the PP population will be described in the statistical analysis 
plan. 
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All statistical analyses on secondary efficacy endpoints will be done on the PP population. 
However, in case mITT and PP populations differ by more than 5%, statistical analysis of the 
primary endpoint ACPR at Day 28 will be carried out on the mITT population. 
A separate reporting on primary and secondary efficacy endpoints will be provided on “higher” 
NAI population; (Africans >5 years), and Asian population. 
11.4.3.1 Analysis of primary efficacy endpoint 
See Section 9.1.1 for primary efficacy endpoint details. 
 
PCR-adjusted ACPR (4-term composite criterion) at Day 28. 
Within each treatment arm, the following null hypothesis will be tested: 
 
H0: p ≤0.90 
Against the one sided alternative:  
H1: p >0.90 where p is the probability of PCR-adjusted ACPR at Day 28. 
The study will follow a group sequential design with up to 4 interim futility analyses, the first one 
when approximately 50 patients per treatment arm have reached Day 28 and thereafter every time 
another 25 patients per treatment arm (until the final analysis including 150 patients) have reached 
Day 28. 
At each interim analysis, based on PP population one of the following potential decisions is to be 
made: 
 
The treatment arm is stopped for futility if the posterior probability of H0 (that is, response 
rate is below 90%) given the data accumulated at the look for the treatment arm in 
question is too large, that is, Pr(H0|data) ≥0.30. 
 
The treatment arm advances to the next stage if the above conditions is not met (even if 
the observed response rate is 95% or greater). 
A Beta (9.5, 0.5) distribution will be used as prior distribution for the response rate and combined 
with a binomial likelihood to get a Beta posterior distribution (9.5 + x, 0.5 + N-x) with x is the 
number of successes out of N patients and calculate the posterior probability.  
At the final analysis, providing the treatment arm has not been stopped for futility, the null 
hypothesis will be rejected and binary endpoints such PCR-adjusted ACPR, ETF, LCF and LPF at 
Day 28 will be analyzed thanks to a frequency table ie, proportion, percentage and exact binomial 
95% confidence intervals (two-sided by using Clopper-Pearson method for calculating binomial 
confidence intervals) on the per-protocol (PP) population by cohort and treatment arm (one table 
including all patients and one table per cohort). Efficacy of the treatment arm demonstrated if the 
lower limit of the exact 95% confidence interval of PCR-adjusted ACPR rate is >90%.  
Same frequency table will be provided by treatment arm for children population (ie, including 
only Cohort 3 & 4). 
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11.4.3.2 Analyses of secondary efficacy endpoints 
See Section 9.2.1 for secondary efficacy endpoints details 
 
PCR-adjusted ACPR (4-term composite criterion) at Day 42 and Day 63 
PCR-adjusted ACPR, Early Treatment Failure (ETF), Late Clinical Failure (LCF) and 
Late Parasitological Failure (LPF) will be analyzed at Day 42 and Day 63 separately 
thanks to a frequency table ie, proportion, percentage and exact binomial 95% confidence 
intervals (two-sided by using Clopper-Pearson method for calculating binomial confidence 
intervals) by cohort and treatment arm (one table including all patients and one table per 
cohort). 
 
PCR-crude ACPR at Days 28, 42 and 63 
Same analysis using Clopper-Pearson method will be done on PCR-crude ACPR at 
Days 28, 42 and 63. The dose-response association of single-dose OZ439/FQ for PCR-
crude ACPR will also be evaluated. 
 
Time to re-emergence, to recrudescence, to re-infection, time to parasite clearance (PCT) 
and time to fever clearance (FCT). 
Time to event variables (like time to re-emergence, time to recrudescence, time to re-
infection, [FCT], [PCT]) will be analyzed using Kaplan-Meier estimators. Unless specified 
otherwise, all survival times will be calculated from the date/hour of first study drug intake 
to the first time to which the event occurred. For each variable, an overall overview 
including number of events (frequency and %), 25%, median and 75% quantile with 95% 
CI (expressed in weeks), cumulative incidence of events with 95% CI will be provided in a 
summary table for all patients and for each cohort separately. Survival curves will be 
plotted by representing each treatment arm for all patients and separately for each cohort. 
 
Parasite reduction ratio (PRR) 
The calculations and modeling for the PRR will be further discussed in the SAP. This will 
be calculated using microscopic and, when available, qPCR determined parasitemia. 
 
Parasitemia 
Descriptive statistics (n, mean, geometric mean, standard deviation, median, Q1, Q3, 
minimum, and maximum) for parasitemia data (number of parasites/µL) (raw data and 
absolute change from baseline) will be displayed at each post-baseline assessment. Time 
profile plots (Mean ± SEM) of parasitemia will be provided for each treatment arm, one 
curve per arm and also for each cohort separately. These analyses will be done using 
microscopic and qPCR (in patients >5 years) determined parasitemia. 
11.4.3.3 Multiplicity considerations 
No adjustment for multiplicity of comparisons was applied for primary or for secondary analyses. 
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11.4.3.4 Analyses of exploratory endpoints 
See Section 9.4.2 for exploratory endpoints details. 
 
Time to gametocytes clearance 
Time to gametocytes clearance will be analyzed using Kaplan-Meier estimators. An 
overall overview including number of events and cumulative incidence of events with 
95% CI will be provided in a summary table, survival curves will be plotted.  
 
Time to appearance of gametocytes 
The first appearance of gametocytes will be presented by time after enrollment for all 
patients, by treatment arm and separately for each cohort and treatment arm. The 
denominator for computation of percentages is the mITT population within each treatment 
arm. Besides, time to gametocytes clearance will be analyzed using Kaplan-Meier 
estimators in the same way than time to gametocytes clearance. 
 
Kelch 13 and parasite clearance 
Genotype – phenotype associations in the propeller region of Kelch 13 and parasite 
clearance kinetics (like half-life) will be explored graphically thanks to scatter plots. 
Linear mixed models may be used to test associations between parasite genotypes and 
parasite clearance half-lives following OZ439/FQ treatment arm. 
 
Gametocyte detection RT-PCR (in patients >5 years only) 
Standard descriptive statistics will be provided by cohort, treatment arm and time of 
measurement. If relevant, some correlations or modeling will be explored. 
 
Phenotypic and genotypic resistance pattern to conventional ACT of P. falciparum 
infecting patients aged >14 years old in Vietnamese sites 
Standard descriptive statistics will be provided by cohort, treatment arm and time of 
measurement. If relevant, some correlations or modeling will be explored.  
 
In vitro susceptibility testing of P. falciparum infecting patients aged >14 years old in 
Vietnamese sites to OZ439, FQ and both drugs. 
Standard descriptive statistics will be provided by cohort, treatment arm and time of 
measurement. If relevant, some correlations or modeling will be explored. 
11.4.4 Analyses of safety data 
The summary of safety results will be presented by treatment arm thanks to descriptive statistics 
(summary tables, graphics) in the following way: 
 
Summary tables provided separately for “higher NAI” (African patients >5 years) and 
“lower NAI” populations, and within the“lower NAI” population, separately for African 
patients <5 years and Asian patients, by treatment arm, whatever the cohort. 
 
A summary table provided for “higher NAI population” by treatment arm and by cohort 
(Cohort 1 & 2). 
 
A summary table provided for “lower NAI population” by treatment arm and by cohort 
(Cohort 3 & 4). 
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No formal inferential testing will be performed.  
All the safety analyses will be performed using the safety population.  
For all safety data (see Section 9.2.2.1 for details), the observation period will be divided into 
three phases: 
 
The pre-treatment phase defined as the time between the patient gives informed consent 
and the start time of first double-blind IMP administration (excluded). 
 
The on-treatment phase defined as the start time of first dose of double-blind IMP 
administration (included) up to Day 63 visit (included). 
 
The post-treatment phase will be defined as the time after the Day 63 visit (excluded). 
For laboratory, vital signs and ECG parameters, Potentially Clinically Significant Abnormalities 
(PCSAs) will be analyzed using the last available version of PCSA list before database lock.  
The following definitions will be applied to laboratory parameters, vital signs and ECG: 
 
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs and ECG. 
 
PCSA criteria will determine which patients had at least 1 PCSA during the on-treatment 
phase, taking into account all evaluations performed during the on-treatment phase, 
including unscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the PCSA percentage. 
Baseline safety parameters 
The baseline value is defined as the last available value before first double-blind IMP at Visit 1 
(Day-1) for laboratory, vital sign and Visit 2 (Day 0 before IMP administration) for ECG 
parameters. For ECG parameters, baseline will be the mean of the 3 consecutive measures 
(triplicate) done before dosing. 
Baseline definitions specific to each type of safety parameter will be detailed in corresponding 
sections. 
Baseline safety data will be presented along with subsequent safety values assessed during or after 
dosing. 
Drug-induced liver injury 
The liver function tests, namely ALT, AST, alkaline phosphatase and total bilirubin, are used to 
assess possible drug induced liver toxicity. The proportion of patients with PCSA values at any 
post baseline visit by baseline status will be displayed by treatment arm for each parameter.  
A graph of distribution (e-Dish plot) of peak values of ALT versus peak values of total bilirubin 
will be presented. Note that the ALT and total bilirubin values are presented on a logarithmic 
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scale. The graph will be divided into 4 quadrants with a vertical line corresponding to 3 x ULN 
for ALT and a horizontal line corresponding to 2 x ULN for total bilirubin. 
The normalization (to ≤1 x ULN or return to baseline) of elevated liver function tests will be 
summarized by categories of elevation (3 x ULN, 5 x ULN, 10 x ULN, 20 x ULN for ALT and 
AST, 1.5 x ULN for alkaline phosphatase, and 1.5 x ULN and 2 x ULN for total bilirubin), with 
the following categories of normalization: never normalized, normalized after permanent 
discontinuation of study drug. Note that a patient will be counted only under the maximum 
elevation category. 
The incidence of liver-related AEs will be summarized by treatment arm. The selection of 
preferred terms will be based on standardized MedDRA query (SMQ) Hepatic disorder. Time to 
liver-related treatment discontinuation and time to liver death may also be provided based on 
hepatic disorder SMQ. 
11.4.4.1 Analyses of adverse events 
11.4.4.1.1 Definitions 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA, last version available before database lock). 
They will be classified into predefined standard categories according to chronological criteria: 
 
Pre-treatment AEs are defined as AEs that occurred, worsened (according to Investigator 
opinion) or became serious during the pre-treatment phase 
 
Treatment emergent AEs (TEAEs) are defined as AEs that occurred or worsened or 
became serious during the on-treatment phase 
 
Post-treatment AEs are defined as AEs that occurred worsened or became serious during 
the post-treatment phase. 
11.4.4.1.2 Treatment emergent adverse events 
The following frequency tables of TEAEs (incidence tables) will be provided by treatment arm for 
each population (higher and lower NAI) and separately for each cohort (one table per cohort) 
during the on-treatment phase: 
 
Overview of TEAE: Number and percentage of patients with any TEAE, treatment 
emergent SAE and TEAEs leading to death. 
 
Summary of TEAEs (number and percentage of patients) by primary system organ class 
(SOC) (sorted by internationally agreed order), high-level group term (HLGT), high level 
term (HLT) and preferred term (PT) sorted in alphabetical order for each treatment arm. 
Multiple occurrences of the same event in the same patient will be counted only once in 
the tables within a treatment phase. The denominator for computation of percentages is the 
safety population within each treatment arm. 
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 
Summary of TEAEs (number and percentage of patient s) by primary system organ class 
(SOC) and preferred term (PT). 
 
Summary of TEAEs (number and percentage of patient s) by maximal intensity, primary 
system organ class (SOC) and preferred term (PT). 
The following frequency tables of treatment emergent SAEs (incidence tables) will be provided 
by treatment arm for each population (higher and lower NAI and separately for each cohort 
(one table per cohort) during the on-treatment phase: 
 
Summary of treatment emergent SAEs (number and percentage of patients) by primary 
SOC (sorted by internationally agreed order), HLGT, HLT and PT sorted in alphabetical 
order for each treatment arm. 
 
Summary of treatment emergent SAEs (number and percentage of patient s) by primary 
SOC and PT. 
Listing of patients presenting treatment emergent SAEs will be provided by treatment arm, 
patients, primary SOC, PT and onset date and time. 
AESIs:  
Summary tables of patient count (%) for each AESI (PT or pre-specified grouping) by treatment 
arm for each population (higher and lower NAI and separately for each cohort (one table per 
cohort) will be generated: 
 
Number (%) of patients experiencing torsade de pointes/QT prolongation by Primary SOC 
and PT. 
 
Number (%) of patients experiencing hepatic disorders by Primary SOC and PT. 
Death: 
The following deaths summaries will be generated: 
 
Number (%) of patients who died by study period (TEAE, on-study, post-study) 
summarized on the safety population by treatment received. 
 
Death in nonrandomized patients or randomized and not treated patients. 
 
TEAE leading to death (death as an outcome on the AE e-CRF page as reported by the 
Investigator) by primary SOC, HLGT, HLT and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, 
and PT. 
11.4.4.2 Laboratory variables analyses 
Baseline definition 
The values to be used as baselines will be the values collected on Day -1 for each treatment arm. 
If any of the scheduled baseline tests are repeated for any patient, the last rechecked values will be 
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considered as baselines, provided they were done before the start of IMP administration and in the 
same conditions. 
In case of central and local tests performed at the same time, central value will be considered as 
the baseline value provided it was done before the start of IMP administration. If a central test was 
not performed but a local value exists at the same date for the same test, the local value will be 
considered as the baseline. 
Abnormalities analyses 
For parameters with laboratory ranges and/or abnormality criteria (PCSA), an “on-treatment” 
analysis will be performed using all post-baseline assessments done during the on-treatment 
phase, including all unplanned and rechecked values. 
Counts of patients with PCSAs at any time during the on-treatment phase will be summarized by 
treatment arm for each population (higher and lower NAI) and separately for each cohort 
(one table per cohort) in summary tables showing shifts from normal and abnormal baselines to 
post-baseline abnormalities. These tables are split by normal/abnormal status and missing value at 
baseline (if any). 
Descriptive statistics and plots 
For ALT, AST, ALP, total and conjugated bilirubin, raw data and changes from baseline 
(including mean, median, quartile (Q1), Q3, standard deviation, minimum and maximum) will be 
summarized in descriptive statistics, by treatment arm and visit for all patients and separately for 
each cohort (one table per cohort). 
Additionally, time profile plots (mean+/- SD) on raw data and change from baseline will be 
provided for all patients and separately for each cohort and each of these parameters, using 
one curve per treatment arm. 
Listings 
All individual data, for planned hematology and biochemistry including rechecked values, will be 
listed by biological function, cohort, treatment arm and patient, visit. If any, data from 
unscheduled laboratory tests will also be listed. In these listings, individual data will be flagged 
when lower or higher than the lower or upper laboratory limits and/or when reaching the absolute 
limit of PCSA criteria, when defined. A listing of out-of-normal range definitions will also be 
provided. 
A listing of liver function data for patients experiencing at least one of the following situations 
will be provided as an in-text table: 
 
ALT >3 ULN and total bilirubin >2 ULN during the study, with at least one of them being 
post first dose, irrespective of the definition of the on-treatment phase. 
 
Direct bilirubin >35% of total bilirubin and total bilirubin >1.5 ULN, on the same sample 
post first dose, irrespective of the definition for the on-treatment phase. 
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A separate listing of individual data from patients with post-baseline PCSAs will be provided. 
If any, a listing related to increase in ALT ≥2 ULN will be provided, including notably the 
information on IMP intake, medical and surgical history, alcohol habits, trigger factors, event 
details with ALT values, associated signs and symptoms. 
11.4.4.3 Analyses of vital sign variables 
11.4.4.3.1 Heart rate and blood pressure 
Heart rate (HR) and systolic and diastolic blood pressure (SBP and DBP) will be analyzed as raw 
parameter value and change from baseline (for supine position only). 
Baseline definition 
The values to be used as baseline will be the Day-1 for each treatment arm. If any of the 
scheduled baseline tests are repeated for any patient, the last rechecked values will be considered 
as baseline, provided they were done before the start of IMP administration. 
Abnormalities analyses 
For all parameters, an “on-treatment” analysis will be performed using all post-baseline 
assessments done during the on-treatment phase, including all unplanned and rechecked values. 
Counts of patients with post-baseline PCSAs will be provided in summary tables regardless of the 
normal or abnormal status of the baseline. This table will be presented by treatment arm for each 
population (higher and lower NAI) and separately for each cohort (one table per cohort). 
Descriptive statistics 
For heart rate and blood pressures, raw data and changes from baseline (for supine position only 
including mean, median, quartile (Q1), Q3, standard deviation, minimum and maximum) will be 
summarized in descriptive statistics, for each type of measurement and by treatment arm, visit and 
time of measurement for all patients and separately for each cohort (one table per cohort). 
Listings 
Individual data for supine position, including unplanned and rechecked values, will be listed by 
cohort, treatment arm and patient, visit and time of measurement. 
In the listings, values will be flagged when reaching the limits of the PCSA criteria, when defined. 
A separate listing of individual data from patients with post-baseline PCSAs will be provided. 
11.4.4.3.2 Body temperature 
Raw data and changes from baseline will be summarized in descriptive statistics, by type of 
measurement (axillary [recommended], tympanic, oral or rectal), treatment arm, visit and time of 
measurement for all patients and separately for each cohort (one table per cohort). 
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11.4.4.4 ECG parameters analyses 
For all ECG parameters the mean of the 3 consecutive measures of ECG (triplicates) at each time 
of measurement when applicable will be calculated for each parameter, patient and nominal time 
point and will be used for analyses. 
Heart rate, PR-, QRS-, and QT-intervals, corrected QTcF (Fridericia) will be analyzed as raw 
parameter value and change from baseline, as well as percent change from baseline for selected 
parameters. 
Baseline definition 
The value to be used as baseline will be defined as the average of the triplicate assessments done 
on Day 0 T0 for each treatment arm. 
Abnormalities analysis 
For all parameters, an “on-treatment” analysis will be performed using all post-baseline 
assessments done during the on-treatment phase, including all unplanned and rechecked values. 
Counts of patients with post-baseline PCSAs will be provided in summary tables regardless of the 
normal or abnormal status of the baseline. This table will be presented by treatment arm for each 
population (higher and lower NAI) and separately for each cohort. 
A summary of ECG morphological assessments (for all high level types of comments) will be 
provided by cohort and treatment arm. 
Descriptive statistics and plots 
For all parameters, raw data and changes from baseline will be summarized in descriptive 
statistics, by treatment arm, visit and time of measurement for all patients and separately for each 
cohort (one table per cohort). Summary plots (mean+/-SD) on raw data and changes from 
baseline, as well as percent change from baseline for selected parameters will also be generated, 
separately for each cohort and each of these parameters, using one curve per treatment arm. 
Additionally, time profile plots (mean+/- SD) on raw data and change from baseline will be 
provided on all ECG parameters for all patients and separately for each cohort and each of these 
parameters, using one curve per treatment arm. 
Listings 
Individual data, including rechecked values, will be listed by cohort, treatment arm, patient, visit 
and time of measurement. In the listings, values will be flagged when reaching the limits of the 
PCSA criteria, when defined. A separate listing of individual data from patient s with post-
baseline PCSAs will be provided. 
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11.4.5 Analyses of pharmacokinetic and pharmacodynamic variables 
11.4.5.1 Analysis of pharmacokinetic data 
Pharmacokinetic analysis for OZ439, FQ and SSR97213 are described in Section 9.4.1.5. 
Blood and plasma FQ (respectively its metabolite [SSR97213]) observed concentrations, plasma 
OZ439 observed concentrations will be summarized by treatment arm and by time point using 
descriptive statistics for each cohort. Blood/plasma concentration ratio for FQ and SSR97213 will 
be provided by treatment arm and by time point using descriptive statistics for each cohort. 
Additional plots will be prepared, as deemed necessary.  
Pharmacokinetic parameters of FQ, its metabolite SSR97213 and OZ439 compounds will be 
summarized by descriptive statistics (such as arithmetic mean, geometric mean, median, SD, 
SEM, CV, minimum, and maximum) for each treatment arm and each cohort. 
The results of population PK modeling will be reported separately from the study report. 
11.4.5.2 Analysis of pharmacodynamic data 
Not applicable. 
11.4.5.3 Analysis of pharmacokinetic/pharmacodynamic data 
11.4.5.3.1 Relationship between ACPR and dose or concentrations 
For each cohort and for all patients separately, the dose-response association of single-dose 
OZ439/FQ for PCR-adjusted ACPR will demonstrate how the probability of a response in  
PCR-adjusted ACPR increases with increasing dose OZ439/FQ thanks to a logistic regression 
with SAS® PROC LOGISTIC by using ACPR data at Days 28, 42 and 63. Same analysis will be 
done between PCR-adjusted ACPR and exposure. 
Results of logistic regressions of PCR-adjusted ACPR on dose (respectively FQ/SSR97213 blood 
or OZ439 plasma concentrations) of OZ439/FQ will be provided in a summary table including 
odds ratio estimates, the corresponding 95% Wald confidence intervals and p-value. 
11.4.5.3.2 Relationship between PK concentrations and QTc parameters 
Two PK/PD statistical analyses (one for cohort 1a in a first time and then by pooling cohort 1a 
and 1b in a second time) will be done with ECG parameters (HR, PR, QRS and QTcF) regarding 
FQ and SSR97213 compounds by combining the two compounds in the same linear direct/indirect 
model (as covariates or by using the molecular weight formula in order to obtain an “average” 
concentration). A complementary analysis will be performed pooling Cohort 1a and 1b and 
including OZ concentrations as PK variable (in addition to FQ and SSR97213). These 
two analyses will be prepared by a Sponsor’s unblinded independent statistician. 
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The first PK/QTc analysis will include 30 African patients >14 years (Cohort 1a) receiving the 
dose levels OZ439/FQ 800/400, 800/600 and 800/900 mg.  
The second PK/PD analysis will include a total of 42 African patients >14 years (Cohort 1a & 1b) 
receiving the dose levels 800/400, 800/600,800/900 and 800/1200.  
Concentrations below the limit of quantification (LOQ LOQ), will be replaced with ½ LOQ in the 
statistical analyses. LOQ is defined as 1 ng/mL for OZ439 and as 5 ng/mL for FQ and SSR97213.  
Relationships between change from baseline in ECG parameters by combining the two 
compounds FQ and SSR97213, using the molecular weight (MW) 433.77 g.mol-1 for ferroquine 
419.74 g.mol-1 for SSR97213 or by using ferroquine and SSR97213 blood drug concentrations as 
covariates in the same model (selection of the best model will depend of fit statistics criteria), on 
the restricted time window [Day 0 T2h – Day 2 T48h] will be explored using data from OZ439/FQ: 
1st step: 800/400, 800/600 and 800/900 mg dose levels from Cohort 1a. 
2nd step: 800/400, 800/600, 800/900 and 800/1200 mg dose levels from Cohorts 1a and 1b. 
(OZ concentration to be added as PK variable in the complementary analysis with the 
molecular weight (MW) of 469.28 g.mol-1). 
These PK/QTc analyses may or may not be reviewed by the DMC at the same time as the safety 
data review and therefore may or may not be considered by the DMC for DMC decision rule. 
A third PK/PD analysis will include all patients of all cohorts receiving the dose levels 800/400, 
800/600, 800/900 mg and/or 800/1200 mg at the end of the study. Relationships between change 
from baseline in ECG parameters versus FQ (respectively SSR97213 and OZ439) blood drug 
concentrations, on the restricted time window [Day 0 T2h – Day 2 T48h]. 
11.4.5.3.3 Exploratory plots 
The relationship between change from baseline in HR, PR, QRS and QTcF and FQ (respectively 
SSR97213 and OZ439 [complementary analysis at end of Cohort 1 and final analysis only]) 
concentrations, respectively, from Day 0 T2h to Day 2 T48h will be first explored graphically, in 
order to investigate any potential delayed or sustained effects and the type of PK/PD modelling to 
be done, using the following plots: 
 
Plot of Mean (± SEM) change from baseline in HR, PR, QRS and QTcF and FQ 
(respectively SSR97213 and OZ439 [complementary analysis at end of Cohort 1 and final 
analysis only]) concentrations, versus time (hours post-dose) overlaid onto the same plot; 
the same plot will be produce on the log concentration; 
 
Hysteresis plot of individual and mean change from baseline in HR, PR, QRS and QTcF 
and FQ (respectively SSR97213 and OZ439 [complementary analysis at end of Cohort 1 
and final analysis only]) concentrations, respectively; 
 
Histogram of distribution of time of largest change from baseline in HR, PR, QRS and 
QTcF and largest FQ (respectively SSR97213 and OZ439 [complementary analysis at end 
of Cohort 1 and final analysis only]) concentrations, respectively; 
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 
Histogram of distribution of time of smallest change from baseline in HR, PR, QRS and 
QTcF and largest FQ (respectively SSR97213 and OZ439 [complementary analysis at end 
of Cohort 1 and final analysis only]) concentrations, respectively. 
11.4.5.3.4 Modeling: linear model 
A random coefficients linear regression of QTcF (respectively HR, RR) change from baseline vs. 
concentration will be used from Day 0 T2h to Day 2 T48h, with fixed terms for common intercept 
and slope, with or without time effect, and with random terms for patient -specific intercept and 
slope, and using an unstructured variance-covariance structure for random coefficients and a 
common variance for error, using SAS® PROC MIXED procedure: 
Change from baseline QTcFij = (α + Ai) + Timej + (β + Bi) × Concentrationij + error, 
with i = patient and j = Time  
Estimates and 90% CIs of coefficients (intercept corresponding to the mean of individual time 
Intercept in case of time effect is included in the model and slope) of the linear regression model, 
and the prediction (estimate and 90% CI) in change from baseline of ECG parameters 
corresponding to the Cmax value (geometric mean) for each FQ dose group will be provided for 
FQ and SSR97213 respectively (OZ439 compound for the complementary analysis at end of 
Cohort 1 and final analysis only), and will be calculated following the formula βestimated × observed 
geometric mean Cmax: 
 
OZ439 800 mg/FQ xxx mg/ at geometric mean of Cmax for each dose of OZ439/FQ. 
 
Scatter plots of change from baseline versus FQ and SSR97213 concentrations, 
respectively, with the regression line overlaid, will also be provided. 
11.4.5.3.5 Model Averaging to Concentration-QT analysis 
By combining estimates obtained from several competing models (linear, exponential and Emax), 
Model averaging (MA) will provide estimators which will have good robustness properties 
compared to the linear model or non-linear model estimates. 
The estimated endpoint will be the drug effect on delta QTcF at the Cmax value (geometric mean) 
observed concentrations at the maximal dose (OZ439 800 mg/FQ 1200 mg). 
11.4.6 Analyses of quality of life/health economics variables 
Not applicable. 
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11.5 
INTERIM ANALYSIS 
Safety review 
No interim analysis is planned. However unblinded safety data of each cohort (N=10 patients/arm 
for Cohort 1, 5 patients/arm for Cohort 2 and 8 patients/arm for Cohort 3 & 4) will be analyzed by 
the Sponsor’s independent unblinded statistician and reviewed by the DMC (see Section 11.4.5.3).  
Also, PK/QTc modeling data (Cohort 1a and pooled of Cohort 1a & 1b) will be prepared by a 
Sponsor’s independent unblinded statistician and reviewed by the DMC (See Section 11.4.5.3).  
Go/No Go for transition from one cohort to the next and FQ dose step-up procedure toOZ439/FQ-
800/1200 mg will be based on DMC’s assessment and recommendation. 
These PK/QTc analyses may or may not be reviewed by the DMC at the same time as the safety 
data review and therefore may or may not be considered by the DMC for DMC decision rule. 
Efficacy review: interim futility analyses 
Up to 4 interim futility analyses may be planned and will be performed by the Sponsor’s 
independent unblinded statistician and reviewed by the DMC. 
As soon as the first 50 patients/treatment arm have completed the 28-days treatment period, the 
1st analysis will be performed by the DMC statistician to assess the primary endpoint (response 
rate of PCR-adjusted ACPR at Day 28, Section 11.4.3) in order to pursue or not the recruitment of 
each treatment arm. Thereafter, subsequent interim futility analysis will be performed every time 
another 25 patients per treatment arm (ie, 75 patients/treatment arm for the 2nd IA, 
100 patients/treatment arm for the 3rd IA, 125 patients/treatment arm for the 4th IA until 
150 patients/treatment arm for the final analysis) will be enrolled in the study and will have 
completed the primary endpoint at Day 28. Recruitment continues until each treatment arm is 
deemed to be futile or until 150 patients per treatment arm for the final per protocol analysis is 
reached.  
The results of each interim futility analysis will be reviewed by the DMC which will recommend 
continuing or not the recruitment of patients in each treatment arm depending of the cohort age 
group if the following conditions are met: 
 
The treatment arm is stopped for futility if the posterior probability of H0 (that is, response 
rate is below 90%) given the data accumulated at the look for the treatment arm in 
question is too large, that is, Pr(H0|data) ≥0.30, 
 
The treatment arm advances to the next stage if the above conditions is not met (even if 
the observed response rate is 95% or greater). 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the Sponsor, the Investigator, delegated Investigator staff 
and Subinvestigator, in accordance with the principles laid down by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies, and the International Conference of Harmonization (ICH) guidelines for good clinical 
practice (GCP), all applicable laws, rules and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient (and the 
parent[s] or guardian[s]) of all pertinent aspects of the clinical trial including the written 
information given approval/favorable opinion by the ethics committee (Institutional Review 
Board/Independent Ethics Committee [IRB/IEC]). All participants should be informed to the 
fullest extent possible about the study in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the informed consent form should be signed, 
name filled in and personally dated by the patient, the patient’s parent(s) or by the patient’s 
legally acceptable representative, and by the person who conducted the informed consent 
discussion. A copy of the signed and dated written informed consent form will be provided to the 
patient. When applicable, local law must be observed in deciding whether 1 or both 
parents/guardians consent is required. If only 1 parent or guardian signs the consent form, the 
Investigator must document the reason for only 1 parent or guardian’s signature. 
In addition, participants will assent as detailed below or will follow the Ethics Committee 
(IRB/IEC) approved standard practice for pediatric participants at each participating center (age of 
assent to be determined by the IRB’s/IEC’s or be consistent with the local requirements): 
Participants who can read the assent form will do so before writing their name and dating or 
signing and dating the form. 
Participants who can write but cannot read will have the assent form read to them before writing 
their name on the form. 
Participants who can understand but who can neither write nor read will have the assent form read 
to them in presence of an impartial witness, who will sign and date the assent form to confirm that 
assent was given. 
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The informed consent form and the assent form used by the Investigator for obtaining the 
Patient’s Informed Consent must be reviewed and approved by the Sponsor prior to submission to 
the appropriate Ethics Committee (IRB/IEC) for approval/favorable opinion. 
In relation with the population of patients exposed in the trial ie, pediatric/minor patients, the 
IRB/IEC should ensure proper advice from specialist with pediatrics expertise (competent in the 
area of clinical, ethical and psychosocial problems in the field of pediatrics) according to national 
regulations. This should be documented. 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the appropriate IRB/IEC, and is required to forward to the respective other party a 
copy of the written and dated approval/favorable opinion signed by the Chairman with IRB/IEC 
composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure, Investigator’s 
curriculum vitae [CV], etc) and the date of the review should be clearly stated on the written 
(IRB/IEC) approval/favorable opinion. 
IMP will not be released at the study site and the Investigator will not start the study before the 
written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the IRB/IEC before implementation, unless the change is necessary to eliminate an 
immediate hazard to the patients, in which case the IRB/IEC should be informed as soon as 
possible. It should also be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical trial, in particular any change in safety. All updates to the 
Investigator’s Brochure will be sent to the IRB/IEC. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATORS 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient’s data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as Sub-
investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Sub-investigators shall be appointed and listed in a timely manner. The Sub-
investigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
13.3 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the CRFs. Thus, the main duty of 
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the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
13.4 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
personnel, the Ethics Committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records which support the data on the CRFs (eg, patient's medical file, 
appointment books, original laboratory records, etc). These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.5 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the e-CRF. 
13.6 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Sub-investigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator's Brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
Ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Sub-investigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Sub-investigators of the confidential nature of the clinical trial. 
The Investigator and the Sub-investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party’s account. 
14.3 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff / Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
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As the case may be, the Investigator and/or the Sub-investigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.4 
DATA PROTECTION 
 
The patient’s personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations; 
 
When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party; 
 
The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
Patient race/ethnic origin (African, Asian) will be collected in this study because these data 
support the sub-population definition: higher and lower NAI population (see Section 7.4.1). 
14.5 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document. 
14.6 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, GCP and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
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Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.7 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.7.1 By the Sponsor 
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
 
The information on the product leads to doubt as to the benefit/risk ratio; 
 
Patient enrollment is unsatisfactory; 
 
The Investigator has received from the Sponsor all IMP, means and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon; 
 
Non-compliance of the Investigator or Sub-investigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP; 
 
The total number of patients are included earlier than expected; 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
14.7.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days’ prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.8 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
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14.9 
PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway or 
planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) 
to clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial. Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the Investigator and by the Sponsor and the signed amendment will be filed with this 
clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary. 
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BIBLIOGRAPHIC REFERENCES 
1. Methods for surveillance of antimalarial drug efficacy, WHO, 2009, ISBN 978 92 4 159753 1. 
2. World malaria report: 2013; WHO, ISBN 978 92 4 156469 4. 
3. Gallup JL, Sachs JD. The economic burden of malaria. Am J Trop Med Hyg. 2001;64(1-2 
Suppl):85-96. 
4. Guidelines for the treatment of malaria - 2nd edition, WHO. 2010, ISBN 978 92 4 154792 5. 
5. Bassat Q, González R, Machevo S, Nahum A, Lyimo J, Maiga H, et al. Similar efficacy and 
safety of artemether-lumefantrine (Coartem®) in African infants and children with 
uncomplicated falciparum malaria across different body weight ranges. Malar J. 
2011;10(1):369. 
6. Jambou R, Le Bras J, Randrianarivelojosia M. Pitfalls in new artemisinin-containing 
antimalarial drug development. Trends Parasitol. 2011;27(2):82-90. 
7. Ding XC, Beck HP, Raso G. Plasmodium sensitivity to artemisinins: magic bullets hit elusive 
targets. Trends Parasitol. 2011;27(2):73-81. 
8. Held J*, Supan C*, Salazar CL, Tinto H, Bonkian L, Nahum A et al. Ferroquine and 
artesunate in African adults and children with Plasmodium falciparum malaria : a phase 2, 
multicenter, randomised, double-blind, dose-ranging, non-infectiority study. Lancet Infect Dis. 
2015;15(12):1409-19. 
9. Data on file. DRI10382 Clinical Study Report. 
10. Anderson BJ, Allegaert K,  Holford NH. Population clinical pharmacology of children: 
modelling covariate effects. Eur J Pediatr. 2006;165(12):819-29. 
11. A manual: measuring and interpreting malnutrition and mortality - World Food Programme 
and Centers for Diseases Control and Prevention, 2005. Available from: URL: 
http://www.unhcr.org/45f6abc92.pdf 
 
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17 
APPENDICES 
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Appendix A 
Severe P. falciparum malaria definition  
Clinical features of severe malaria 
 
impaired consciousness (including unrousable coma); 
 
prostration, ie, generalized weakness so that the patient is unable to sit, stand or walk 
without assistance; 
 
multiple convulsions: more than two episodes within 24h; 
 
deep breathing and respiratory distress (acidotic breathing); 
 
acute pulmonary oedema and acute respiratory distress syndrome; 
 
circulatory collapse or shock, systolic blood pressure <80 mmHg in adults and <50 mmHg 
in children; 
 
acute kidney injury; 
 
clinical jaundice plus evidence of other vital organ dysfunction; and abnormal bleeding. 
Laboratory and other findings 
 
 hypoglycaemia (<2.2 mmol/l or <40 mg/dL); 
 
metabolic acidosis (plasma bicarbonate <15 mmol/L); 
 
severe normocytic anaemia (haemoglobin <5 g/dL, packed cell volume <15% in children; 
<7 g/dL, packed cell volume <20% in adults); 
 
haemoglobinuria; 
 
hyperlactataemia (lactate >5 mmol/L); 
 
renal impairment (serum creatinine >265 μmol/L); and 
 
pulmonary oedema (radiological). 
 
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Appendix B 
CYPs inducer/inhibitor/substrate, P-gp substrate (non-exhaustive 
list) 
 
Compound (INN) 
Terminal half life 
Reason for exclusion 
Aliskiren 
38h 
Pgp substrate 
Amiodarone 
25 days 
CYP2C and CYP3A inhibitor 
Atomoxetine 
20h 
main CYP2D6 substrate 
Avasimibe 
24h 
CYP inducer 
Boceprevir 
3h 
Strong CYP3A inhibitor 
Bosentan 
7h 
CYP inducer 
Carbamazepine 
15h 
CYP inducer 
Carvedilol 
2h 
main CYP2D6 substrate 
Chlorpromazine 
30h 
main CYP2D6 substrate 
Clarithromycin 
3h 
Strong CYP3A inhibitor 
Colchicine 
31h 
Pgp substrate 
Conivaptan 
5h 
Strong CYP3A inhibitor 
Dabigatran etexilate 
11h 
Pgp substrate 
Danoprevir/ritonavir 
2h/5h 
Strong CYP3A inhibitor 
Desipramine 
28h 
main CYP2D6 substrate 
Dextromethorphan 
3h 
main CYP2D6 substrate 
Digoxin 
36h 
Pgp substrate 
Efavirenz 
3 days 
CYP inducer 
Elvitegravir/ritonavir 
8h/5h 
Strong CYP3A inhibitor 
Encainide 
3h 
main CYP2D6 substrate 
Enzalutamide 
6h 
CYP inducer 
Etoposide 
8h 
Pgp substrate 
Etravirine 
40h 
CYP inducer 
Everolimus 
30h 
Pgp substrate 
Fexofenadine 
15h 
Pgp substrate 
Flecainide 
11h 
main CYP2D6 substrate 
Fluconazole 
32h 
Strong CYP2C inhibitor 
Fluoxetine 
2 days 
CYP2C and CYP3A inhibitor 
Fluvoxamine 
15h 
Strong CYP2C inhibitor 
Gemfibrozil 
1h 
Strong CYP2C inhibitor 
Genistein 
8h 
CYP inducer 
Grapefruit juice 
- 
Strong CYP3A inhibitor 
Imipramine 
16h 
main CYP2D6 substrate 
Indinavir, Indinavir/ritonavir 
2h/5h 
Strong CYP3A inhibitor 
Itraconazole 
21h 
Strong CYP3A inhibitor 
Ketoconazole 
3h 
Strong CYP3A inhibitor 
Lapatinib 
14h 
Pgp substrate 
Lersivirine 
6h 
CYP inducer 
Linezolide 
5h 
Pgp substrate 
Loperamide 
11h 
Pgp substrate 
Lopinavir, 
Lopinavir/ritonavir 
5h 
Strong CYP3A inhibitor, CYP inducer 
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Compound (INN) 
Terminal half life 
Reason for exclusion 
Maprotiline 
45h 
main CYP2D6 substrate 
Maraviroc 
18h 
Pgp substrate 
Metoprolol 
3h 
main CYP2D6 substrate 
Mibefradil 
22h 
Strong CYP3A inhibitor 
Miconazole 
24h 
Strong CYP2C inhibitor 
Mitotane 
18-159 days 
Potent CYP inducer 
Modafinil 
11h 
CYP inducer 
Nafcillin 
2h 
CYP inducer 
Nebivolol 
11h 
main CYP2D6 substrate 
Nefazodone 
4h 
Strong CYP3A inhibitor 
Nelfinavir 
5h 
Strong CYP3A inhibitor 
Nilotinib 
17h 
Pgp substrate 
Nortriptyline 
31h 
main CYP2D6 substrate 
Paroxetine 
17h 
main CYP2D6 substrate 
Perphenazine 
9h 
main CYP2D6 substrate 
Phenobarbital 
4 days 
CYP inducer 
Phenytoine 
24h 
CYP inducer 
Pimozide 
5 days 
main CYP2D6 substrate 
Posaconazole 
35h 
Strong CYP3A inhibitor, Pgp substrate 
Propafenone 
6h 
main CYP2D6 substrate 
Propranolol 
4h 
main CYP2D6 substrate 
Ranolazine 
7h 
Pgp substrate 
Rifabutine 
28-62h 
CYP inducer 
Rifampin 
4h 
CYP inducer 
Rifapentine 
18h 
CYP inducer 
Risperidone 
3h 
main CYP2D6 substrate 
Ritonavir 
5h 
Strong CYP3A inhibitor 
Saquinavir, 
Saquinavir/ritonavir 
12h/5h 
Strong CYP3A inhibitor, Pgp substrate 
Semagacestat 
2.5h 
CYP inducer 
Sirolimus 
62h 
Pgp substrate 
St John’s wort 
- 
CYP inducer 
Talinolol 
9h 
Pgp substrate 
Talviraline 
- 
CYP inducer 
Telaprevir 
11h 
Strong CYP3A inhibitor 
Telithromycin 
12h 
Strong CYP3A inhibitor 
Thioridazine 
24h 
main CYP2D6 substrate 
Ticlopidine 
4 days 
Strong CYP2C inhibitor 
Timolol 
3h 
main CYP2D6 substrate 
Tipranavir/ritonavir 
6h/5h 
Strong CYP3A inhibitor 
Tolterodine 
2h 
main CYP2D6 substrate 
Tolvaptan 
12h 
Pgp substrate 
Trimipramine 
24h 
main CYP2D6 substrate 
Troleandomycine 
3h 
Strong CYP3A inhibitor 
Venlafaxine 
5h 
main CYP2D6 substrate 
Voriconazole 
7h 
Strong CYP3A inhibitor 
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Appendix C 
Drugs known to modify QT interval (non exhaustive list) 
 
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 Page 104 
 
Or https://www.crediblemeds.org/pdftemp/pdf/CombinedList.pdf 
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Appendix D 
General Guidance for the follow-up of laboratory abnormalities by 
Sanofi  
Neutrophils < 1500/mm3 or according to ethnic 
group
NEUTROPENIA
Repeat immediately a full blood count if value 
close to 1500/mm3
Neutrophils < 1500/mm3 confirmed 
with signs of infection  
Neutrophils < 1500/mm3 confirmed 
with no signs of infection  
1.
DISCONTINUE
Investigational Medicinal 
Product, hospitalization 
should be considered
2.
PERFORM biological 
investigations for infection
1.
DISCONTINUE
Investigational 
Medicinal Product
2.
INVESTIGATE for 
infection
In both situations
3.
INFORM the local monitor
4.
INVESTIGATE previous treatments particularly long-term, even a long time ago, 
exposure to toxic agents, e.g., benzene, X-rays, etc.
5.
PERFORM and collect the following investigations (results): 
•
RBC and platelet counts
•
Serology: EBV, (HIV), mumps, measles, rubella
6.
DECISION for bone marrow aspiration: to be taken in specialized unit
7.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
8.
MONITOR the leukocyte count 3 times per week for at least one  week, then twice a 
month until it returns to normal
Note: 
•The procedures described in the above flowchart are to be discussed with the patient only in case 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
•For individuals of African descent, the relevant value of concern is <1000/mm3
Neutropenia is to be recorded as AE only if at least one of the criteria listed in Section 10.4.3 is met
 
Neutropenia is to be recorded as AE only if at least one of the criteria listed in the General 
guidelines for reporting adverse events in Section 10.4.2 is met. 
Due to single dose regimen, instructions regarding IMP discontinuation/resumption do not apply. 
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For patients with low platelets count (Platelets <100 000/ mm3), after immediately repeating the count (rule 
out EDTA anticoagulant in the sample), the instructions from point 2 to 8 must be followed, if at least 
one of the following situations is present: 
 
If the confirmed decrease (repeat measure) is deemed by the investigator larger than expected due 
to underlying disease 
 
50 000 ≤Platelets <100 000/ mm3 confirmed with bleeding 
 
Platelets <50 000/ mm3 confirmed 
Platelets < 100 000/mm3 (rule out EDTA – induced 
pseudo-thrombocytopenia)
THROMBOCYTOPENIA
Repeat immediately the count (rule out EDTA 
anticoagulant in the sample)
Platelets  < 100 000/mm3 confirmed 
with bleeding  
Platelets  < 100 000/mm3 confirmed 
with no bleeding
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE for 
bleeding
In both situations
3.
INFORM the local Monitor
4.
QUESTION about last intake of quinine (drinks), alcoholism, heparin administration
5.
PERFORM or collect the following investigations: 
•
Complete blood count, schizocytes, creatinine
•
Bleeding time and coagulation test (fibrinogen, INR or PT, aPTT), Fibrin 
Degradation Product
•
Viral serology: EBV, HIV, mumps, measles, rubella
6.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
7.
DECISION for bone marrow aspiration: to be taken in specialized unit
•
On Day 1 in the case of associated anemia and/or leukopenia
•
On Day 8 if platelets remain < 50 000/mm3
8.
MONITOR the platelet count every day for at least one week and then regularly 
until it returns to normal
Note: 
The procedures above flowchart are to be discussed with the patient only in case described in the 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
Thrombocytopenia is to be recorded as AE only if at least one of the criteria listed in Section 10.4.3 
is met
 
Thrombocytopenia is to be recorded as AE only if at least one of the criteria listed in the General 
guidelines for reporting adverse events in Section 10.4.2 is met. 
Due to single dose regimen, instructions regarding IMP discontinuation/resumption do not apply. 
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INCREASE IN ALT 
 
NOTE: ALT ≥3 ULN (IF BASELINE ALT <LN) OR ALT ≥2 TIMES THE BASELINE VALUE (IF BASELINE ALT ≥ULN) SHOULD 
BE NOTIFIED WITHIN 24 HOURS TO THE MONITORING TEAM (SEE SECTION 10.4.1.4, SECTION 10.4.5).  
IN ADDITION, IF ALT < 3 ULN MEETS A SERIOUSNESS CRITERION, THE EVENT SHOULD BE NOTIFIED WITHIN 24 HOURS 
TO THE MONITORING TEAM. 
Due to single dose regimen, instructions regarding IMP discontinuation/resumption do not apply. 
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Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below
50 mL/mn
ACUTE RENAL FAILURE
Can be rapidly reversed:
• By volume repletion
• Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: anemia, 
hyperkalemia, hyperuricemia, metabolic 
acidosis, cardiac insufficiency, 
pulmonary edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
Investigational Medicinal Product by 
renal route
1.
Investigational Medicinal 
Product may be continued
2.
MONITOR serum creatinine 
until return to baseline level
1.
INFORM the local monitor
2.
DISCONTINUE
Investigational Medicinal Product 
administration
3.
HOSPITALIZATION should be 
considered and seek for nephrologic  
advice
4.
PERFORM the following 
examinations: 
•
BP, HR, hydration status, ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
COLLECT/STORE one sample 
following handling procedures 
described in PK sections (for studies 
with PK sampling) and freeze one 
serum sample (5 mL) on Day 1 
(cessation of investigational 
medicinal product)
6.
MONITOR renal function until 
return to baseline level (every day at 
the beginning, then every week)
Acute renal failure is to be recorded as AE only if at least one of the criteria listed in 
Section 10.4.3 is met
 
Acute renal failure is to be recorded as AE only if at least one of the criteria listed in the General 
guidelines for reporting adverse events in Section 10.4.2 is met. 
Due to single dose regimen, instructions regarding IMP discontinuation/resumption do not apply. 
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If Increase in CPK (expressed in ULN)
> 3 ULN
Repeat immediately the count.
If confirmed, inform the local monitor and
INVESTIGATE for the origin:
- PERFORM:
•
ECG
•
CPK-MB -MM 
•
Troponin
•
Creatinine
•
Iono (k+, Ca2+)
•
Transaminases + Total and conjugated bilirubin
•
Myoglobin (serum and urines)
- COLLECT/STORE one sample following handling procedures described in PK sections (for 
studies with PK sampling) and freeze one serum sample (5 mL) on Day 1 (cessation of 
investigational medicinal product). 
- INTERVIEW the patient about a recent intensive muscular effort, trauma, convulsions, electrical 
injury, injury or stress to the skeletal muscle, multiple intramuscular injections, recent surgery, 
concomitant medications, consumption of alcohol, morphine, cocaine.
- SEARCH for alternative causes to cardiac or muscular toxicity, ie: stroke, pulmonary infarction, 
dermatomyositis or polymyositis, convulsions, hypothyroidism, delirium tremens, muscular 
dystrophies.
If either the cardiac origin or the 
rhabdomyolysis is confirmed or if CPK 
> 10 ULN:
1. DISCONTINUE Investigational 
Medicinal Product administration
2. MONITOR CPK every 3 days for the 
first week then once weekly until return 
to normal or for at least 3 months
3. HOSPITALIZATION should be 
considered
If the cardiac origin or the rhabdomyolysis is 
ruled out and if CPK 10 ULN:
MONITOR CPK every 3 days for the first week 
then once weekly until return to normal or for 
at least 3 months
Muscular symptoms (myalgia, pain, weakness, 
dark urines)
Systematic CPK assessment as per 
protocol
Perform CPK
SUSPICION OF RHABDOMYOLYSIS
Suspicion of rhabdomyolysis is to be recorded as AE only if at least one of the criteria listed in Section 10.4.3 
is met
 
Suspicion of rhabdomyolysis is to be recorded as AE only if at least one of the criteria listed in the 
General guidelines for reporting adverse events in Section 10.4.2 is met. 
Due to single dose regimen, instructions regarding IMP discontinuation/resumption do not apply. 
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STATISTICAL ANALYSIS PLAN 
DRI12805 
A RANDOMIZED, DOUBLE-BLIND, PHASE IIB STUDY TO 
INVESTIGATE THE EFFICACY, SAFETY, TOLERABILITY AND 
PHARMACOKINETICS OF A SINGLE DOSE REGIMEN OF FERROQUINE 
(FQ) WITH ARTEFENOMEL (OZ439) IN ADULTS AND CHILDREN 
WITH UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA
AUTHOR: 
 
VERSION NUMBER AND DATE: V2.0, 19DEC2019 
NCT02497612




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MODIFICATION HISTORY 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from Previous 
Authorized Version 
1.0 
19SEP2019 
Not Applicable 
2.0 
19DEC2019 
Updated to reduce the number of statistical 
outputs and focus on key outputs for the 
primary population of interest (Cohort 3 and 
4). 
 
 
 


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TABLE OF CONTENTS 
Statistical Analysis Plan _____________________________________________________________ 1 
Statistical Analysis Plan Signature Page ________________________________________________ 2 
Modification History _______________________________________________________________ 3 
Table of Contents __________________________________________________________________ 4 
Abbreviations ____________________________________________________________________ 10 
1. 
Introduction ______________________________________________________________ 12 
2. 
Study Objectives ___________________________________________________________ 12 
2.1. 
Primary Objective __________________________________________________________ 12 
2.2. 
Secondary Objectives _______________________________________________________ 12 
2.3. 
Exploratory Objectives ______________________________________________________ 13 
3. 
Study Design ______________________________________________________________ 13 
3.1. 
General Description ________________________________________________________ 13 
3.1.1. Protocol Amendment 3______________________________________________________ 14 
3.1.2. Determination of sample size _________________________________________________ 16 
3.2. 
Schedule of Events _________________________________________________________ 16 
3.3. 
Changes to Analysis from Protocol ____________________________________________ 16 
3.4. 
Changes to Analysis from SAP Version 1.0 ______________________________________ 17 
4. 
Planned Analyses __________________________________________________________ 17 
4.1. 
Data Monitoring Committee (DMC) ____________________________________________ 17 
4.2. 
Interim Analyses ___________________________________________________________ 17 
4.3. 
Final Analysis ______________________________________________________________ 19 
5. 
Analysis Populations ________________________________________________________ 19 
5.1. 
Randomized Population [RND] ________________________________________________ 20 
5.2. 
Safety Populations [SAF] ____________________________________________________ 20 
5.2.1. Cohorts 3 and 4 Safety Population [C3&4SAF] ___________________________________ 20 
5.2.2. Asian Safety Population [ASAF] _______________________________________________ 21 
5.2.3. African >5 Years Safety Population [A5SAF] _____________________________________ 21 


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5.3. 
Modified Intent-to-Treat Populations __________________________________________ 21 
5.3.1. Modified Intent-to-Treat Population [mITT] _____________________________________ 21 
5.3.2. Asian Modified Intent-to-Treat Population [AmITT] _______________________________ 21 
5.3.3. African >5 Years Modified Intent-to-Treat Population [A5mITT] _____________________ 22 
5.4. 
Per-Protocol Populations [PP] ________________________________________________ 22 
5.4.1. Per-Protocol Population at Day 28 [PP28] _______________________________________ 22 
5.4.2. Per-Protocol Population at Day 42 [PP42] _______________________________________ 23 
5.4.3. Per-Protocol Population at Day 63 [PP63] _______________________________________ 23 
5.4.4. Asian Per-Protocol Populations [APP28, APP42, APP63] ___________________________ 23 
5.4.5. African >5 years Per-Protocol Populations [A5PP28, A5PP42, A5PP63] ________________ 23 
5.5. 
Pharmacokinetic Population _________________________________________________ 24 
5.6. 
Pharmacokinetic/Pharmacodynamic Population _________________________________ 24 
6. 
General Considerations _____________________________________________________ 24 
6.1. 
Reference Start Date and Study Day ___________________________________________ 24 
6.2. 
Baseline __________________________________________________________________ 24 
6.3. 
Retests, Unscheduled Visits and Early Termination Data ___________________________ 25 
6.4. 
Windowing Conventions ____________________________________________________ 25 
6.4.1. Time Windows for Efficacy Evaluation __________________________________________ 25 
6.4.2. Time Windows for Safety Evaluation ___________________________________________ 26 
6.4.2.1. Time Windows for Laboratory Evaluation _______________________________________ 27 
6.4.2.2. Time windows for Vital Signs Evaluation ________________________________________ 27 
6.4.2.3. Time windows for ECG Evaluation _____________________________________________ 27 
6.5. 
Statistical Tests ____________________________________________________________ 28 
6.6. 
Common Calculations _______________________________________________________ 28 
6.7. 
Software Version __________________________________________________________ 28 
7. 
Statistical Considerations ____________________________________________________ 28 
7.1. 
Multicenter Studies ________________________________________________________ 28 
7.2. 
Missing Data ______________________________________________________________ 29 


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7.2.1. Handling of Medication Missing/Partial Dates/Times _____________________________ 29 
7.2.2. Handling of AEs with Missing or Partial Date/Time of Onset ________________________ 29 
7.2.3. Handling of AEs when Missing Date and Time of First IMP Administration _____________ 29 
7.2.4. Handling of Missing Assessment of Relationship of AEs to IMP ______________________ 29 
7.2.5. Handling of PCSAs __________________________________________________________ 30 
7.3. 
Multiple Comparisons/ Multiplicity ____________________________________________ 30 
7.4. 
Examination of Sub-Populations and Subgroups _________________________________ 30 
8. 
Disposition and Withdrawals _________________________________________________ 31 
8.1. 
Randomization and Drug Dispensing Irregularities ________________________________ 32 
9. 
Demographic and other Baseline Characteristics _________________________________ 33 
9.1. 
Demographic Characteristics _________________________________________________ 33 
9.2. 
Other Baseline Characteristics ________________________________________________ 34 
9.2.1. Disease Characteristic at Baseline _____________________________________________ 34 
9.3. 
Surgical and Medical History _________________________________________________ 34 
10. 
Medications _______________________________________________________________ 34 
10.1. 
Prior Medications __________________________________________________________ 35 
10.2. 
Concomitant Medications ___________________________________________________ 35 
10.3. 
Anti-Malarial Medication Taken after Study Medication ___________________________ 36 
11. 
Study Medication Administration and Exposure __________________________________ 36 
11.1. 
Derivations _______________________________________________________________ 36 
12. 
Study Medication Compliance ________________________________________________ 37 
13. 
Efficacy Outcomes __________________________________________________________ 37 
13.1. 
Definitions ________________________________________________________________ 37 
13.2. 
Objectives ________________________________________________________________ 38 
13.3. 
Crude and PCR-adjusted ACPR Outcome Derivation _______________________________ 39 
13.4. 
Efficacy Analysis and Sub-populations __________________________________________ 42 
13.5. 
Primary Analysis of Primary Efficacy Variable(s) __________________________________ 44 
13.5.1. Statistical Analysis _________________________________________________________ 44 


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13.5.2. Additional Analysis of Primary Variables ________________________________________ 46 
13.5.2.1. 
Crude and PCR-adjusted ACPR ____________________________________________ 46 
13.5.2.2. 
ETF, LCF and LPF _______________________________________________________ 46 
13.6. 
Analysis of Secondary Efficacy Variable(s) _______________________________________ 47 
13.6.1. PCR-adjusted ACPR at Days 42 and 63, and Crude ACPR at Day 28, 42 and 63 __________ 47 
13.6.2. Kaplan-Meier Analysis for Time to Re-emergence, Recrudescence and Re-infection _____ 47 
13.6.3. Parasite Clearance Time (PCT) (hours) __________________________________________ 48 
13.6.4. Fever Clearance Time (FCT) (hours) ____________________________________________ 49 
13.6.5. Parasite Reduction Ratio ____________________________________________________ 50 
13.6.5.1. 
Parasite Clearance Parameters ___________________________________________ 50 
13.6.6. Parasitaemia ______________________________________________________________ 51 
13.7. 
Analysis of Pharmacokinetic Parameters ________________________________________ 51 
13.8. 
Analysis of Pharmacodynamic Parameters ______________________________________ 52 
13.8.1. Relationship between ACPR and Exposure to OZ439/FQ ___________________________ 52 
13.8.2. Relationship between Observed PK Concentrations and ECG Parameters _____________ 52 
13.8.3. Exploratory Plots ___________________________________________________________ 53 
13.8.4. Modeling: Linear Model _____________________________________________________ 54 
13.8.5. Model Averaging ___________________________________________________________ 55 
13.9. 
Analysis of Exploratory Efficacy Variables _______________________________________ 55 
13.9.1. Kaplan-Meier Analysis for the Risk of Having Gametocytes _________________________ 55 
13.9.2. Kelch-13 Genotype _________________________________________________________ 56 
13.9.3. Clinical Signs And Symptoms Of Malaria ________________________________________ 57 
13.9.4. Further Exploratory Analysis _________________________________________________ 57 
14. 
Safety Outcomes ___________________________________________________________ 58 
14.1. 
Observation Period _________________________________________________________ 58 
14.2. 
Potentially Clinically Significant Abnormality (PCSA) ______________________________ 58 
14.3. 
Adverse Events ____________________________________________________________ 59 
14.3.1. Adverse Event Observation Period ____________________________________________ 59 


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14.3.2. General Conventions _______________________________________________________ 59 
14.3.3. All TEAEs _________________________________________________________________ 60 
14.3.3.1. 
Severity ______________________________________________________________ 60 
14.3.3.2. 
Relationship to Study Medication _________________________________________ 61 
14.3.4. TEAEs Leading to Discontinuation of Study Medication ____________________________ 61 
14.3.5. Serious Adverse Events ______________________________________________________ 61 
14.3.6. Adverse Events Leading to Death ______________________________________________ 62 
14.3.7. Adverse Events of Special Interest _____________________________________________ 62 
14.3.8. General AEs Listings ________________________________________________________ 63 
14.4. 
Deaths ___________________________________________________________________ 63 
14.5. 
Laboratory Evaluations ______________________________________________________ 63 
14.5.1. General Conventions _______________________________________________________ 64 
14.5.2. Descriptive Statistics ________________________________________________________ 64 
14.5.3. Analyses of Abnormalities ___________________________________________________ 65 
14.5.4. Drug-Induced Liver Injury ____________________________________________________ 65 
14.5.5. General Laboratory Listings __________________________________________________ 66 
14.6. 
ECG Parameters ___________________________________________________________ 66 
14.6.1. General Conventions _______________________________________________________ 66 
14.6.2. Descriptive Statistics ________________________________________________________ 67 
14.6.3. Analyses of Abnormalities ___________________________________________________ 67 
14.6.4. Analysis of QTc Prolongation _________________________________________________ 67 
14.6.5. General ECG Listings ________________________________________________________ 67 
14.7. 
Vital Signs and Physical Measurements _________________________________________ 68 
14.7.1. General Conventions _______________________________________________________ 68 
14.7.2. Descriptive Statistics ________________________________________________________ 68 
14.7.3. Analyses of Abnormalities ___________________________________________________ 68 
14.7.4. General Vital Sign and Physical Measurements Listings ____________________________ 68 
14.8. 
Physical Examination _______________________________________________________ 69 


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15. 
References ________________________________________________________________ 70 
APPENDIX 1. 
Programming Conventions for Outputs __________________________________ 71 
Dates & Times ___________________________________________________________________ 71 
Spelling Format __________________________________________________________________ 71 
APPENDIX 2. 
Partial Date Conventions ______________________________________________ 71 
Algorithm for TEAEs _______________________________________________________________ 71 
Algorithm for Prior/ Concomitant Medications _________________________________________ 72 
APPENDIX 3. 
Potentially Clinically Significant Abnormalities Ariteria ______________________ 73 
PCSA Definition for Laboratory Parameters ____________________________________________ 73 
PCSA Definition for ECG parameters __________________________________________________ 76 
PCSA Definition for Vital Signs Parameters ____________________________________________ 78 
APPENDIX 4. 
Power and Sample Size _______________________________________________ 80 
 
 
 


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ABBREVIATIONS 
 
ACPR 
Adequate Clinical and Parasitological Response  
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
AST 
Aspartate Aminotransferase  
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BDR 
Blinded Data Review 
BUN 
Blood Urea Nitrogen 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form  
ETF 
Early treatment failure  
FCT 
Time to fever clearance  
FQ 
Ferroquine  
HLGT 
High Level Group Term  
HLT 
High Level Term 
IA 
Interim Analysis 
IMP 
Investigational Medicinal Product 
IVRS 
Integrated Voice Recognition System 
LCF 
Late clinical failure  
LDH 
Lactate Dehydrogenase  
LLQ 
Lower Limit of Quantification 
LPF 
Late parasitological failure  
MedDRA 
Medical Dictionary for Regulatory Activities  
mITT 
modified Intent-To-Treat 
NAI 
Naturally Acquired Immunity 
PCE 
Parasite Clearance Estimator 
PCR 
Polymerase Chain Reaction 
PCSA 
Potentially Clinically Significant Abnormality  


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PCT 
Time to parasite clearance  
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PRR 
Parasite Reduction Ratio  
PT 
Preferred Term  
RBC 
Red Blood Cell  
RDT 
Rapid Diagnostic Test  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SoC 
Standard of Care 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper Limit of Normal 
ULQ 
Upper Limit of Quantification 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
 
 


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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy, safety, 
pharmacokinetics (PK), pharmacokinetic/pharmacodynamics (PK/PD) and genotyping data for Protocol 
DRI12805 (Compounds: SSR97193/ferroquine [FQ] in association with artefenomel [OZ439]). It describes the 
data to be summarized and analyzed, including specifics of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on Amended Protocol No. 03 (i.e. integrating Protocol Amendment 
03), dated 10 April 2019. 
A Blinded Data Review (BDR) plan, defining populations for the interim and final analyses will be created to 
compliment this SAP. A separate Data Monitoring Committee (DMC) SAP is contained within the DMC Charter 
Version 5.0, dated 1 July 2019. Separate analysis plans will also be produced for the PK-ACPR analyses. 
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
The primary objective is to determine whether a single dose combination of OZ439/FQ is an efficacious treatment 
for uncomplicated P. falciparum malaria in adults and children. 
2.2. SECONDARY OBJECTIVES 
The secondary objectives are: 
 
To evaluate the efficacy of OZ439/FQ: 
• 
To determine the incidence of recrudescence and re-infection. 
• 
To determine the time of fever and parasite clearances. 
 
To evaluate the safety and tolerability of OZ439/FQ in adults and children. 
 
To evaluate the pharmacokinetics of OZ439/FQ: 
• 
To characterize the pharmacokinetics of OZ439 in plasma, FQ and its active metabolite SSR97213 in 
blood. 
• 
To determine the blood/plasma ratio for FQ and SSR97213 in some patients at limited time points in 
selected sites. 


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2.3.  EXPLORATORY OBJECTIVES 
The exploratory objectives are to further explore efficacy of OZ439/FQ: 
• 
To evaluate the proportion of patients with gametocytes at each parasitological assessment. 
• 
To characterize gametocyte carriage. 
• 
To evaluate the relationship between Adequate Clinical and Parasitological Response (ACPR) and 
exposure to OZ439/FQ. 
• 
To explore the relationship between Kelch-13 genotype and parasite clearance kinetics. 
• 
To explore in vitro drug resistance of P. falciparum infecting patients >14 years old in Vietnamese sites. 
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
This is a multicenter, multinational, randomized, double-blind, single-dose, 3 to 4 dose-regimen study in patients 
with uncomplicated P. falciparum malaria. Adults and children were to be included sequentially in four cohorts 
through a progressive age step-down procedure and FQ dose step-up procedure. Dose groups could be dropped 
during the study following DMC decision or futility analyses. 
 
The cohorts are defined as follows: 
• 
Cohort 1: 14 years<age <70 years and body weight ≥35 kg 
• 
Cohort 2: 5 years<age≤14 years 
• 
Cohort 3: 2 years<age≤5 years 
• 
Cohort 4: 6 months<age≤2 years 
 
After a screening phase of up to 1 day, patients were to be centrally randomized to one of 4 possible treatment 
groups (OZ439/FQ: 800/400 mg, 800/600 mg, 800/900 mg and 800/1200 mg) via Integrated Voice Recognition 
System (IVRS) using permuted block randomization schedules. Inclusion of cohorts of decreasing age was based 
on review of safety data from the preceding higher age group by the DMC, as shown in Figure 1. Recruitment to 
the 800/1200 mg dose was dependent on a positive safety assessment by the DMC following review of the 
PK-QTc relationship of treatments 1, 2 and 3 in Cohort 1a and treatments 3 and 4 in Cohort 1b. 
This randomization was to be stratified by region, (however due to the decision to stop recruitment in Asia [see 
Section 3.1.1], no patients from Asia were recruited into cohorts 3 and 4 and therefore this was not required after 
cohort 2) and within Africa, age class (14-70 years/Africa; 5-14 years/Africa; 2-5 years/Africa; 6 months -
2 years/Africa). 
 
 
For patients ≥35 kg: 


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Scenario A: design with 3 treatment arms (OZ439/FQ 800/400 mg, 800/600 mg and 800/900 mg) if, following 
DMC review of Cohort 1a, the 4th treatment arm (OZ439/FQ 800/1200 mg) is not started or, is stopped following 
DMC review at the end of Cohort 1b. 
 
Scenario B: design with 4 treatment arms (OZ439/FQ 800/400 mg, 800/600 mg, 800/900 mg and 800/1200 mg) 
if, following DMC review of Cohort 1a & 1b respectively, the 4th treatment arm (OZ439/FQ 800/1200 mg) is 
started and is continued after DMC reviews. 
 
• 
Treatment arm 1 = OZ439 800 mg - FQ 400 mg 
• 
Treatment arm 2 = OZ439 800 mg - FQ 600 mg 
• 
Treatment arm 3 = OZ439 800 mg - FQ 900 mg 
• 
Treatment arm 4 = OZ439 800 mg - FQ 1200 mg (if the DMC agrees to proceed with this dose). 
 
For patients <35 kg: 
Weight-adjusted doses for OZ439 predicted to achieve exposure (based on Area under the curve [AUC]) not 
exceeding 1.5-fold that of a 60 kg adult and not exceeding that of the lightest adult (35 kg) for the lightest patient 
in each weight band. 
 
Weight adjusted doses for FQ predicted to achieve FQ and SSR97213 exposure (based on mean Cmax and AUC) 
not exceeding 1.3-fold that of a lightest adult (35 kg) for the lightest patient in each weight band. 
 
This study is an adaptive design with pre-defined interim analyses to drop doses with a high probability of futility 
early. Assuming the dose is not dropped early, recruitment will continue until a maximum of 150 evaluable 
patients per treatment arm is reached. Figure 1 shows the age step-down & FQ dose step-up procedures. 
 
Patients likely to have higher naturally acquired immunity (NAI) i.e. African patients >5 years old to <70 years 
old were only to be considered for safety review, and patients likely to have lower NAI (African children ≤5 years 
and all Asian patients) were to be considered for safety review, and also for interim futility analyses. 
3.1.1. 
PROTOCOL AMENDMENT 3 
Recruitment was stopped in Asia (Vietnam) on the guidance of the DMC, due to a low efficacy rate in this 
population. As a result of the study stop in Asia, Protocol Amendment 3 redefined the efficacy populations for the 
interim and final efficacy analyses to include only African children ≤5 years of age (i.e. Cohorts 3 and 4). Asian 
patients were excluded from the efficacy populations. A total of 21 Asian patients were recruited prior to the 
recruitment stop. The terms low NAI and high NAI used in the Protocol will not now be used within the Clinical 
Study Report (CSR) as further detailed in Section 3.4 of this SAP. 
 
Thus, in the scenario where no dose regimen is dropped, a maximum of approximately 662 African patients 
(62 patients in Cohorts 1 and 2 and about 150 patients per dose group in Cohorts 3 and 4) will be recruited and 


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randomized from approximately 18 sites, to achieve approximately 600 African patients <5 years of age evaluable 
for the primary endpoint of Polymerase Chain Reaction (PCR)-adjusted ACPR at Day 28 (see Section 12.1 for 
definition of PCR-adjusted ACPR, and Section 5.4 for definition of patients evaluable for PCR-adjusted ACPR), 
plus the additional 21 Asian patients. 
 
Figure 1: DMC safety review for age step-down & FQ dose step-up procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*:A minimum number of 10 patients (Cohort 1) per treatment arm for DMC safety & PK/QTc evaluation. 
**: A minimum number of 5 patients (Cohort 2) per treatment arm for DMC review 
***: A minimum number of 8 patients (Cohorts 3 & 4) per treatment arm for DMC review 


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After all these age step-down stages, the recruitment will be fully open. Approximately 62 patients will be recruited in 
Cohorts 1 and 2 for Scenario B. The remaining patients will comprise Cohorts 3 and 4. At least 10% of the lower NAI 
population will come from African patients of Cohort 4 (patients 6 months <2 years, Protocol Amendment 3). 
****: DMC review before starting Cohort 2 recruitment will be made on pooled data (Cohorts 1a & 1b) with a total number 
of patients N ≥42. 
3.1.2. 
DETERMINATION OF SAMPLE SIZE 
Given the adaptive nature of the study design, the total number of patients to be recruited can only be estimated. 
Simulations for different PCR-adjusted ACPR response rates at Day 28 showed that a sample size of 
150 evaluable patients per treatment arm will provide ≥80% probability to reject the null hypothesis (H0: 
probability of PCR-adjusted ACPR at Day 28 ≤0.90) at the final analysis, for the true rate of 96.4%. See table in 
Appendix 4 for details on power for different sample size and success rate hypotheses. 
 
Recruitment will continue until each treatment arm is deemed to be futile or until 150 evaluable patients per 
treatment arm is reached. 
 
In addition, a minimum of 15 African patients >5 years per treatment arm (likely to have higher NAI and therefore 
not included in the efficacy analysis populations i.e. the modified Intent-To-Treat [mITT] and Per Protocol [PP] 
populations) will be included for the DMC safety review. 
3.2. SCHEDULE OF EVENTS 
Schedule of events can be found in Section 1.1 of the Protocol. 
3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
The following items will differ in this SAP from what is specified in Protocol Amendment 3: 
• 
The final analysis will include patient data from doses that were stopped early for futility. Final efficacy 
results may be different from the Interim Analysis (IA) because recruitment may continue during the IA. 
• 
The Protocol defines a “lower” NAI population and a “higher” NAI population. Since Asian patients are 
now excluded from the main analysis population, these population names are no longer useful and are 
therefore not used in the SAP. Instead, we define the efficacy populations (mITT and PP) which are 
based on the protocol defined “lower” NAI population in Africa. A separate population with African 
>5 years is defined based on the protocol defined “higher” NAI population. 
• 
The Safety population defined in the SAP differs from the Protocol definition in that it also includes 
Asian patients. Safety sub-populations are, however, defined in the SAP, and the sum of the Cohort 3 
and 4 Safety (C3&4SAF) and African >5 years Safety (A5SAF) sub-populations equate with the safety 
population described in the Protocol. 


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• 
2 separate PK/PD populations will be used for analysis of PK-ACPR and PK-QTc. This was ambiguous 
in the Protocol. The PK-QTc population is defined in this document and the PK-ACPR population is 
defined in a separate analysis plan. 
• 
Given sub-populations have been defined, no by cohort summaries are planned. 
• 
Protocol Section 11.2 defined screened patients as “as any patient who signed the informed consent and 
met the inclusion criteria” while in the SAP, Section 8 defines screened patients as all patients who 
signed informed consent irrespective of adherence to eligibility criteria. 
• 
The Protocol specifies that the table of treatment-emergent AEs (TEAEs) will be sorted by the 
internationally agreed System Organ Class (SOC) order then by Preferred Terms (PTs) sorted in 
alphabetical order within SOC, however this ordering is not logical, therefore these tables will be sorted 
by the internationally agreed SOC order then by decreasing frequency of PTs in the total column. 
• 
QTcB parameter is added as ECG parameter. 
3.4. CHANGES TO ANALYSIS FROM SAP VERSION 1.0 
The statistical analyses were reduced to focus the analysis on the key outputs of relevance for the stage of 
development, and for the primary population of interest (Cohort 3 and 4). 
4. PLANNED ANALYSES 
The following analyses will be performed for this study: 
• 
Analyses for DMC meetings (refer to DMC SAP contained within DMC Charter) 
• 
Interim Analyses (test for futility; Section 4.2) 
• 
Final Analysis (efficacy outcomes: Section 12, safety outcomes: Section 13) 
4.1. DATA MONITORING COMMITTEE (DMC) 
A DMC SAP describing the methodology and presentation of results for the DMC meetings is contained within 
the DMC Charter Version 5.0, dated 1st July 2019. 
4.2. INTERIM ANALYSES 
Timing 
 
As planned in the Protocol, up to 4 interim futility analyses will be performed during the conduct of the study to 
stop recruitment in treatment arm(s) deemed to be futile. 
 
Futility will be assessed in the PP population and is based on the primary endpoint of the study (PCR-adjusted 


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ACPR at Day 28). The PP population evaluable for the PCR-adjusted ACPR excludes patients with re-infection as 
described in section 13.1. 
 
The first IA will be performed on approximately 50 evaluable patients per treatment arm, who must have 
completed the 28-day efficacy assessment (within the allowed time-window of Day 28, see Table A in 
Section 6.4.1). 
 
Based on an estimated proportion of patients expected to be non-evaluable for the primary endpoint, 
approximately 220 randomized patients would be needed in order to have approximately 200 evaluable patients for 
the primary efficacy endpoint. 
 
Thereafter, subsequent interim futility analyses will be performed when each additional 25 evaluable patients per 
treatment arm are available (i.e. 75 patients/treatment arm for the 2nd IA, 100 patients/treatment arm for the 3rd IA, 
125 patients/treatment arm for the 4th IA). Since the number of randomized patients to achieve the target number 
of patients evaluable for the primary endpoint may change during the study dependent on geography and season 
etc., this will be tracked during the study to estimate the timing of each IA. 
 
Recruitment will continue until each treatment arm is deemed to be futile or until a maximum of approximately 
150 evaluable patients per remaining treatment arm reach the Day 28 evaluation point. 
 
At each IA, a treatment arm is stopped for futility if the posterior probability of H0 (that is, response rate is below 
90%) given the data accumulated at the look for the treatment arm in question is too large, that is, Pr(H0|data) 
≥0.30. The treatment arm advances to the next stage if the above condition is not met (even if the observed 
response rate is 95% or greater). 
 
A data cut off will be applied before each interim and DMC analysis, the date of this cut will be discussed and 
decided upon before each delivery. 
 
The results of each interim futility analysis will be reviewed by the DMC. 
 
Method 
 
The futility for a given dose i (1≤ i ≤4) will be tested as follows: 
The observed proportion of PCR-adjusted ACPR at Day 28 in treatment arm i at the time of the IA will be treated 
as an observation from a binomial distribution, with unknown probability of success pi having a beta prior. 
To take into account initial trust (prior information) on the unknown probability of success pi, pi will be following 
an informative Beta(9.5, 0.5) prior distribution. 
 
The prior distribution of pi will then be updated in light of the observed number of PCR-adjusted ACPR at Day 28 
in the treatment arm i at the time of the IA using Bayes’ formulae, to obtain the posterior distribution of pi: 
Bêta(9.5+ ni1, 0.5+Ni- ni1), where ni1 is the number of PCR-adjusted ACPR observed at Day 28 out of Ni in the 


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treatment arm i. 
 
The following decision rule then will apply: 
• 
If P(X ≤ 0.9) ≥ 0.3, where X is a random variable following the posterior distribution Bêta(9.5+ ni1, 
0.5+Ni- ni1), then the treatment arm i is deemed to be futile and stopped. 
• 
If P(X ≤ 0.9) < 0.3, where X is a random variable following the posterior distribution Bêta(9.5+ ni1, 
0.5+Ni- ni1), then the treatment arm i is kept until next step. 
4.3. FINAL ANALYSIS 
All final, planned analyses identified in this SAP will be performed following finalization of this SAP, relevant set 
of the Tables, Listings and Figures shells, the final analysis population assignments, database lock and routine 
study unblinding. 
 
The final analysis is to be performed on a clean database. The database will be considered clean when: 
• 
All outstanding data issues and queries resolved. 
• 
All unresolvable data issues documented in the data handling report (DHR) from Data Management. 
• 
All coding of medications and adverse events (AEs) completed. 
• 
Serious adverse events (SAEs) reconciliation completed. 
• 
All reconciliation of vendor data with the electronic Case Report Form (eCRF) data completed 
successfully. 
 
At the final analysis, the null hypothesis will be tested and binary endpoint for the primary outcome; 
PCR-adjusted ACPR at Day 28, will be analyzed in a frequency table i.e. frequency, percentage and exact 
binomial 95% confidence intervals (two-sided by using Clopper-Pearson method for calculating binomial 
confidence intervals) on the PP population by treatment arm. Efficacy of the treatment arm is demonstrated if the 
lower limit of the exact 95% confidence interval of PCR-adjusted ACPR rate is >90% (see Section 13: Efficacy 
Outcomes for further details). 
5. ANALYSIS POPULATIONS 
Analysis populations are described below. Further details on the allocation of patients to analysis populations will 
be described in the BDR plan for this study. Agreement and authorization of patients included/ excluded from 
each analysis population will be conducted prior to the unblinding of the study and will be documented in a BDR 
report. 
 
For any patient randomized more than once, only the data associated with the first randomization will be used in 
any analysis population. The safety experience associated with any later randomization will be assessed 


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separately. 
5.1. RANDOMIZED POPULATION [RND] 
The randomized population (RND) includes all patients who have given their informed consent and who have 
been allocated to a randomized treatment regardless of whether the treatment kit was used or not. For analyses and 
displays based on RND population, patients will be classified according to the treatment to which they were 
randomized. 
5.2. SAFETY POPULATIONS [SAF] 
The safety population (SAF) will contain all patients in the RND population who receive at least one dose or part 
of a dose of the study medication. Patients will be classified according to the treatment actually received. 
 
In addition, randomized patients for whom it is unclear whether they took the study medication will be included in 
the SAF population as randomized. 
 
In case of an OZ439 re-dosing mistake (e.g., erroneous kit dispensing at protocol planned re-dosing, protocol 
planned re-dose not performed, or re-dose performed wrongly), patients will be presented in the treatment group 
corresponding to the initial dosing. Such cases will be tracked through quantitative deviations. 
 
For patients erroneously re-dosed with FQ, patients will be presented in the treatment group with the FQ dose 
which is closest to the sum of the FQ doses actually administered to the patient. Such cases can only be tracked 
through qualitative deviations. 
 
Non-randomized but treated patients will not be part of the SAF population. However, their safety data will be 
listed separately. Patients taking only a fraction of their randomized treatment but for whom the actual amount 
received is unknown will be presented per treatment, as randomized. 
 
 
For the purpose of statistical analysis and presentation of safety data, patients will be summarized using the 
sub-populations described below: 
5.2.1. 
COHORTS 3 AND 4 SAFETY POPULATION [C3&4SAF] 
Includes all African patients <5 years of age valid for the SAF population. Patients will be classified according to 
the treatment actually received. 


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5.2.2. 
ASIAN SAFETY POPULATION [ASAF] 
Includes all Asian patients valid for the SAF population. Patients will be classified according to the treatment 
actually received. 
5.2.3. 
AFRICAN >5 YEARS SAFETY POPULATION [A5SAF] 
Includes all African patients aged >5 years valid for the SAF population. Patients will be classified according to 
the treatment actually received. 
5.3. MODIFIED INTENT-TO-TREAT POPULATIONS 
5.3.1. 
MODIFIED INTENT-TO-TREAT POPULATION [MITT] 
The mITT population includes all randomized African patients ≤5 years with parasitologically confirmed P. 
falciparum malaria at screening/ baseline, who received at least the single administration OZ439/FQ, and 
excluding patients who required rescue treatment due to vomiting during investigational medicinal product (IMP) 
administration. (Patients required rescue treatment if they vomited during or after FQ dosing and before OZ439 
administration, or if they vomited within 5 minutes of OZ439 re-dosing after already having vomited within 
5 minutes of the first OZ439 dosing). 
African patients >5 years and Asian patients will not belong to mITT. 
 
For analyses and displays, patients will be classified according to the randomized treatment regardless of actual 
treatment received. 
 
For the purpose of statistical analysis and presentation of efficacy data, patients will also be summarized using the 
sub-populations described below. Their derivation will follow the same rules as for the main population of interest 
i.e. the mITT. 
5.3.2. 
ASIAN MODIFIED INTENT-TO-TREAT POPULATION 
[AMITT] 
Includes all patients valid for the Asian safety population (ASAF) as defined in Section 5.2.2 with 
parasitologically confirmed P. falciparum malaria at screening/ baseline, who received at least the single 
administration OZ439/FQ, and excluding patients who required rescue treatment due to vomiting during IMP 
administration. (Patients required rescue treatment if they vomited during or after FQ dosing and before OZ439 
administration, or if they vomited within 5 minutes of OZ439 re-dosing after already having vomited within 


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5 minutes of the first OZ439 dosing). Patients will be classified according to the randomized treatment regardless 
of actual treatment received. 
5.3.3. 
AFRICAN >5 YEARS MODIFIED INTENT-TO-TREAT 
POPULATION [A5MITT] 
Includes all patients valid for the African >5 years safety population (A5SAF) as defined in Section 5.2.3 with 
parasitologically confirmed P. falciparum malaria at screening/ baseline, who received at least the single 
administration OZ439/FQ, and excluding patients who required rescue treatment due to vomiting during IMP 
administration. (Patients required rescue treatment if they vomited during or after FQ dosing and before OZ439 
administration, or if they vomited within 5 minutes of OZ439 re-dosing after already having vomited within 
5 minutes of the first OZ439 dosing). Patients will be classified according to the randomized treatment regardless 
of actual treatment received. 
5.4. PER-PROTOCOL POPULATIONS [PP] 
The PP population is defined as all mITT patients without any major protocol deviations affecting efficacy up to, 
and who are evaluable for PCR-crude ACPR at a pre-defined timepoint in the study. For further information 
regarding protocol deviations please refer to the blinded data review (BDR) plan for this study. 
 
The composition of the PP populations for the primary (Day 28) and each secondary timepoint (Day 42 and 
Day 63) may differ depending on the timing of the occurrence of the major protocol deviations. 
 
For analyses and displays, patients will be classified according to the randomized treatment. 
 
Note, “evaluable for PCR-adjusted ACPR” relates to recrudescent infections only and hence treats re-infections as 
follows: Patients with re-infections occurring before the relevant endpoint day (Day 28, 42, 63) are counted as 
missing. Patients with re-infections occurring on the day of evaluation, (Day 28, 42, 63) are included in the 
population (and are counted as cured). See Table F in Section 13.3 for details of the derivation criteria of treatment 
outcome for crude and PCR-adjusted ACPR for the PP and mITT populations. 
5.4.1. 
PER-PROTOCOL POPULATION AT DAY 28 [PP28] 
The primary efficacy population will be the PP population at Day 28. This population contains all patients valid 
for the mITT population (defined in Section 5.3.1) without major protocol violations impacting efficacy 
assessment, who are evaluable for PCR-crude ACPR at Day 28.  
 
Patients with other species of malaria infection at baseline (including mixed infection with P. falciparum) are 


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excluded from the PP28 population. 
5.4.2. 
PER-PROTOCOL POPULATION AT DAY 42 [PP42] 
The PP population at Day 42 contains all patients valid for the mITT population (defined in Section 5.3.1) without 
major protocol violations impacting efficacy assessment, who are evaluable for PCR-crude ACPR at Day 42. 
 
Patients with other species of malaria infection at baseline (including mixed infection with P. falciparum) are 
excluded from the PP42 population. 
5.4.3. 
PER-PROTOCOL POPULATION AT DAY 63 [PP63] 
The PP population at Day  63 contains all patients valid for the mITT population (defined in Section 5.3.1) 
without major protocol violations impacting efficacy assessment, who are evaluable for PCR-crude ACPR at 
Day 63. 
 
Patients with other species of malaria infection at baseline (including mixed infection with P. falciparum) are 
excluded from the PP63 population. 
 
 
For the purpose of statistical analysis and presentation of efficacy data, patients will also be summarized using the 
sub-populations described below. Their derivation will follow the same rules as for the main population of interest 
i.e. the PP28, PP42 and PP63. 
5.4.4. 
ASIAN PER-PROTOCOL POPULATIONS [APP28, 
APP42, APP63] 
Includes all patients valid for the Asian mITT population (AmITT) as defined in Section 5.3.2 without major 
protocol deviations affecting efficacy up to, and who are evaluable for PCR-crude ACPR at a pre-defined 
timepoint in the study. 
5.4.5. 
AFRICAN >5 YEARS PER-PROTOCOL POPULATIONS 
[A5PP28, A5PP42, A5PP63] 
Includes all patients valid for the African >5 years mITT population (A5mITT) as defined in Section 5.3.3 without 
major protocol deviations affecting efficacy up to, and who are evaluable for PCR-crude ACPR at a pre-defined 
timepoint in the study. 


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5.5. PHARMACOKINETIC POPULATION 
The PK population will comprise all treated patients (SAF) with at least one evaluable blood sample for PK post 
double-blind IMP administration and with adequate documentation of date of dosing and date of sampling. 
5.6. PHARMACOKINETIC/PHARMACODYNAMIC POPULATION 
There are two PK/PD populations. An efficacy PK/PD population for exploration of the relationship between 
concentration and ACPR, and a PK/PD ECG population for exploration of the relationship between concentration 
and ECG. The efficacy PK/PD population will be defined in a separate analysis plan and will be reported in a 
separate PK/PD report. The PK/PD ECG population will contain all patients included in the PK population and 
having a baseline QTc assessment and at least one post-baseline assessment in QTc evaluation regarding the three 
PK/QTc analyses (one for Cohort 1a, a second polling Cohorts 1a & 1b, and final analysis including all cohorts). 
6. GENERAL CONSIDERATIONS 
6.1. REFERENCE START DATE AND STUDY DAY 
Reference start date is defined as the day of the first dose of study medication (Day 0 is the day of the first dose of 
study medication). For patients randomized but not treated, reference start date is defined as the day of 
randomization. Study Day will be calculated from the reference start date and will be used to show start/ stop day 
of assessments and events. Study Day will appear in every listing where an assessment date or event date appears: 
Study Day = (date of event – reference date). 
 
In the situation where the event date is partial or missing, the date will appear partial or missing in the listings, and 
Study Day, and any corresponding durations will be presented based on the imputations specified in Appendix 2 
Partial Date Conventions. 
6.2. BASELINE 
Unless otherwise specified, baseline is defined as the value collected on Day -1 (or Day 0 if screening and IMP 
administration are performed on the same day). If any of the scheduled baseline tests are repeated, the last 
rechecked values will be considered as baselines, provided they were done before the start of IMP administration. 
 
For patients randomized but not treated, baseline is defined as the last non-missing measurement taken on or 
before the reference start date. 


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6.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION 
DATA 
Unscheduled visit measurements of safety data, i.e. laboratory data, vital signs, and electrocardiogram (ECG), will 
be included in the by-time point summaries, and will be used for computation of baseline, worst values, and 
potentially clinically significant abnormalities (PCSAs). 
 
In the case of a retest (same visit number assigned), the measurement nearest the visit date will be used for by-visit 
summaries.  
 
Early termination data will be mapped to the next available visit number for by-visit summaries and also reported 
together as a separate End of Treatment visit. 
 
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
6.4. WINDOWING CONVENTIONS 
Time windows are used to assigned protocol planned time points based on the actual timing of the considered 
assessment rather than based on the theoretical timing of the visit it comes from. 
 
The actual hour of an assessment (scheduled or unscheduled) for which the date and time are available is 
calculated in number of hours from the date and time of IMP start as: (date & time of assessment - date & time of 
IMP start). 
 
While the actual day of an assessment is calculated in number of days from the date of IMP start as: (date of 
assessment - date of IP start). 
 
In case, the actual timing is outside below time windows, then the assigned time point comes down to the actual 
timing. 
 
Handlings of assessments performed outside defined time windows will depend on the analyses and are detailed in 
dedicated sections, as well as handling of several assessments performed within the same time window. 
6.4.1. 
TIME WINDOWS FOR EFFICACY EVALUATION 
Before Day 4, time points assigned to scheduled or unscheduled parasitemia and to concomitant - i.e. from the 
same visit - body temperature, will be based on the actual hour of the blood thick film and allowed time windows, 
as specified in Table A. In case, the blood thick film is missing at a visit, but body temperature assessment is 


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available, then the theoretical time point of the visit will be assigned because only the date (no time) of assessment 
is collected for body temperature. 
Table A: 
Time windows definition for assessments performed on or before Day 3 
Protocol planned 
time point 
Allowed deviation from 
targeted hour 
Corresponding window of time for blood 
film actual hour 
Hour 6 
-1/+2 hours 
5 hours to 8 hours 
Hour 12* 
-1/+2 hours 
11 hours to 14 hours 
Hour 18 
-1/+2 hours 
17 hours to 20 hours 
Hour 24 (Day 1) 
-1/+2 hours 
23 hours to 26 hours 
Hour 36 (Day 1) 
-2/+3 hours 
34 hours to 39 hours 
Hour 48 (Day 2) 
± 3 hours 
45 hours to 51 hours 
Hour 72 (Day 3) 
± 4 hours 
68 hours to 76 hours 
* Scheduled for cohort 1 only. 
 
From Day 4, time points assigned to scheduled or unscheduled parasitemia or body temperature will be based on 
the actual day of assessment and allowed time windows, as specified in Table B. 
Table B: 
Time windows definition from Day 4 
Protocol planned time 
point 
Allowed deviation from 
targeted day 
Allowed window of time for day of 
assessment 
Day 5 
± 1 day 
4 days to 6 days 
Day 7 
+ 1 day 
7 days to 8 days 
Day 10 
± 1 day 
9 days to 11 days 
Day 14 
- 2 days 
12 days to 14 days 
Day 15-18 
Not applicable 
15 days to 18 days 
Day 21 
± 2 days 
19 days to 23 days 
Day 24-25 
Not applicable 
24 days to 25 days 
Day 28 
- 2 days / + 10 days 
26 days to 38 days 
Day 42 
- 3 days / + 17 days 
39 days to 59 days 
Day 63 
- 3 days / + 17 days 
60 days to 80 days 
6.4.2. 
TIME WINDOWS FOR SAFETY EVALUATION 
In the case where more than one assessment of a safety parameter falls within the same time window, only the 
assessment closest to the targeted time point will be used. In cases where two assessments are equally close to the 
targeted time point, the first assessment will be used. 


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6.4.2.1. TIME WINDOWS FOR LABORATORY EVALUATION 
Table C: 
Time windows for laboratory evaluation 
Protocol planned time point 
Time window for actual day of laboratory assessment 
Baseline 
Before IMP start 
Day 3 
After IMP start to Day 4 
Day 7 
Day 5 to Day 10 
Day 14 
Day 11 to Day 17 
Day 21* 
Day 18 to Day 24 
Day 28 
Day 25 to Day 31 
* only for patients >5 years old. 
6.4.2.2. TIME WINDOWS FOR VITAL SIGNS EVALUATION 
Only the date (no time) of assessment is collected for vital signs, therefore, time windows are only defined for 
actual timing greater or equal to 4 days. For lower timings, the eCRF visit will be used. In particular, baseline will 
be Visit 1 assessment. 
Table D: 
Time windows for vital signs evaluation 
Protocol planned time point 
Time window for actual day of vital sign assessment 
Day 7 
Day 4 to Day 8 
Day 10 
Day 9 to Day 11 
Day 14 
Day 12 to Day 17 
Day 21 
Day 18 to Day 24 
Day 28 
Day 25 to Day 34 
Day 42 
Day 35 to Day 44 
Day 63 
Day 45 to Day 69 
6.4.2.3. TIME WINDOWS FOR ECG EVALUATION 
Table E: 
Time windows for ECG  evaluation 
Protocol planned time point 
Time window for ECG assessment timing 
Baseline 
Before IMP start 
Hour 2 
After IMP end to <3 hours 


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Protocol planned time point 
Time window for ECG assessment timing 
Hour 4 
3 hours to <5 hours 
Hour 6 
5 hours to <7 hours 
Hour 8 
7 hours to <10 hours 
Hour 12 
10 hours to <18 hours 
Hour 24 
18 hours to <36 hours 
Day 3 
36 hours to <Day 5 
Day 7 
Day 5 to <Day 9 
Using the date and time of the first record from the triplicate ECG before Day 4, and using only the date 
thereafter. 
6.5. STATISTICAL TESTS 
The default significant level will be 5%; confidence intervals will be 95%, all tests will be two-sided, and no 
adjustment for multiplicity will be applied, unless otherwise specified in the description of the analyses. 
6.6. COMMON CALCULATIONS 
Demographic formulas: 
• 
Age at randomization in years: (date of randomization - date of birth)/365.25 
• 
Age at randomization in months: (date of randomization - date of birth)/30.4375 
• 
Time from first diagnosis of current malaria infection in days: (date of randomization - date of diagnosis 
of current malaria infection) 
 
Change from baseline: (test value at visit x – baseline value) 
Percent change from baseline: (change from baseline / baseline value)*100 
6.7. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4  
7. STATISTICAL CONSIDERATIONS 
7.1. MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple centers internationally. Randomization to 


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treatment arms within Cohort 2 is stratified by region. 
7.2. MISSING DATA 
Missing efficacy data will be handled as described in Section 13.3 and in each specific subsection of Section 13 of 
this SAP. 
 
 
For categorical variables, patients with missing data will not be included in calculations of percentages unless 
otherwise specified. When relevant, the number of patients with missing data will be presented. 
7.2.1. 
HANDLING OF MEDICATION MISSING/PARTIAL 
DATES/TIMES 
No imputation of medication start/end dates will be performed. If a medication date is missing or partially missing 
the conventions detailed in Appendix 2 will be used to assign the medication to a period (prior, concomitant or 
post treatment), note medications can occur in more than one period. 
7.2.2. 
HANDLING OF AES WITH MISSING OR PARTIAL 
DATE/TIME OF ONSET 
No imputation of adverse event start/end dates will be performed. If an AE date is missing or partially missing the 
conventions detailed in Appendix 2 will be used to assign the AE as treatment-emergent or not. 
7.2.3. 
HANDLING OF AES WHEN MISSING DATE AND TIME 
OF FIRST IMP ADMINISTRATION 
When the date and time of the first IMP administration is missing, all AEs that occurred on or after the day of 
randomization should be considered as TEAEs. The exposure duration should be kept as missing. 
7.2.4. 
HANDLING OF MISSING ASSESSMENT OF 
RELATIONSHIP OF AES TO IMP 
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be assumed and the AE 
considered as such in the frequency tables of possibly related AEs, but no imputation should be done at the data 


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level. 
7.2.5. 
HANDLING OF PCSAS 
If a patient has a missing baseline, he will be grouped in the category “normal/missing at baseline”. 
 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and the other on a 
threshold value, with the first condition being missing, the PCSA will be based only on the second condition. 
 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this threshold if the 
normal range is missing; e.g. for eosinophils the PCSA is >0.5 GIGA/L or > Upper Limit of Normal (ULN) if 
ULN ≥0.5 GIGA/L; when ULN is missing, the value 0.5 should be used. 
 
Measurements flagged as invalid by the laboratory will not be summarized or considered in the computation of 
PCSA values. 
7.3. MULTIPLE COMPARISONS/ MULTIPLICITY 
No adjustment for multiplicity of comparisons will be applied for primary or for secondary analyses. The overall 
type I error rate may therefore exceed 5%. 
7.4. EXAMINATION OF SUB-POPULATIONS AND SUBGROUPS 
Summaries will be produced for the following sub-populations as described in Section 13.4: 
• 
Cohorts 3 and 4 combined 
• 
Asian 
• 
African >5 years 
 
It should be noted that the study was not designed to detect treatment effect with high statistical power within sub-
populations other than the sub-population that forms the efficacy population (Cohorts 3 and 4 combined). 
 
The following subgroups will be assessed and described within the efficacy analysis sections. These subgroups 
will be used to further explore the data collected for the mITT and PP populations only (i.e. Cohort 3 and 4). 
• 
Country (Benin, Gabon, Kenya, Mozambique, Uganda, Burkina Faso)  
• 
Baseline parasitemia (≤Q1, >Q1 to ≤ Q2, >Q2 to ≤Q3, >Q3)  
• 
Age at randomization (≤2.0 years, >2.0 to <5.0 years) 
• 
Weight at screening (<7 kg, ≥7 to <10 kg, ≥10 to <15 kg, ≥15 to <24 kg) 


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8. DISPOSITION AND WITHDRAWALS 
All patients who provide informed consent will be accounted for in this study. 
Patient disposition and withdrawals, and reasons for exclusion from each analysis population and protocol 
deviations, including inclusion and exclusion criteria will be presented for the RND population. 
 
This section describes patient disposition for both patient study status and the analysis populations. 
 
Screened patients are defined as any patient who signed the informed consent. 
 
Randomized patients consist of all patients for whom there is a signed informed consent/ assent form and who 
have had a treatment kit number allocated and recorded in the IVRS database, regardless of whether the treatment 
kit was used or not. 
 
For patient study status, the total number of patients in each of the following categories will be presented in the 
CSR using summary tables Cohort 3 and 4 combined, Asian, and African >5 years separately and also overall: 
• 
Screened patients 
• 
Screen failure patients and reasons for screen failure 
• 
Non-randomized but treated patients, only if occurring 
• 
Randomized patients 
• 
Randomized but not treated patients, only if occurring 
• 
Randomized and treated patients 
• 
Patients who met criteria for established anti-malarial treatment 
• 
Patients who prematurely discontinued the study (overall and by main reason for discontinuation) 
• 
Status at last study contact (information coming from the patient status panel and computation of lost to 
follow-up status as defined below). 
 
For all categories of patients (except for the screened and non-randomized categories) percentages will be 
calculated using the number of randomized patients in the considered population as denominator in tables giving 
numbers and percentages by treatment group. This summary will also be provided by treatment group within each 
age range and country in the Cohort 3 and 4 population. 
 
A patient is considered lost to follow-up at the end of the study if he/she is not assessed using the procedure 
normally planned for the end-of-study visit and if the time from the last successful contact (from the vital patient 
status case report form) to the last protocol planned visit is greater than 3 days. 
 
All critical or major deviations potentially impacting efficacy analyses, randomization, and drug-dispensing 
irregularities, and other critical or major deviations will be summarized in tables giving numbers and percentages 
of deviations by treatment group, in the mITT population. 
 


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Additionally, the various analysis populations (e.g. safety, efficacy, pharmacokinetics, 
pharmacokinetics/pharmacodynamics, exploratory) will be summarized in a table giving numbers and percentages 
of patients by treatment group, in the randomized population. 
 
Safety populations: 
• 
Cohorts 3 and 4 Safety population 
• 
Asian Safety population 
• 
African >5 years Safety population 
 
Efficacy populations:  
• 
PP populations (at Days 28, 42 and 63 and overall)  
• 
mITT populations 
 
Pharmacokinetics populations: 
• 
PK population 
• 
PK/PD population 
 
A listing of populations with reasons of exclusion will also be provided. 
8.1. RANDOMIZATION AND DRUG DISPENSING IRREGULARITIES 
Randomization and drug-dispensing irregularities occur whenever: 
 
A randomization is not in accordance with the protocol-defined randomization method, such as a) an ineligible 
patient is randomized, b) a patient is randomized based on an incorrect stratum, c) a patient is randomized twice, or 
d) a non-existent patient is randomized. 
 
OR 
 
A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, such as a) a patient at any 
time in the study is dispensed a different treatment kit than as randomized (which may or may not contain the 
correct-as-randomized IMP), or b) a non-randomized patient is treated with IMP reserved for randomized patients. 
 
Randomization and drug-dispensing irregularities will be monitored throughout the study and reviewed on an 
ongoing basis. 
 
All randomization and drug-dispensing irregularities will be documented in the CSR. If the number of irregularities 
is large enough to make a tabular summary useful, the irregularities will be categorized and summarized among 
randomized patients (number and percentages). Non-randomized, treated patients will be described separately. 
 


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Randomization and drug-dispensing irregularities to be prospectively identified include but are not limited to: 
• 
Kit dispensation without IVRS transaction 
• 
Erroneous kit dispensation 
• 
Kit not available 
• 
Non-eligible patient randomized by error 
• 
Patient randomized twice 
• 
Stratification error 
• 
Randomization of a non-existent patient 
• 
Patient switched to another site 
9. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the RND population. 
 
No statistical testing will be carried out for demographic or other baseline characteristics. 
Continuous and qualitative variables will be summarized using descriptive statistics. Continuous data will be 
summarized using the number of available data, mean, standard deviation (SD), median, minimum, and maximum 
for each treatment group and overall. Categorical and ordinal data will be summarized using the number of 
available data, the number and percentage of patients in each category by treatment group and overall. 
9.1. DEMOGRAPHIC CHARACTERISTICS 
The following demographic characteristics will be captured and be reported for this study. Parameters will be 
summarized by treatment group and overall for all patients, and separately for Cohorts 3 and 4 combined, African 
patients >5 years sub-population and Asian patient sub-population. Analyses for the C3&4SAF population will be 
included in the appendices if the size of the C3&4SAF population is different (>10%) from the size of that in the 
RND population for any treatment group. 
• 
Gender (Male, Female) 
• 
Race (White, Black or African American, Asian, Other) 
• 
Region (Asia, Africa), derived from the patient’s site number. Note: Region will be captured only on the 
all randomized patients summary table as by definition the region will be ‘Africa’ for summary tables on 
the Cohorts 3 and 4 and on the African patients >5 years sub-populations and ‘Asia’ for summary table 
on the Asian patient sub-population. 
• 
Age at randomization in years to 1 decimal place (quantitative and qualitative variables: ≤2, >2 – ≤5, >5 – 
≤14, >14 - <18, ≥18) 
• 
Age at randomization in months to 1 decimal place for Cohort 3 and 4 summary table 
• 
Weight at screening in kg (quantitative variable recorded to 1 decimal place, qualitative variable: (<5, 
≥5 - <7, ≥7 - <10, ≥10 - <15, ≥15- <24, ≥24 - <35, ≥ 35)) 
• 
Body Mass Index (BMI) at screening in kg/m2 (quantitative variable recorded to 1 decimal place, 


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qualitative variable: (<30, ≥30) for summaries of African >5 years and Asian sub-populations 
9.2. OTHER BASELINE CHARACTERISTICS 
No specific description of the safety parameters will be provided at baseline. If relevant, the baseline values will be 
described along with each safety analysis. 
 
No specific description of the efficacy parameters will be provided at baseline. If relevant, the baseline values will 
be described along with each efficacy analysis. 
9.2.1. 
DISEASE CHARACTERISTIC AT BASELINE 
Time in days from first diagnosis of current malaria infection as quantitative and qualitative (0, 1 - 2, >2) 
variables. 
Parameter will be summarized by treatment group and overall for all patients and separately for Cohorts 3 and 4 
combined, African patients >5 years sub-population and Asian patient sub-population. For the Cohorts 3 and 4, 
parameter will also be summarized within each country. Analyses for the C3&4SAF population will be included 
in the appendices if the size of the C3&4SAF population is different (>10%) from the size of that in the RND 
population for any treatment group. 
 
 
Any technical details related to computation are described in Section 6.6. 
9.3. SURGICAL AND MEDICAL HISTORY 
Medical or surgical history other than uncomplicated malaria will be coded using the version of Medical Dictionary 
for Regulatory Activities (MedDRA) currently in effect at IQVIA three months prior to database lock or data 
cut-off for interim deliverables. The dictionary version in effect will be displayed in a footnote. 
 
Medical or surgical history reported in the eCRF will be presented by SOC and PT for the RND population. 
10. MEDICATIONS 
Medications taken prior to screening and until the end of the study, including anti-malarial medications other than 
IMP, are to be reported in the dedicated eCRF pages. 
 
• 
‘Prior’ medications are medications which started and stopped prior to the first dose of study medication. 
• 
‘Concomitant’ medications are medications which:  


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o 
started prior to, on or after the first dose of study medication and started no later than 63 days 
following end of study medication, 
AND 
o 
ended on or after the date of first dose of study medication or were ongoing at the end of the 
study. 
• 
‘Post’ medications are medications which started more than 63 days following the last dose of study 
medication. 
Any technical details related to imputation for missing dates are described in Appendix 2. 
 
Prior, concomitant medications and anti-malarial medications will be presented for the RND population by 
treatment group and overall for all patients. 
 
'Post' medications will be listed only. 
 
All medications will be presented as coded by the World Health Organization (WHO)-Drug Dictionary 
considering the first digit of the anatomical therapeutic chemical (ATC) class (anatomic category) and the first 
3 digits of the ATC class (therapeutic category). The dictionary version in effect will be displayed in a footnote. 
All ATC codes corresponding to a medication will be summarized, and patients will be counted once in each ATC 
category (anatomic or therapeutic) linked to the medication. Therefore, patients may be counted more than once 
for a single medication. The numbers and percentages of patients in each level will be presented. 
10.1. PRIOR MEDICATIONS 
Prior medications, including anti-malarial medications taken prior to the first dose of study medication, will be 
summarized by anatomic and therapeutic category. The tables will be sorted by decreasing frequency of ATCs 
(anatomic or therapeutic categories) based on the overall incidence across treatment groups. In case of equal 
frequency regarding ATCs, alphabetical order will be used. 
10.2. CONCOMITANT MEDICATIONS 
Concomitant medications, excluding anti-malarial medications taken after the first dose of study medication, will 
be summarized by anatomic and therapeutic category. The tables will be sorted by decreasing frequency of ATCs 
(anatomic or therapeutic categories) based on the incidence in the highest dose experimental arm. In case of equal 
frequency regarding ATCs, alphabetical order will be used. 
 
In addition, the following specific medication may be summarized if deemed necessary: 
• 
Paracetamol 


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10.3. ANTI-MALARIAL MEDICATION TAKEN AFTER STUDY 
MEDICATION 
Anti-malarial medications other than IMP taken after the first dose of study medication will be summarized by 
anatomic and therapeutic category and presented according to three time periods in line with efficacy time points: 
 
• 
Day 0 - Day 28 period: defined as the period of time starting the first IMP intake day and ending with the 
Day 28 time window defined in Section 6.4.1. 
• 
Day 0 - Day 42 period: defined as the period of time starting the first IMP intake day and ending with the 
Day 42 time window defined in Section 6.4.1. 
• 
Day 0 - Day 63 period: defined as the period of time starting the first IMP intake day and ending with the 
Day 63 time window defined in Section 6.4.1. For this period, summary will be repeated separately for 
Cohorts 3 and 4 combined, African patients >5 years sub-population and Asian patient sub-population. 
11. STUDY MEDICATION ADMINISTRATION AND EXPOSURE 
IMPs intake and exposure will be summarized by actual treatment group for the SAF population. 
Study drug administration and associated information collected at the time of administration, such as fasting 
status, method of administration (capsule/suspension), total/partial administration and reason for partial 
administration, occurrence and timing of vomiting, will be summarized for initial administration of FQ and OZ, 
and where applicable, for OZ re-dosing. 
Duration of administration will be summarized descriptively as a quantitative variable (number, mean, SD, 
median, minimum, and maximum). 
11.1. DERIVATIONS 
Durations are calculated as follows: 
• 
Time between FQ and OZ administrations, separately for FQ given as capsules and FQ given as solution:  
(start date and time of OZ intake) - (start date and time of FQ intake.) 
Not defined in cases where FQ is given after OZ. 
• 
Duration of OZ administration, for initial administration and, if any, for re-dose separately:  
(end date and time of OZ intake) - (start date and time of OZ intake) 
• 
Overall administration duration for initial administration: 
(end date and time of OZ intake (initial administration)) - (start date and time of FQ intake). 
Not defined in cases where FQ is given after OZ. 


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12. STUDY MEDICATION COMPLIANCE 
Calculation of study medication compliance is not applicable as this is a single-dose treatment administration. 
 
Cases of overdose (defined as at least twice the intended dose within the intended therapeutic interval, adjusted 
according to the tested drug) will constitute an adverse event of special interest (AESI - serious or non-serious) if 
symptomatic and will be listed as such. Asymptomatic overdose must be reported as a standard AE. 
13. EFFICACY OUTCOMES 
13.1. DEFINITIONS 
Treatment outcome is to be established according to the following modified standard WHO classification. Refer to 
Glossary of the Protocol, according to a modification of the standard WHO classification, WHO Methods for 
surveillance of antimalarial drug efficacy, 2009: 
 
Early treatment failure (ETF) (Day 1 to 3) = ‘Yes’ if any of the following criteria are met: 
• 
Danger signs or severe malaria on Day 1, 2 or 3 in the presence of parasitemia. 
• 
Parasitemia on Day 2 higher than on Day 0, irrespective of axillary temperature. 
• 
Parasitemia on Day 3 with axillary temperature ≥37.5 ºC. 
• 
Parasitemia on Day 3 ≥25% of count on Day 0. 
Late clinical failure (LCF) (Day 4 to 63) = ‘Yes’ if any of the following criteria are met: 
• 
Danger signs or severe malaria in the presence of parasitemia on any day between Day 4 and Day 63 in 
patients who did not previously meet any of the criteria of ETF. 
• 
Presence of parasitemia on any day between Day 4 and Day 63 with axillary temperature ≥37.5 ºC (or 
history of fever) in patients who did not previously meet any of the criteria of ETF. 
Late parasitological failure (LPF) = ‘Yes’ if any of the following criteria are met: 
• 
Presence of parasitemia on any day between Day 7 and Day 63 and axillary temperature <37.5 ºC in 
patients who did not previously meet any of the criteria of ETF or LCF. 
 
Treatment failure is defined as patients who met any of the criteria for ETF, LCF or LPF. 
 
Re-emergence/Recurrence (recrudescence and re-infection): The appearance of asexual parasites after clearance of 
initial infection irrespective of genotype. 
Recrudescence: The appearance of asexual parasites after clearance of initial infection with a genotype identical to 
that of parasites present at baseline. Recrudescence is confirmed by microscopy (positive blood smear) and by 
genotyping PCR analysis. 
Re-infection: The appearance of asexual parasites after clearance of initial infection with a genotype that differs 
from that of parasites present at baseline. Re-infection is confirmed by microscopy (positive blood smear) and by 


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genotyping PCR analysis. Confirmed new infection will not be regarded as treatment failure or recrudescence. 
 
Adequate Clinical and Parasitological Response (ACPR) is defined as absence of parasitemia on Day (D), 
irrespective of axillary temperature, in patients who did not previously meet any of the criteria of treatment 
failure; ETF, LCF or LPF. 
 
PCR crude ACPR does not distinguish between re-infection (by a new clone of parasite) and recrudescence (re-
emergence of the original clone of parasite that was present at baseline); i.e. presence of either a new clone or 
genotypically identical parasite will be considered a treatment failure. 
 
PCR-adjusted ACPR applies only to recrudescence; (i.e. patients with re-infection are considered non-evaluable 
for the analysis of PCR-adjusted ACPR). Presence of a genotypically identical parasite will be considered a 
treatment failure (See Table F for derivations). 
 
The following aspects are to be used in the above definitions: 
• 
P. falciparum asexual parasite count and other species results as obtained from the Thick and Thin 
Malaria Blood Film data. 
• 
Parasitemia refers to P. falciparum asexual parasites present (count >0 parasites/µL). 
• 
Day 0 (or Day -1 if screening slide collected within 4 hours of dosing) refers to Baseline P. falciparum 
asexual parasites (/µL). 
• 
Body temperature - Presence of signs and symptoms of complicated/severe malaria as obtained from the 
eCRF. 
• 
Analysis windows defined in Section 6.4.1 are taken into account. 
• 
PCR-analysis results: 
o 
Recrudescence or Re-infection as determined by PCR analysis as specified above. 
o 
Indeterminate. If no genotyping result is available following re-emergence due to a missing or 
unusable sample, or uninterpretable result, the reasons for the missing data must be indicated; 
i.e., sample not taken, missing follow-up sample, no PCR result or uninterpretable result. 
o 
Negative. ‘No PCR result’, hence ‘No’ P. falciparum DNA detected. 
13.2. OBJECTIVES 
The primary objective is to determine whether a single dose combination of OZ439/FQ is an efficacious treatment 
for uncomplicated P. falciparum malaria in adults and children. This will be evaluated in terms of: 
• 
PCR-adjusted ACPR at Day 28. 
 
 
The secondary objectives are: 
 
• 
To determine the incidence of recrudescence and re-infection. This will be evaluated in terms of: 


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o 
PCR-adjusted ACPR at Day 42 and 63. 
o 
Crude ACPR at Day 28, 42 and 63. 
o 
Incidence rate up to Day 63 of: 
 
Re-emergence. 
 
Recrudescence. 
 
Re-infection. 
 
• 
To determine the time to relief of fever and parasite clearance. This will be evaluated in terms of: 
o 
Parasite clearance time (PCT). 
o 
Fever clearance time (FCT): 
o 
Parasite reduction ratio (PRR). 
 
• 
To evaluate the safety and tolerability of OZ439/FQ in adults and children. 
 
• 
To evaluate the pharmacokinetics of OZ439/FQ: 
o 
To characterize the pharmacokinetics of OZ439 in plasma, FQ and its active metabolite 
SSR97213 in blood. 
o 
To determine the blood/plasma ratio for FQ and SSR97213 in some patients at limited time 
points in selected sites. 
 
 
The exploratory objectives are to further explore the efficacy of OZ439/FQ. This will be evaluated in order: 
• 
To evaluate the proportion of patients with gametocytes at each parasitological assessment. 
• 
To characterize gametocyte carriage. 
• 
To evaluate the relationship between ACPR and exposure to OZ439/FQ. 
• 
To explore the relationship between Kelch-13 genotype and parasite clearance kinetics. 
• 
To explore in vitro drug resistance of P. falciparum infecting patients >14 years old in Vietnamese sites. 
 
 
In order to evaluate the data collected and complete each objective, all efficacy analyses will be presented by 
treatment arm and overall for the populations (see Section 5)) as detailed in Section 13.4, and by subgroups (see 
Section 7.4). 
 
In addition to the efficacy analyses planned for the PP and mITT populations and associated sub-groups, a subset 
of efficacy analyses will be conducted on the African >5 years A5mITT and A5PP populations and on the Asian 
AmITT and APP populations to allow full reporting of the data. 
13.3. CRUDE AND PCR-ADJUSTED ACPR OUTCOME DERIVATION 
The below table summarizes the treatment outcome assignment for both crude and PCR-adjusted ACPR at 


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Day (D) for the mITT and PP populations, and for the A5mITT, AmITT, A5PP and APP populations. Possible 
treatment outcome for crude and PCR-adjusted ACPR at Day (D) are: 
1 = Cure. 
2 = Failure. 
3 = Missing. 
Table F: 
Derivation Criteria of Treatment Outcome Crude ACPR and PCR-adjusted ACPR 
at Day (D) 
Criteria 
PP Population 
mITT Population 
Treatment 
Outcome 
Crude ACPR 
Treatment 
Outcome 
PCR-adjusted 
ACPR 
Treatment 
Outcome 
Crude ACPR 
Treatment 
Outcome 
PCR-adjusted 
ACPR 
Completed up to Day (D) 
without re-emergence (re-
infection/ recrudescence) of 
parasites after initial clearance, 
thus ACPR at Day (D). 
Cure 
Cure 
Cure 
Cure 
Missing assessment on Day (D), 
but parasite free (No 
P. falciparum asexual parasites) 
after Day (D). 
Cure 
Cure 
Cure 
Cure 
Missing assessment on Day (D), 
no more assessments thereafter. 
Missing 
Missing 
Failure 
Failure 
Missing assessment on Day (D), 
recrudescence (confirmed by 
PCR-adjusted result) at first 
assessment after Day (D). 
Failure 
Failure 
Failure 
Failure 
Missing assessment on Day (D), 
re-infection (confirmed by PCR-
adjusted result) at first 
assessment after Day (D). 
Failure 
Cure 
Failure 
Cure 
Re-infection before Day (D) 
(thus on or after Day 7 to before 
Day (D)) 
Failure 
Missing 
Failure 
Failure 


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Criteria 
PP Population 
mITT Population 
Treatment 
Outcome 
Crude ACPR 
Treatment 
Outcome 
PCR-adjusted 
ACPR 
Treatment 
Outcome 
Crude ACPR 
Treatment 
Outcome 
PCR-adjusted 
ACPR 
Re-infection on Day (D). 
Failure 
Cure 
Failure 
Cure 
Recrudescence before or on 
Day (D) (thus on or after Day 7 
to Day (D)) 
Failure 
Failure 
Failure 
Failure 
Re-emergence before or on 
Day (D) but PCR-adjusted result 
is indeterminate, negative or 
missing. 
Failure 
Missing 
Failure 
Failure 
Late clinical failure from Day 4 
to Day 6. 
Failure 
Failure 
Failure 
Failure 
Early treatment failure from 
Day 1 to Day 3. 
Failure 
Failure 
Failure 
Failure 
Other Plasmodium species before 
Day (D) (in the absence of P. 
falciparum). 
Missing 
Missing 
Failure 
Failure 
Other Plasmodium species on 
Day (D) (in the absence of P. 
falciparum). 
Cure 
Cure 
Cure 
Cure 
Other Plasmodium species before 
or on Day (D) (in the presence of 
P. falciparum), PCR-analysis 
result missing, negative or 
indeterminate. 
Failure 
Missing 
Failure 
Failure 
Prematurely discontinued from 
the study before Day (D) and 
received SoC. 
Failure 
Missing 
Failure 
Failure 


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Criteria 
PP Population 
mITT Population 
Treatment 
Outcome 
Crude ACPR 
Treatment 
Outcome 
PCR-adjusted 
ACPR 
Treatment 
Outcome 
Crude ACPR 
Treatment 
Outcome 
PCR-adjusted 
ACPR 
Prematurely discontinued from 
the study before Day (D) and no 
record of SoC. 
Missing 
Missing 
Failure 
Failure 
SoC: Standard of care. 
Patients included in the mITT population with no post-baseline efficacy data available are to be regarded as failure 
for both the crude and PCR-adjusted ACPR at Day (D) treatment outcome assignments. 
Based on the above definitions and derivations according to the criteria set out in Table F: Derivation Criteria of 
Treatment Outcome Crude ACPR and PCR-adjusted ACPR at Day (D), crude and PCR-adjusted ACPR at 
Day (D) are to be derived taking into account analysis visit windows defined in Table B (Section 6.4.1). 
Preference is to be given to the actual endpoint Day (D) scheduled visit result, if it falls within the predefined visit 
window. In cases where there is no endpoint visit, and an unscheduled visit falls within the analysis window of 
Day (D), the unscheduled data is to be used as the endpoint result. If neither exists, the endpoint result at Day (D) 
is regarded as missing and subsequently the crude and PCR-adjusted ACPR is to be derived using supporting data 
as detailed in Table F. 
13.4. EFFICACY ANALYSIS AND SUB-POPULATIONS 
The following table summarizes the efficacy analyses that will be conducted for the mITT and the PP populations. 
 
Sub-group Analyses (Cohorts 3 and 4)
Domain/Variable
Analysis 
Population
All (Cohorts 3&4) ≥ 
0.5 to ≤5.0 years
>2.0 to 
≤5.0 years 
(Cohort 3) 
≥0.5 to ≤2.0 
years 
(Cohort 4)
Weight 
Baseline 
parasitemia Country 
Crude and ACPR-
adjusted
mITT & PP
Y
Y (only for 
the PP)
Y (only 
for the 
PP)
Y (only for 
the PP)
Y
ETF, LCF and LPF
mITT & PP
Y
Y (on for the 
PP) 
Y (only 
for the 
PP)
Y (only for 
the PP)
Y
Kaplan-Meier for 
re-emergence, 
mITT
Y
N
N
N
Y


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For the African >5 years mITT (A5mITT) and PP (A5PP) and for the Asian mITT (AmITT) and PP (APP) 
populations the following analysis is planned: 
 
recrudescence and 
re-infection
Fever clearance time
PP excluding 
patients who 
received 
Paracetamol
Y
Y
N
N
N
Parasitemia 
(microscopy)
mITT
Y
Y
N
N
N
Parasitemia (qPCR, 
>14 years)
mITT
N
N
N
N
N
Parasite clearance time, 
Parasite reduction rate,  
PC half-life 
PP
Y
Y
N
Y
Y
Kelch-13 genotype 
mITT & PP
Y (all Africans 
combined, i.e. 
including African >5 
years)
N
N
N
N
Relationship between 
PC half-life and Kelch-
13 genotype 
PP
Y (all Africans 
combined, i.e. 
including African >5 
years)
N
N
N
N
Signs & symptoms of 
malaria
PP
Y
Y
N
N
N
Gametocyte carriage 
(microscopy)
mITT
Y
Y
N
Y
Y
Gametocyte carriage 
(RT-PCR, >14 years)
mITT
N
N
N
N
N
Domain/Variable 
Analysis Population 
Africans >5 years 
Asians 
Crude and ACPR-adjusted
AmITT, A5mITT 
APP, A5PP
Y (summary tables 
only)
Y (summary 
tables only)
ETF, LCF and LPF
AmITT, A5mITT 
APP, A5PP
Y (summary tables 
only)
Y (summary 
tables only)
Kaplan-Meier for re-emergence, 
recrudescence and re-infection
APP, A5PP
Y
Y
Fever clearance time
APP, A5PP excluding patients 
who received Paracetamol
Y
Y
Parasitaemia (microscopy)
AmITT, A5mITT
Y
Y
Parasitaemia (qPCR, >14 years)
AmITT, A5mITT
Y
Y
Parasite clearance time,  
Parasite reduction rate,  
PC half-life
APP, A5PP
Y
Y


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13.5. PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
13.5.1. STATISTICAL ANALYSIS 
The primary analysis will be the analysis of the PCR-adjusted ACPR at Day 28 in the PP28 population. The 
PCR-adjusted ACPR at Day 28 is defined in Section 13.3. The PP28 and the population evaluable for the primary 
efficacy endpoint is defined in Section 5.4. 
 
 
Let k, the number of treatment arms at the time of final analysis (k = 1, 2, 3 or 4). All treatments will be evaluated 
separately without adjustment. 
 
The proportion of PCR-adjusted ACPR at Day 28 observed among evaluable patients from the PP population and 
receiving the treatment arm i (i = 1, …, k) will be seen as an observation from a binomial distribution, with 
unknown probability of success pi . 
 
For each treatment arm i (i = 1, …, k), the null hypothesis is that: 
 
Hi0: pi ≤0.90 
 
And this will be tested against the alternative hypothesis: 
 
Hi1: pi >0.90, at two-sided α level of 5%, as follows: 
 
Let piL, the lower bound of the exact (Clopper-Pearson) 95% two-sided confidence interval for pi, then: 
 
if piL > 0.9, then Hi0 will be rejected. Indeed: 
 
Let Ni, the number of evaluable patients in the treatment arm i. 
Let ni, the number of PCR-adjusted ACPR at Day 28 observed in the treatment arm i. 
The test statistic is Xi, the number of PCR-adjusted ACPR at Day 28, distributed as Bin(Ni,pi), binomial 
Kelch-13 genotype 
AmITT, APP 
N (combined with 
African ≤5 years)
Y
Relationship between PC half-life and 
Kelch-13 genotype
APP
N (combined with 
African ≤5 years)
Y
Signs & symptoms of malaria
APP, A5PP
Y
Y
Gametocyte carriage (microscopy)
AmITT, A5mITT
Y
Y
Gametocyte carriage (RT-PCR, 
>14 years)
AmITT, A5mITT
Y
Y


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distribution with unknown probability of success pi. Xi is observed through ni. 
 
piL is obtained from ni as the Inf{θ: Pθ(Xi≥ni ) >α/2}. If piL >0.9, then by definition of piL: P0.9(Xi≥ni) ≤ α/2. 
Under Hi0, the function Pθ(Xi≥ni) being monotone in θ, then Ppi(Xi≥ni) ≤ P0.9(Xi≥ni). 
 
The probability to wrongly reject Hi0 when piL >0.9 is then at most equals to α/2, and is given by P0.9(Xi≥ni). 
This p-value will be provided in addition to the exact (Clopper-Pearson) 95% confidence interval for pi. 
No adjustment for multiple testing will be made, therefore the overall type I error when testing the k hypotheses 
may exceed 5% if k ≥ 2. 
 
 
The primary analysis is to be performed for the PP population and will be repeated as a sensitivity analysis for the 
mITT. 
 
For analysis purposes the PCR-adjusted ACPR at Day 28 is to be categorized as: 
1 = Cure 
0 = Failure 
 
For the PP population  
• 
Only a definite ‘Cure’ or ‘Failure’ result as derived per Table F is to be used in the analysis. 
• 
n = Number of patients with the treatment outcome of ‘Cure’. 
• 
N = Total number of patients in the relevant analysis population with a definite response of ‘Cure’ or 
‘Failure’. 
• 
% = Percentage of patients in each category calculated relative to the total number of patients in the 
relevant analysis population with a definite response. 
• 
PCR-adjusted ACPR rate at Day 28 = (Number of patients with the treatment outcome ‘Cure’)/(Number 
of patients in the relevant analysis population with a definite result) * 100. 
 
For the sensitivity analysis on the mITT population: 
• 
Missing response as derived per Table F is to be set to failure and included in the analysis. 
• 
n = Number of patients with the treatment outcome of ‘Cure’. 
• 
N = Total number of patients in the relevant analysis population. 
• 
% = Percentage of patients in each category to be calculated relative to the total number of patients in the 
analysis population. 
• 
PCR-adjusted ACPR rate at Day 28 = (Number of patients with the treatment outcome ‘Cure’)/(Number 
of patients in the mITT population) * 100. 
 
The following by-patient listing is to be presented for the mITT population: 
• 
Crude and PCR-adjusted ACPR 


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13.5.2.  ADDITIONAL ANALYSIS OF PRIMARY VARIABLES 
13.5.2.1. 
CRUDE AND PCR-ADJUSTED ACPR 
As noted in Section 13.5.1, the primary analysis will be repeated for the mITT population as a sensitivity analysis. 
 
Summaries will be repeated for each of the following subgroups as detailed in Sections 7.4 and 13.4: 
• 
Age group 
• 
Weight group 
• 
Baseline parasitemia 
• 
Country 
 
In addition, the descriptive statistics for the African >5 years and Asian mITT and PP populations will also be 
presented as described in Section 13.4. 
13.5.2.2. 
ETF, LCF AND LPF 
The following tables are to be presented for the mITT and PP populations: 
• 
The number and percentage (%) of patients with a treatment failure outcome, including ETF, LCF and 
LPF up to Day 28. 
• 
The number and percentage (%) of patients with crude and PCR-adjusted result following re-emergence 
of asexual parasites, i.e. recrudescence, re-infection, indeterminate and negative up to Day 28. 
 
These tables will also be repeated separately for each of the following subgroups as detailed in Sections 7.4 and 
13.4: 
• 
Age group 
• 
Weight group 
• 
Baseline parasitemia 
• 
Country 
 
In addition, tables will be repeated for the African >5 years and Asian mITT and PP populations as described in 
Section 13.4. 
 
The following bar charts are to be presented for the mITT and PP populations: 
• 
Separate bar charts of crude and PCR-adjusted cure rate over time. 
 
These bar charts will also be repeated separately for each of the following subgroups as detailed in Sections 7.4 
and 13.4: 


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• 
Age group 
• 
Weight group 
• 
Baseline parasitemia 
• 
Country 
 
The following by-patient listing is to be presented for the mITT population: treatment failure (ETF, LCF and 
LPF). 
13.6. ANALYSIS OF SECONDARY EFFICACY VARIABLE(S) 
13.6.1. PCR-ADJUSTED ACPR AT DAYS 42 AND 63, AND 
CRUDE ACPR AT DAY 28, 42 AND 63 
The PCR-adjusted ACPR at Day 42 and 63, and crude ACPR at Day 28, 42 and 63 are defined, analyzed and 
presented in a similar manner as for the primary efficacy endpoint PCR-adjusted ACPR at Day 28 (refer to 
Section13.3: Crude and PCR-adjusted ACPR Outcome Derivation). 
13.6.2. KAPLAN-MEIER ANALYSIS FOR TIME TO 
RE-EMERGENCE, RECRUDESCENCE AND RE-INFECTION 
The following time to event variables are to be derived: 
• 
Time to re-emergence (days): Defined as the time to appearance of asexual parasites after clearance of 
initial infection irrespective of genotype. 
• 
Time to recrudescence (days): Defined as the time to appearance of asexual parasites after clearance of 
initial infection with a genotype identical to that of parasites present at Baseline. 
• 
The time to re-infection (days): Defined as the time to appearance of asexual parasites after clearance of 
initial infection with a genotype different to that of parasites present at Baseline. 
• 
Censored: Patients with no event are censored at the time of study completion, premature study 
discontinuation, including switch to established anti-malarial treatment or start of any other treatment 
with anti-malarial activity as captured on the Prior and Concomitant Medications eCRF, whichever is 
earliest. 
 
The time to event is calculated from date of study drug administration to the onset of the event in days: 
Time to event (days) = (Date of event – Start date of study drug administration) 
 
The median time to event and 95% confidence interval for each treatment arm is to be estimated using the 
Kaplan-Meier method. 


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The following is to be presented for the mITT population overall and by country and repeated for the African 
>5 years and Asian mITT populations as described in Sections 7.4 and 13.4: 
• 
Kaplan-Meier estimates of time to re-emergence, recrudescence and re-infection of asexual parasites in 
days. 
• 
Kaplan-Meier estimates of incidence rates until Days 28, 42 and 63. 
• 
Kaplan-Meier plots of the cumulative incidence for each treatment arm (within specified population/ 
sub-group) is to be presented for time to re-emergence, recrudescence and re-infection of asexual 
parasites in days. 
13.6.3. PARASITE CLEARANCE TIME (PCT) (HOURS) 
The following clearance time variables are to be derived: 
Defined as the time (in hours) from start of study drug administration until the time of first negative film (no 
asexual parasites). This negative film is to be confirmed by a second negative film, taken within (≥)6 to 
(≤)12 hours of the first. Parasite clearance is concluded following confirmation of the second negative film. A 
deviation of 2 hours is allowed for the time interval. If the second film is performed less than 6 hours after the 
first, then the parasite clearance will be confirmed or invalidated by a third thick film, whatever the timing of this 
third film: 
• 
If this third film is negative, then the clearance is confirmed. 
• 
If this third film is positive, then the clearance is invalidated. 
Time to clearance (hours) = (Date and time first thick film – Start date and time of study drug administration) 
 
Censored: In the event that there is no second/ third film during the stipulated time period to confirm/not confirm 
parasite clearance, but the next available film thereafter is negative, the time to parasite clearance will be censored 
at the time of the first negative film. In the event that parasite clearance is not observed or confirmed before 
withdrawal (for any reason) or before the start of rescue therapy, the time to parasite clearance will be censored at 
the time of the last blood film (using the post-dose timing above defined) before withdrawal or start of rescue 
therapy, whichever is earliest. Blood films performed the day of rescue start are regarded as before rescue. 
 
The parasite clearance time is to be analyzed using Kaplan-Meier estimates. The median and quartiles clearance 
time is to be presented together with the corresponding 95% confidence interval for the median. 
 
Percentage parasite clearance achieved: 
• 
At 24 hours (Day 1): number of patients with PCT ≤24 hours. 
• 
At 48 hours (Day 2): number of patients with PCT ≤48 hours. 
• 
At 72 hours (Day 3): number of patients with PCT ≤72 hours. 
 
The following is to be presented for the PP population overall and by age, by baseline parasitemia, and country as 
described in Sections 7.4 and 13.4. 


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The proportion of patients and the 95% confidence intervals will be calculated for patients who have parasite 
clearance after study drug administration overall and at 24 hours (Day 1), 48 hours (Day 2) and 72 hours (Day 3) 
using Kaplan-Meier estimates. 
 
Kaplan-Meier plots of the cumulative incidence for each treatment arm over time to parasites clearance in hours is 
to be presented. 
13.6.4. FEVER CLEARANCE TIME (FCT) (HOURS) 
Only patients with measured fever (adjusted body temperature ≥37.5 °C) present at Baseline and who did not 
receive paracetamol on day of study drug administration until 96 hours after study drug administration are to be 
included. Patients entered in the study on the basis of history of fever and who do not subsequently have an 
increased body temperature measurement indicating presence of fever at pre-dose, are not included in the analysis 
of fever clearance time. 
 
Calculated as the time from start of study drug administration to the first assessment of adjusted body temperature 
<37.5 °C. This assessment is to be confirmed by a second assessment, taken within (≥)6 to (≤)12 hours of the first. 
Fever clearance is to be concluded for the first assessment, following confirmation of temperature <37.5 °C on the 
second assessment. 
 
Time to clearance (hours) = (Date and time of first clearance assessment – Start date and time of study drug 
administration) 
 
Censored: Patient who did not have second assessment during the stipulated time period to confirm/not confirm 
fever clearance, but were fever-free at the next available assessment time point, are censored at the time of the first 
assessment of body temperature <37.5 °C. Patients who did not have fever clearance are censored at premature 
study discontinuation, including switch to established anti-malarial treatment or start of any other treatment with 
anti-malarial activity as captured on the Prior and Concomitant Medications eCRF, whichever is earliest.  
 
The proportion of patients who have fever clearance after study drug administration are to be calculated and the 
95% confidence intervals for the single binomial proportion is to be calculated according to Clopper-Pearson 
method. 
 
The fever clearance time is to be analyzed using Kaplan-Meier estimates. The median and quartiles clearance time 
is to be presented together with the corresponding 95% confidence intervals for the median (expressed in weeks).  
The table is to be presented for the PP population overall and by age, as described in Sections 7.4 and 13.4. 
 
The following figures are to be presented for the PP population overall and by age group:  
• 
Kaplan-Meier plots of the cumulative incidence for each treatment arm over time for patients with 


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measured fever at Baseline to parasites clearance in hours, excluding patients receiving paracetamol 
during the first 96 hours after study drug administration. 
13.6.5. PARASITE REDUCTION RATIO 
The following method will be used for estimating slopes: 
 
A Tobit regression model (SAS PROC LIFEREG) will be used in order to take into account for censored 
observations (i.e. negative parasitemia) however only the first zero sustained (i.e. followed by negative slides 
only) will be included in the analysis. In addition, a linear regression model starting from the second parasite 
measurement will be fitted if this second measurement exceeded the first measurement (baseline) by more than 
25%. The Tobit model is a censored regression model, where the response variable Yi is related to a latent (or 
unobservable) variable Y*i by: 
 
Yi = Y*i if Y*i >YL, Yi = YL if Y*i ≤YL. 
 
The latent variable is then modelled in the standard way: Y*i =Xiβ+ε. And the regression model is solved using 
maximum likelihood techniques, however the likelihood function is now a truncated normal distribution in the 
case when Y*i ≤YL. 
13.6.5.1. 
PARASITE CLEARANCE PARAMETERS 
The following parasite clearance parameters are to be estimated using the WWARN parasite clearance estimator 
(PCE) based on the linear part of the individual natural log parasitemia-time profiles for both microscopic and 
qPCR determined parasitemia. 
• 
Clearance rate constant (1/hours) 
• 
PC half-life 
• 
Time to 50%, 90% and 99% parasite reduction (PC50, PC90 and PC99) 
 
Analyzable data: Identifies the data per scheduled timepoint to be used for the PCE especially in view of patients 
switching to established anti-malarial treatment or start of any other treatment with anti-malarial activity as 
captured on the Prior and Concomitant Medications eCRF. This flag excludes those test results obtained whilst on 
alternative treatment and only data up to 168 hours post study drug administration are to be included for the 
parasite parameter analysis. 
Analyzable result: Identifies the parasite clearance parameter results to be used in the summary tables. Results 
from patients with a poor fit to the linear model (r2 <0.75) or with <3 data points are excluded from the analysis.  
For asexual parasite assessments equal to ‘Absent’, the WWARN calculator use 8 /µL as the limit of detection. 
 
Parasite reduction rate (PRR) at 24 and 48 hours derivations: 


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• 
The clearance rate constant (1/hours) obtained from the WWARN PCE calculator and defined as the 
minus slope of the final model fitted after exclusion of outliers, lag phase and tail are to be used to 
calculate PRR24 and PRR48. Hence PRR24 and PRR48 is the drop in log units over 24 and 48 hours. 
o 
PRR24 = ln (clearance rate constant [1/hours]*24 hours). 
o 
PRR48 = ln (clearance rate constant [1/hours]*48 hours). 
 
The following table is to be presented for the PP population overall and by age, by baseline parasitemia and 
country as described in Sections 7.4 and 13.4. 
• 
Descriptive statistics (n, minimum, 25th percentile, median, 75st percentile, maximum) for the parasite 
clearance parameters, i.e. PRR24, PRR48, PC half-life, PC50, PC90 and PC99 as estimated with the use 
of the PCE developed by WWARN. 
 
The following result are to be presented in a by-patient listing for the PP population: 
• 
The parasite clearance parameters, i.e. clearance rate constant (1/hours), PC half-life, PC50, PC90 and 
PC99, including the calculated PRR24 and PRR48 results. 
13.6.6. PARASITAEMIA 
The following tables are to be presented for the mITT population overall and by age as described in Section 13.4. 
 
• 
Descriptive statistics (n, mean, geometric mean, SD, median, Q1, Q3, minimum, and maximum) for 
parasitemia data (number of parasites/µL) (raw data and absolute change from baseline) using 
microscopic determined parasitemia will be displayed at each post-baseline assessment. 
 
The following tables are to be presented for the African >5 years population and Asian population as described in 
Section 13.4. 
• 
Descriptive statistics (n, mean, geometric mean, SD, median, Q1, Q3, minimum, and maximum) for 
parasitemia data (number of parasites/µL) (raw data and absolute change from baseline) using 
microscopic determined parasitemia and qPCR (quantitative polymerase chain reaction) (in patients 
>14 years) determined parasitemia, will be displayed at each post-baseline assessment. 
• 
qPCR: A polymerase chain reaction method is used to quantify the amount of Plasmodium falciparum 
(P. falciparum)-specific DNA present and is transformed into number of parasites/µL. 
13.7. ANALYSIS OF PHARMACOKINETIC PARAMETERS 
Blood and plasma FQ (respectively its metabolite [SSR97213]) observed concentrations, plasma OZ439 observed 
concentrations will be summarized by treatment arm and by time point using descriptive statistics (mean, 
geometric mean, median, standard deviation, standard error of mean, coefficient of variation, minimum, 
maximum and number of available observations) for each cohort. 


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Blood/plasma ratio for FQ and SSR97213 will be provided by treatment arm and by time point using above 
descriptive statistics for each cohort. Blood and plasma concentrations will be kept for the descriptive statistics if 
sampling occurs within ± 15% of theoretical time. Additional plots will be prepared, as deemed necessary. 
 
The population PK analysis for both OZ439 and FQ/ SSR97213 will be performed using non-linear mixed effect 
modeling. Subsequently, for each patient the individual OZ439, FQ and SSR97213 exposures (Cmax, AUCs, 
CDay 7, CDay 14, CDay 21 and CDay 28) will be estimated using each patient’s estimated individual PK 
parameters. These will be summarized by various subgroups. Data from previously conducted studies might be 
added for model development. More details will be provided in a separate pharmacokinetic analysis plan. The 
pharmacokinetic analyses will be reported separately from the main CSR. A summary of the methods and results 
will be reported in the main CSR. 
13.8. ANALYSIS OF PHARMACODYNAMIC PARAMETERS 
13.8.1. RELATIONSHIP BETWEEN ACPR AND EXPOSURE TO 
OZ439/FQ 
An exploratory objective of this study is to evaluate the relationship between ACPR and exposure to OZ439/FQ. 
More details will be provided in a separate analysis plan. A summary of the methods and results may be reported 
in the main CSR. 
13.8.2. RELATIONSHIP BETWEEN OBSERVED PK 
CONCENTRATIONS AND ECG PARAMETERS 
Two PK/PD statistical analyses (one for Cohort 1a in a first time and then by pooling Cohort 1a and 1b in a 
second time) will be done with ECG parameters (HR, PR, QRS, QTcB and QTcF) regarding FQ and SSR97213 
compounds by combining the two compounds in the same linear direct/indirect model (as covariates or by using 
the molecular weight formula in order to obtain a “total” concentration). A complementary analysis will be 
performed pooling Cohort 1a and 1b and including OZ concentrations as PK variable (in addition to FQ and 
SSR97213). These two analyses will be prepared by a Sponsor’s unblinded independent statistician. 
The first PK/QTc analysis will include 30 African patients >14 years (Cohort 1a) receiving the dose levels 
OZ439/FQ 800/400, 800/600 and 800/900 mg. 
The second PK/PD analysis will include a total of 42 African patients >14 years (Cohort 1a & 1b) receiving the 
dose levels 800/400, 800/600, 800/900 and 800/1200 mg. 
Post-dose concentrations below the lower limit of quantification (LLOQ), will be replaced with ½ LLOQ in the 
statistical analyses. LLOQ is defined as 1 ng/mL for OZ439 and as 5 ng/mL for FQ and SSR97213. 
 


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Relationships between changes from baseline in ECG parameters with FQ/OZ439 concentrations on the restricted 
time window [Day 0 T2h – Day 2 T48h] will be explored in two ways by combining the two compounds FQ and 
SSR97213, using the molecular weight (MW) 433.77 g.mol-1 for ferroquine and 419.74 g.mol-1 for SSR97213, in 
order to obtain a “total” concentration separately from OZ439 [mol/L] = C_FQ/433.77 + C_ SSR97213/419.74 
Total concentration (FQ+SSR97213) [µmol/L] = Concentration (µg/L)/433.77 (µg/µmol) + 
Concentration_SSR97213 (µg/L)/419.74 (µg/µmol), by using ferroquine and SSR97213 blood drug 
concentrations as covariates in the same model. 
 
For the complementary analyses, when OZ439 will be included in the model, the concentrations will be converted 
to µmol/L using its molecular weight (469.28 g.mol-1) for the first approach and will be used unchanged for the 
second approach. 
The selection of the best model will depend of fit statistics criteria. 
 
The PK/PD analysis will be performed in three successive steps: 
• 
1st step: 800/400, 800/600 and 800/900 mg dose levels from Cohort 1a. 
• 
2nd step: 800/400, 800/600, 800/900 and 800/1200 mg dose levels from Cohorts 1a and 1b. (OZ 
concentration to be added as PK variable in the complementary analysis). 
These PK/QTc analyses may or may not be reviewed by the DMC at the same time as the safety data review 
and therefore may or may not be considered by the DMC for DMC decision rule. 
• 
A third PK/PD analysis will include all patients of all cohorts receiving the dose levels 800/400, 800/600, 
800/900 mg and/or 800/1200 mg at the end of the study. 
13.8.3. EXPLORATORY PLOTS 
The relationship between change from baseline in HR, PR, QRS, QTcB and QTcF and FQ (respectively 
SSR97213, their total concentrations using MW and OZ439 [complementary analysis at end of Cohort 1 and final 
analysis only]) concentrations, respectively, from Day 0 T2h to Day 2 T48h will be first explored graphically, in 
order to investigate any potential delayed or sustained effects and the type of PK/PD modelling to be done, using 
the following plots: 
• 
Plot of Mean (± SEM) change from baseline in HR, PR, QRS, QTcB and QTcF with FQ (respectively 
SSR97213, their total concentrations using MW and OZ439 [complementary analysis at end of Cohort 1 
and final analysis only]) concentrations, versus time (hours post-dose) overlaid onto the same plot; the 
same plot will be produced on the log concentration; 
• 
Hysteresis plot of individual and mean change from baseline in HR, PR, QRS, QTcB and QTcF and FQ 
(respectively SSR97213, their total concentrations using MW and OZ439 [complementary analysis at 
end of Cohort 1 and final analysis only]) concentrations, respectively;  
• 
Histogram of distribution of time of largest change from baseline in HR, PR, QRS, QTcB and QTcF and 
largest FQ (respectively SSR97213 and OZ439 [complementary analysis at end of Cohort 1 and final 
analysis only]) concentrations, respectively; 
• 
Histogram of distribution of time of smallest change from baseline in HR, PR, QRS, QTcB and QTcF 


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and largest FQ (respectively SSR97213, their total concentrations and OZ439 [complementary analysis 
at end of Cohort 1 and final analysis only]) concentrations, respectively. 
 
A graphical exploration will be performed to assess appropriateness of QT correction methods by plotting baseline 
individual QTc values on the y-axis and baseline HR (or RR) values on the x-axis. A regression line will be fitted 
between QTc and HR. These plots will be performed separately by age cohort for the final analysis. 
13.8.4. MODELING: LINEAR MODEL 
A random coefficients linear regression of QTcF (respectively HR, PR, QRS and QTcB) change from baseline vs. 
concentration will be used from Day 0 T2h to Day 2 T48h, with fixed terms for common intercept and slope, and 
with random terms for patient - specific intercept and slope, and using an unstructured variance-covariance 
structure for random coefficients and a common variance for error, using SAS® PROC MIXED procedure: 
For the model with ferroquine and SSR97213 total concentration using MW: 
Change from baseline = (α + Ai) + (β + Bi) × Concentrationij + error, with i = patient and j = time 
For the model where ferroquine and SSR97213 blood drug concentrations will be used as covariates 
simultaneously: 
Change from baseline = (α + Ai) + (β1 + B1i) × Ferroquine Concentrationij + (β2 + B2i) × SSR97213 
Concentrationij + error, with i = patient and j = time 
 
When OZ439 will be added to the model [complementary analysis at end of Cohort 1 and final analysis only], a 
term (β3 + B3i) × OZ439 Concentrationij will be added to the model, OZ439 concentrations being used unchanged 
or converted to µmol/L depending on the model used. 
 
Estimates and 90% CIs of coefficients of the linear regression model, and the prediction (estimate and 90% CI) in 
change from baseline of ECG parameters corresponding to the observed Cmax value (geometric mean) for each 
FQ dose group will be provided for FQ and SSR97213 respectively (OZ439 compound for the complementary 
analysis at end of Cohort 1 and final analysis only), and will be calculated as follows: 
• 
For the models with ferroquine and SSR97213 total concentration using MW:  
o 
Estimated change from baseline at total concentration Cmax = βestimated x total concentration 
Cmax geometric mean (GM) 
• 
For the models with ferroquine and SSR97213 concentrations as covariates: 
o 
Estimated change from baseline at ferroquine Cmax = β1 estimated x ferroquine Cmax GM + β2 
estimated x (mean of SSR97213 concentrations obtained at individual ferroquine tmax) 
o 
Estimated change from baseline at SSR97213 Cmax = β1 estimated x (mean of ferroquine 
concentrations obtained at individual SSR97213 tmax) + β2 estimated x SSR97213 Cmax GM 
• 
For the models including OZ439 [complementary analysis at end of Cohort 1 and final analysis only], 
contribution of OZ439 will be addressed in the same way, that is, by estimating the change from baseline 
at OZ439 Cmax GM conditioned to mean concentrations for ferroquine, SSR97213 or the total of their 
concentrations obtained at OZ439 tmax, or by conditioning predictions for ferroquine, SSR97213 or the 


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total of their concentrations by the mean of OZ439 concentrations obtained at the tmax of interest. 
 
Scatter plots of changes from baseline versus FQ, SSR97213 concentrations and OZ439 (for the complementary 
analysis at end of Cohort 1 and final analysis only), respectively, with the regression line overlaid, will also be 
provided. 
 
Goodness-of-fit and residual plots will be provided. In case of lack of fit (i.e., the linear model is not adequate), 
alternative models like non-linear models (exponential, Emax) and/or Model Averaging) might be explored. 
13.8.5. MODEL AVERAGING 
By combining estimates obtained from several competing models (linear, exponential and Emax), Model 
averaging (MA) will provide estimators which will have good robustness properties compared to the linear model 
or non-linear model estimates. 
The estimated endpoint will be the drug effect on delta QTcF at the Cmax value (geometric mean) observed 
concentrations at the maximal dose (OZ439 800 mg/FQ 1200 mg). 
13.9. ANALYSIS OF EXPLORATORY EFFICACY VARIABLES 
13.9.1. KAPLAN-MEIER ANALYSIS FOR THE RISK OF HAVING 
GAMETOCYTES 
The following time to event variables are to be derived: 
 
• 
The time to appearance (days): 
Only patients without gametocytes at Baseline are to be included, i.e. gametocytes equal to ‘Absent’ at 
Screening (Baseline). 
Calculated from the start of study drug administration until the appearance of gametocytes. 
Time to appearance of gametocytes (days) = (Date of appearance of gametocytes – Date of study drug 
administration). 
Censored: Patients who did not have an event of appearance of gametocytes are censored at the time of 
study completion, premature study discontinuation, including switch to established anti-malarial 
treatment or start of any other treatment with anti-malarial activity as captured on the Prior and 
Concomitant Medications eCRF, whichever is earliest. 
 
• 
Gametocyte clearance time (PCT) (days):  
Only patients with gametocytes present at Baseline are to be included, i.e. gametocytes assessment equal 
to ‘Present’ at Screening (Baseline) with a gametocyte count greater than zero. 


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Calculated as the time from start of study drug administration to the first negative (no gametocytes 
detected) film. This negative film is to be confirmed by a second negative film, taken within (≥)6 to 
(≤)12 hours of the first. Gametocyte clearance is concluded following confirmation of the second 
negative film. 
Time to gametocytes clearance (days) = (Date of first negative film – Date of study drug administration). 
Censored: Patients who did not have second film within the stipulated time period to confirm/not 
confirm gametocyte clearance are censored at the time of first negative film if the next available film is 
negative for gametocytes. Patients who did not have gametocyte clearance are censored at the time of 
study completion, premature study discontinuation, including switch to established anti-malarial or start 
of any other treatment with anti-malarial activity as captured on the Prior and Concomitant Medications 
eCRF, whichever is earliest. 
 
The median time to event and 95% CI for each treatment are to be estimated using the Kaplan-Meier method.  
The following tables are to be presented for the mITT population: 
• 
Kaplan-Meier estimates of time to appearance of gametocytes in days, for patients with no gametocytes 
at Baseline. The percentage of patients in each category are to be calculated relative to the total number 
of patients in the relevant analysis population without gametocytes at Baseline. 
• 
Kaplan-Meier estimates of gametocyte clearance time in days, for patients with gametocytes at Baseline. 
The percentage of patients in each category are to be calculated relative to the total number of patients in 
the relevant analysis population with gametocytes present at Baseline. 
 
The following figures are to be presented: 
• 
Kaplan-Meier plots of the cumulative incidence for each treatment arm is to be presented for time to 
appearance of gametocytes for patients without gametocytes present at Baseline. 
• 
Kaplan-Meier plots of the cumulative incidence for each treatment arm is to be presented for 
gametocytes clearance time for patients with gametocytes present at Baseline. 
13.9.2. KELCH-13 GENOTYPE  
Analysis of Kelch-13 genotype associated with Artemisinin resistance is to be carried out on the pre-dose blood 
spot samples. If insufficient blood spot samples at Baseline, alternative blood spots collected as specified in the 
schedule of assessments are to be used. 
 
Binary Classification: 
• 
Per patient: Kelch-13 data is to be categorized as either true wild type or mutation, where: 
o 
True wild type (WT): Defined for patient with no mutations at any of the tested loci. 
o 
Mutation: Defined for patient with at least one mutation tested loci. 
• 
The “mixed” infection, meaning sample contained both mutants and wild type, will be considered as 
“mutant” in the analyses. 
 


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The following table is to be presented for the mITT and PP populations grouping all African patients together as 
described in Section 13.4. In addition, the following table will also be presented for the Asian population: 
• 
Number (n) and percentage (%) of patients carrying WT parasites, and carrying each mutation are to be 
calculated relative to the total number of patients in the relevant analysis population with an evaluable 
result (‘wild type’ or ‘mutation’) at any of the tested loci per patient overall and per tested loci. 
 
The following data are to be presented in a by-patient listing for the mITT: 
• 
Kelch-13 mutations and wild types. 
 
The following figures are to be presented:  
• 
Stacked bar chart of the frequency of occurrence of Kelch-13 of wild type and each mutation. The 
percentage (%) of patients in each category are to be calculated relative to the total number of patients in 
the mITT population (for all African patients together and separately for Asian patients) with an 
evaluable result (‘wild type’ or ‘mutation’) at any of the tested loci. 
• 
Scatter plot of the correlation of parasite clearance half-life and true wild type and Kelch 13 mutations in 
the PP population for all African patients together and separately for Asian patients). 
13.9.3. CLINICAL SIGNS AND SYMPTOMS OF MALARIA 
Descriptive statistics of the number (%) of patients experiencing clinical signs or symptoms related to malaria will 
be provided at each visit and for each sign or symptom, regardless of the presence of the sign/symptom at baseline, 
and within the subset of patients who has the sign/symptom at baseline. Assessments performed after start of rescue 
treatment will not be included in above summaries. 
 
The following table is to be presented for the PP population and separately for the PP population by age at 
randomization subgroup as defined in Sections 7.4 and 13.4: 
• 
Number (n) and percentage (%) of patients having any signs and symptoms of malaria per scheduled 
visit, calculated relative to the total number of patients at the visit.  
 
The following by-patient listing is to be presented for the mITT population: 
• 
Clinical signs and symptoms of malaria, including information on clinical signs and symptoms of 
uncomplicated malaria present. 
13.9.4. FURTHER EXPLORATORY ANALYSIS 
Drug resistance of P. falciparum infecting patients >14 years old in Vietnamese sites will be explored further by 
defining phenotypic and genotypic resistance patterns to conventional ACT of P. falciparum infecting patients 
aged >14 years old in Vietnamese sites (blood sample taken at screening). This data will be reported separately 
and will not be included in the CSR. 


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In vitro susceptibility testing of P. falciparum infecting patients aged >14 years old in Vietnamese sites to OZ439, 
FQ and both drugs (blood sample taken in case criteria for rescue treatment is met). This data will be reported 
separately and will not be included in the CSR. 
14. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the SAF population. 
There will be no statistical comparisons between the treatment groups for safety data, unless otherwise specified 
with the relevant section. 
 
All safety analyses described will be presented as follows: 
• 
For all patients in safety population (SAF) by treatment group (pooled cohorts) and overall 
And if specified in the relevant sub-sections: 
• 
For the Cohorts 3 and 4 safety population (C3&4SAF) by treatment group (pooled cohorts) and overall 
• 
For Asian patients (ASAF) by treatment group and overall 
• 
For African patients >5 years (A5SAF) by treatment group (pooled cohorts) and overall 
14.1. OBSERVATION PERIOD 
The on-study observation period is defined as the time from start of IMP until the end of the study (defined as 
last protocol planned visit or the resolution/stabilization of all SAEs and AEs with prespecified monitoring). 
The post-study period is defined as the time from the last protocol planned visit until database lock. 
 
The observation period will be divided into three phases: 
• 
The pre-treatment phase is defined as the time between the patient provides informed consent and the 
start time of the first double-blind IMP administration (excluded). 
• 
The on-treatment phase is defined as the time from the start of the first dose of double-blind IMP 
administration (included) up to the Day 63 visit (included). 
• 
The post-treatment phase is defined as the time after the Day 63 visit (excluded). 
 
The TEAE period is the on-treatment study phase. 
14.2. POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITY 
(PCSA) 
The PCSA values are defined as abnormal values considered medically important by the Sponsor according to 
predefined criteria/thresholds based on literature review and defined by the Sponsor for clinical laboratory tests, 
vital signs, and ECG parameters (PCSA version dated May 2014 or as updated thereafter). PCSA definitions 


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depend on the age, race, or sex of the patient and are detailed in Appendix 3. Specific PCSA criteria for children will 
use children’s age at time of safety assessment. 
 
PCSA criteria will determine which patients had at least one PCSA during the TEAE period, taking into account all 
evaluations performed during the TEAE period, including non-scheduled or repeated evaluations. The number of all 
such patients will be the numerator for the PCSA percentage. 
 
The denominator for the PCSA percentage for a given parameter will be based on the number of patients assessed 
for that given parameter in the TEAE period on the considered safety population. In addition, the denominator could 
be adjusted if only adults or children are concerned by the PCSA. 
 
PCSA definitions depending on age, sex or race cannot be displayed within line headers of incidence tables. 
Therefore, specific tables providing the PCSA definitions for laboratory, vital sign and ECG parameters will be 
generated. 
 
 
For quantitative safety parameters based on central laboratory/reading measurements, descriptive statistics will be 
used to summarize results and change from baseline values by visit and treatment group. Summaries will include 
the worst value, defined as the nadir and/ or the peak according to the direction (minimum or maximum) of the 
abnormality as defined in the PCSA list, during the TEAE period. 
14.3. ADVERSE EVENTS 
The occurrence of all AEs (including SAEs and AESIs) will be recorded from the time of signed informed 
consent until the end of the study. 
14.3.1. ADVERSE EVENT OBSERVATION PERIOD 
Pre-treatment AEs are AEs that developed or worsened or became serious during the pre-treatment phase. 
Treatment-emergent AEs are AEs that developed or worsened or became serious during the TEAE period 
(on-treatment phase). 
Post-treatment AEs are AEs that developed or worsened or became serious during the post-treatment phase. 
 
The primary focus of adverse event reporting will be on TEAEs. 
14.3.2. GENERAL CONVENTIONS 
If an AE date/time is missing or partial, the conventions in Appendix 2 will be used to classify the AE as 
treatment-emergent or otherwise. 


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All AEs (including SAEs and AESIs) will be coded to a lower-level term (LLT), preferred term (PT), high-level 
term (HLT), high-level group term (HLGT), and associated primary system organ class (SOC) using the version of 
MedDRA currently in effect at IQVIA three months prior to database lock or data cut-off for interim deliverables. 
 
Adverse event incidence tables will present the number (n) and percentage (%) of patients experiencing an AE by 
SOC and PT. Multiple occurrences of the same event in the same patient will be counted only once in the tables 
within a treatment phase. 
 
Sorting within tables will ensure the same presentation for the set of all AEs within each observation period 
(pre-treatment, treatment-emergent, and post-treatment). For that purpose, the table of all TEAEs presented by 
SOC and PT sorted by the internationally agreed SOC order and decreasing frequency of PTs within SOCs will 
define the presentation order for all other tables unless otherwise specified. Sorting for decreasing frequency of PTs 
within SOC will be based on results for the pooled treatment groups (“Total” column). 
14.3.3. ALL TEAES 
Incidence of TEAEs will be presented by SOC and PT and also broken down further by maximum severity and 
relationship to study medication. 
 
The following TEAE tables will be generated for the SAF population: 
• 
Overview of TEAEs, summarizing number (%) of patients with at least one  
o 
TEAE 
o 
Serious TEAE 
o 
TEAE leading to death 
o 
TEAE (other than treatment failure) leading to discontinuation of the study medication. 
 
Table will be repeated for C3&4SAF, ASAF and A5SAF sub-populations. 
• 
A summary of all TEAEs (number and percentage of patients) by primary SOC and PT. 
 
Table will be repeated for C3&4SAF, ASAF and A5SAF sub-populations 
• 
A summary of all TEAEs (number and percentage of patients) by maximal severity, primary SOC and 
PT. 
• 
Summaries of all TEAEs (number and percentage of patients) by relationship to study medications (FQ 
and OZ439 separately), primary SOC and PT. 
• 
Summaries (number and percentage of patients) of all adverse drug reactions (TEAEs considered related 
to the study medication FQ or OZ439 separately) by maximal severity, primary SOC and PT. 
14.3.3.1. 
SEVERITY 
Severity is classed as mild, moderate, or severe (increasing severity). TEAEs with a missing severity will be 


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classified as severe. 
 
If a patient reports a TEAE more than once within a primary SOC/ PT, the AE with the worst-case severity will be 
used in the corresponding severity summaries. 
14.3.3.2. 
RELATIONSHIP TO STUDY MEDICATION 
Relationship to the study medication, as indicated by the Investigator, is classed as related (i.e., ‘reasonable 
possibility that the AE was caused by FQ/OZ’) or not related (i.e., ‘no reasonable possibility that the AE was 
cause by FQ/OZ’). TEAEs with a missing relationship to study medication will be classified as related. 
 
If a patient reports the same TEAE more than once within a primary SOC/ PT, the AE with the worst-case 
relationship to study medication (i.e., “related” if both “related” and “not related” were attributed to the different 
events) will be used in the corresponding relationship summaries. 
14.3.4. TEAES LEADING TO DISCONTINUATION OF STUDY 
MEDICATION 
TEAEs leading to permanent discontinuation of study medication will be identified by using the ‘Action taken’ 
question on the AE page of the eCRF. This is specified as ‘Drug withdrawn’. 
 
The following incidence table of TEAEs leading to discontinuation of study medication will be presented: 
• 
A summary of all TEAEs leading to discontinuation of either FQ or OZ439 (number and percentage of 
patients) by primary SOC and PT. 
14.3.5. SERIOUS ADVERSE EVENTS 
Serious adverse events will be identified as any untoward medical occurrence that at any dose: 
• 
Results in death, or 
• 
Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the patient was 
at risk of death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
• 
Requires hospitalization or prolongation of existing hospitalization, or 
• 
Results in persistent or significant disability/ incapacity, or 
• 
Is a congenital abnormality/ birth defect, or 
• 
Is a medically important event (for further information regarding the definition of medically important 
events see Section 10.4.1.2 of the Protocol). 


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An ALT increase >3xULN is also an SAE in any of the following circumstances: 
• 
Possible Hy’s law (ALT or AST >3xULN and bilirubin >2xULN and (>35% direct bilirubin) in the 
absence of a serum alkaline phosphatase level >2xULN. [If fractionation is unavailable, record presence 
of detectable urinary bilirubin on dipstick indicating direct bilirubin elevations and suggesting liver 
injury] 
• 
When ALT >10xULN 
• 
When associated with jaundice 
• 
When associated with coagulation disorder (PT<50%) 
• 
In the presence of signs of hepatic encephalopathy 
 
The following incidence tables of treatment-emergent SAEs will be presented: 
• 
A summary of all treatment-emergent SAEs (number and percentage of patients) by primary SOC and 
PT. 
14.3.6. ADVERSE EVENTS LEADING TO DEATH 
TEAEs leading to death are those events where the outcome is recorded as “Fatal” on the AE page of the eCRF. 
 
No tables of TEAEs leading to death will be presented, this will be identified in data listings. 
14.3.7. ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse event of special interest is an AE (serious or non-serious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the Investigator to the 
Sponsor is required. 
Adverse events of special interest will be identified using a dedicated question in eCRF “Does event meet the 
criteria for AE of special interest per protocol?” and include: 
• 
Pregnancy (occurring in a female patient entered in the clinical trial or in a female partner of a male patient 
entered in the clinical trial) 
• 
Symptomatic overdose with IMP 
• 
Increase in alanine transaminase (ALT): ALT≥3xULN (if baseline ALT<ULN) or, ALT≥2 times the 
baseline value (if baseline ALT≥ULN) 
• 
QTcF≥500 ms or QTcF increase from baseline >60 ms 
 
Further details regarding AESIs can be found in Section 10.4.1.3 of the study Protocol. 
 
Summary table of AESIs (number and percentage) will be generated for each AESI (PT or pre-specified 
grouping). This will include: 


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• 
Patients (number and percentage) experiencing QTc-interval prolongation 
• 
Patients (number and percentage) experiencing hepatic disorders. 
Table will be repeated for C3&4SAF, ASAF and A5SAF sub-populations. 
14.3.8. GENERAL AES LISTINGS 
All individual AE data will be listed, including verbatim terms, coded terms, start and stop dates and times, 
severity, outcome, relationship to study medication, action taken with study medication, seriousness (including 
criteria met) and whether or not the event was of special interest. 
14.4. DEATHS 
Deaths during the study will be presented in a data listing. 
The observation period for deaths are per the observation periods defined in Section 14.1. 
14.5. LABORATORY EVALUATIONS 
Clinical laboratory data consists of blood analyses (including hematology and clinical chemistry) and urinalysis. 
Blood samples for clinical laboratories will be taken as per the schedule of assessments found in Section 1.1 of the 
Protocol. 
 
Laboratory parameters will be classified according to biological function as follows: 
• 
Hematology: 
o 
Red blood cells and platelets and coagulation: hematocrit, hemoglobin, absolute reticulocytes, 
erythrocyte count (RBC), platelet count. 
o 
White blood cells: leukocytes (WBC) with differential count* including eosinophils. 
(*): in one site, manual counts have been reported due to an issue with the machine to read the 
results of differential count. 
• 
Clinical chemistry: 
o 
Metabolism: albumin, creatine kinase, glucose 
o 
Electrolytes: sodium, potassium, magnesium (Visit 1 only), calcium (Visit 1 only) 
o 
Renal function: creatinine, creatinine clearance, blood urea nitrogen (BUN) 
o 
Liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (ALP), haptoglobin, lactate dehydrogenase (LDH), total bilirubin (also direct, 
when total bilirubin is ≥ULN) 
• 
Urinalysis dipstick: 
o 
specific gravity, pH, glucose, protein, bilirubin, ketones, leukocytes and blood were evaluated 
but not recorded in the clinical database and thus will not be reported in the CSR. 


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o 
Pregnancy test: urine β-HCG for females of childbearing potential 
• 
Urinalysis microscopy if the dipstick is abnormal: WBC, RBC and casts (if required) 
14.5.1. GENERAL CONVENTIONS 
Clinical laboratory values will be analyzed in standard international (SI) units after conversion to these as 
appropriate. 
 
Baseline 
The values to be used as baselines will be the values collected on Day -1 for each patient. If any of the scheduled 
baseline tests are repeated for any patient, the last re-checked values will be considered as baselines, provided they 
were done before the start of IMP administration and under the same conditions (e.g. fasted) as the original test. 
In case of central and local tests performed at the same time, the central value will be considered as the baseline 
value provided it was done before the start of IMP administration. If a central test was not performed but a local 
value exists at the same date for the same test, the local value will be considered as the baseline. 
 
Quantitative laboratory measurements reported as “<X”, i.e. below the lower limit of quantification (LLQ), or 
“>X”, i.e. above the upper limit of quantification (ULQ), will be converted to X for the purpose of quantitative 
summaries, but will be presented as recorded, i.e. as “<X” or “>X” in the listings. 
 
For hematology, only local measures are available and will be used for quantitative summary statistics without 
normalization of data. 
 
For creatinine clearance: it has to be noted that for African patients more than 14 years old (i.e. Cohorts 1a and 1b), 
the used assay method for central laboratory based serum creatinine (Jaffre) was not suitable for Schwartz 
calculation of the creatinine clearance, therefore only Cockroft and Gault formula was used by the central laboratory 
in this population. For other patients, creatinine clearance is calculated locally and/ or centrally according to formulae 
specified in the protocol (Cockroft and Gault formula for patients more than 18 years old and GFR Bedside Schwartz 
formula for other patients). 
 
For glucose, only fasted assessments will be used for quantitative summaries. 
14.5.2. DESCRIPTIVE STATISTICS 
Summary statistics (including number, mean, SD, median, first and third quartiles, minimum and maximum) of all 
laboratory variables (values and changes from baseline) will be calculated for each visit or study assessment time 
point (baseline, each post-baseline time point, worst (as defined by medical team) TEAE period value (as defined 
in Section 14.1)). 
 


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This section will be organized by biological function as specified above. Tables will be repeated by age group for 
C3&4SAF. Table for liver tests will be repeated for C3&4SAF, ASAF and A5SAF sub-populations. 
14.5.3. ANALYSES OF ABNORMALITIES 
The incidence of PCSAs (list provided in Appendix 3) at any time during the TEAE period will be summarized by 
biological function whatever the baseline level and/ or according to the following baseline status categories: 
• 
Normal/missing 
• 
Abnormal according to PCSA criterion or criteria 
 
Creatinine clearance PCSA definition for adults will be used in African children more than 14 years. 
 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range will be provided. 
 
Summary tables for liver function will be repeated for C3&4SAF, ASAF and A5SAF sub-populations. 
 
All laboratory abnormalities will be listed. 
14.5.4. DRUG-INDUCED LIVER INJURY 
The incidence of liver-related AEs will be summarized. The selection of PTs will be based on standardized 
MedDRA query (SMQ) Hepatic disorder. 
 
A graph of distribution (e-Dish plot) of peak values of ALT versus peak values of total bilirubin will be presented. 
ALT and total bilirubin values will be presented on a logarithmic scale. The graph will be divided into 4 quadrants 
with a vertical line corresponding to 3xULN for ALT and a horizontal line corresponding to 2xULN for total 
bilirubin. 
 
A listing will be presented of possible Hy’s law cases identified by treatment group (i.e., patients with any elevated 
ALT>3xULN, and an associated increase in bilirubin >2xULN) with ALT, AST, alkaline phosphatase, total 
bilirubin, and the following complementary parameters: conjugated bilirubin and prothrombin time/international 
normalized ratio, creatine kinase, creatinine, full blood count. Other relevant parameters (anti-HAV IgM, anti-HBc IgM, 
anti-HCV and HCV RNA, anti-CMV IgM and anti-HEV IgM antibodies, auto-antibodies: anti-nuclear, anti-DNA, anti-
smooth muscle, Epstein-Barr virus, herpes viruses, and anti-LKM) will be presented as available. 
 
A listing will be presented of all patients with increase in ALT≥2xULN, including information on IMP intake, 
medical and surgical history, alcohol habits, trigger factors, event details with ALT values, associated signs and 
symptoms. 


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14.5.5. GENERAL LABORATORY LISTINGS 
All individual data, for planned hematology and biochemistry tests, including re-checked and unscheduled values, 
will be listed by biological function, cohort, treatment group and patient, visit. In these listings, individual data 
will be flagged when lower or higher than the lower or upper laboratory limits and/or when reaching the absolute 
limit of PCSA criteria, when defined. 
 
A listing of out-of-normal range definitions will also be provided. 
14.6. ECG PARAMETERS 
ECG recordings are performed as per the schedule of assessments in Section 1.1 of the Protocol. 
 
Quantitative ECG parameters include: 
• 
Heart rate 
• 
QRS duration 
• 
RR interval 
• 
PR-interval 
• 
QT-interval, QTcF-interval (corrected according to Fridericia formula: QTcF = QT / (RR1/3), and QTcB-
interval (corrected according to Bazett’s formula: QTcB = QT / (RR1/2). 
 
Morphological ECG parameters include: 
• 
ST segment deviation 
• 
T-wave morphology 
• 
U-wave presence or absence 
14.6.1. GENERAL CONVENTIONS 
For all quantitative ECG parameters, the mean of triplicate ECGs at each time point will be used for all analyses 
including PCSA analyses. As far as at least one record is available from a triplicate, it will be used in the mean 
calculations for analyses. No time restriction is applied for calculation of mean values from triplicate ECGs 
performed at the same visit. 
 
For each set of triplicate ECGs, the associated date and time of the assessment is taken as the date and time of the 
first record of the triplicate. 
 
Baseline 
The value to be used as baseline will be defined as the average of the triplicate assessments done on Day 0 T0 or 
the last available time point prior to first dosing for each treatment group. 


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14.6.2. DESCRIPTIVE STATISTICS 
For all quantitative parameters, raw data and changes from baseline will be summarized using descriptive statistics 
(including number, mean, SD, median, first and third quartiles, minimum and maximum), by visit and time of 
measurement (baseline, each post-baseline time point, and worst on-treatment value). 
Summaries will be repeated by age group for C3&4SAF. Summaries will be repeated for C3&4SAF, ASAF and 
A5SAF sub-populations. 
14.6.3. ANALYSES OF ABNORMALITIES 
The incidence of PCSAs (list provided in Appendix 3) at any time during the TEAE period will be summarized, 
irrespective of the baseline level and/ or according to the following baseline status categories: 
• 
Normal/missing 
• 
Abnormal according to PCSA criterion or criteria 
Table will be repeated for C3&4SAF, ASAF and A5SAF sub-populations. 
 
If possible, a summary of ECG morphological assessments will be provided by cohort and treatment group. 
14.6.4. ANALYSIS OF QTC PROLONGATION 
Absolute QTcF and QTcB values will be summarized per post-baseline time point and worst TEAE period value 
in accordance with the following categories: 
• 
>450 msec 
• 
>480 msec 
• 
>500 msec 
QTcF and QTcB prolongations will be evaluated by tabulating the changes from baseline to each post-baseline 
time point and worst TEAE period value in accordance with the following categories: 
• 
>30 msec 
• 
>60 msec 
Table will be repeated for C3&4SAF, ASAF and A5SAF sub-populations. 
14.6.5. GENERAL ECG LISTINGS 
Individual data, including rechecked values, will be listed by cohort, treatment group, patient, visit and time of 
measurement. In the listings, values will be flagged when reaching the limits of the PCSA criteria, when defined. 


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14.7. VITAL SIGNS AND PHYSICAL MEASUREMENTS 
Vital signs measurements taken on this study include: heart rate (bpm), systolic and diastolic blood pressure in 
supine position (mmHg), and body temperature (⁰C). 
Physical measurements include: body weight (kg), height/length (cm) and BMI (kg/m2). 
 
All assessments are performed as per the schedule of assessments in Section 1.1 of the Protocol. 
14.7.1. GENERAL CONVENTIONS 
Baseline 
The values to be used as baseline will be the Day-1 for each treatment group. If any of the scheduled baseline tests 
are repeated for any patient, the last rechecked values will be considered as baseline, provided they were done 
before the start of IMP administration. 
14.7.2. DESCRIPTIVE STATISTICS 
The summary statistics (including number, mean, SD, median, first and third quartiles, minimum and maximum) of 
all vital signs variables (values and changes from baseline) will be calculated for each visit or study assessment 
(baseline, each post-baseline time point, and worst on-treatment value). 
Summaries will be repeated by age group for C3&4SAF. 
14.7.3. ANALYSES OF ABNORMALITIES 
The incidence of PCSAs (list provided in Appendix 3) at any time during the TEAE period will be summarized, 
irrespective of the baseline level and/ or according to the following baseline status categories: 
• 
Normal/missing 
• 
Abnormal according to PCSA criterion or criteria 
14.7.4. GENERAL VITAL SIGN AND PHYSICAL 
MEASUREMENTS LISTINGS 
Individual data (for the supine position only for heart rate, systolic and diastolic blood pressure), including 
rechecked and unscheduled values, will be listed by cohort, treatment group, patient, visit and time of assessment. 
In the listings, values will be flagged when reaching the limits of the PCSA criteria, when defined. 
 


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14.8. PHYSICAL EXAMINATION 
The physical examination outcome (Normal/Abnormal) will be collected at screening and post baseline visits. 
Any abnormal, clinically significant physical examination assessments will be reported as AEs. 
A full assessment of malaria signs and symptoms will be made alongside the physical examination. 
The following summaries will be provided for physical examination data: 
• 
Incidence of abnormalities at screening 
• 
Incidence of abnormalities post baseline 
 
 
 


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15. REFERENCES 
 
1. 
Flegg, J. A., Guerin, P. J., White, N. J., & Stepniewska, K. Standardizing the measurement of parasite 
clearance in falciparum malaria: the parasite clearance estimator. Malaria journal.2011;10(1): 339 
 
2. Fogarty, C. B., Fay, M. P., Flegg, J. A., Stepniewska, K., Fairhurst, R. M., & Small, D. S. Bayesian 
hierarchical regression on clearance rates in the presence of "lag" and "tail" phases with 
an application to malaria parasites. Biometrics. 2015; 71(3):751-759. 
 
 
 


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APPENDIX 1. 
PROGRAMMING CONVENTIONS FOR OUTPUTS 
DATES & TIMES 
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss. 
SPELLING FORMAT 
English US 
APPENDIX 2. 
PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR TEAES 
START DATE 
STOP 
DATE 
ACTION 
Known 
Known 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Partial 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Missing 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
 
 
Partial, but known components 
show that it cannot be on or after 
study med start date 
Known 
Not TEAE 
 
Partial 
Not TEAE 
 
Missing 
Not TEAE 
 
 
 
Partial, could be on or after study 
med start date 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last 
day of month if day unknown or 31st December if 
day and month are unknown), then: 
If stop date < study med start date, then not TEAE 


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ALGORITHM FOR PRIOR/ CONCOMITANT MEDICATIONS 
STARTDATE 
STOP 
DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior  
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant  
If stop date >= study med start date and start date > end of treatment, 
assign as post study  
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last 
day of month if day unknown or 31st December if 
day and month are unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 


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STARTDATE 
STOP 
DATE 
ACTION 
 
Partial 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown) and impute 
stop date as latest possible date (i.e. last day of month if day unknown 
or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
 
Missing 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Missing 
Known 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Missing 
Assign as concomitant 
 
APPENDIX 3. 
POTENTIALLY CLINICALLY SIGNIFICANT 
ABNORMALITIES ARITERIA 
PCSA DEFINITION FOR LABORATORY PARAMETERS 
Laboratory parameter 
PCSA criteria
Adults 
Children 
Hemoglobin 
Low 
≤ 115g/L (Male) 
≤95 g/L (Female)
28 days/1 month to 23 months old : < 90 g/L 
24 months/2 years to <16/18 years old : < 100 g/L
Decrease from baseline
≥20 g/L
≥2 0 g/L


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High (adults) 
≥ 185 g/L (Male) 
≥165 g/L (Female)
 
Hematocrit
Low 
≤ 0.37 v/v (Male) 
≤0.32 v/v (Female)
28 days/1 month to 23 months old: < 0.29 v/v 
24 months/2 years to <16/18 years old: < 0.32 v/v 
High 
≥ 0.55 v/v (Male) 
≥ 0.5 v/v (Female) 
28 days/1 month to 23 months old: > 0.42 v/v 
24 months/2 years to <16/18 years old: > 0.47 v/v 
Erythrocyte Count 
High (adults)
≥6 Tera/L
Platelet Count
Low
< 100 Giga/L
< 100 Giga/L
High
≥700 Giga/L
≥700 Giga/L
Leukocytes
Low 
< 3.0 Giga/L (Non-
Black) 
< 2.0 Giga/L 
(Black)
Birth/0 to 23 months old: <4.0 Giga /L 
24 months/2 years to <6 years old: <3.0 Giga /L 
6 to <12 years old: <5.0 Giga /L 
High 
≥ 16.0 Giga/L 
Birth/0 to 27 days old: >25.0 Giga /L 
28 days/1 month to 23 months old: >20.0 Giga /L 
24 months/2 years to <6 years old: >16.0 Giga /L 
6 to <12 years old: >17.0 Giga /L 
12 to 16/18 years old: >13.5 Giga /L 
Neutrophils 
Low 
< 1.5 Giga/L (Non-
Black) 
< 1.0 Giga/L 
(Black) 
Birth/0 to 27 days old: 
<4 Giga /L (1 day old) 
<1.5 Giga /L (2-7 days old) 
<1.25 Giga /L (>7 day-1 month old) 
28 days/1 month to 23 months old: 
<1.0 Giga /L (1-3 months) 
<1.2 Giga /L (3-24 months) 
24 months/2 years to <16/18 years old: <1.2 Giga /L 
High (children)
>1 ULN
Lymphocytes 
Low (children) 
 
Birth/0 to 27 days old: <1.2 Giga /L 
28 days/1 month to 23 months old: <2.0 Giga /L 
24 months/2 years to <12 years old: <1.0 Giga /L 
12 to 16/18 years old: <0.6 Giga /L 
High 
> 4.0 Giga/L 
Birth/0 to 27 days old: >17.0 Giga /L 
28 days/1 month to 23 months old: >13.5 Giga /L 
24 months/2 years to <6 years old: >9.5 Giga /L 
6 to <12 years old: >8.0 Giga /L 
12 to 16/18 years old: >6 Giga /L 
Monocytes
High (adults)
> 0.7 Giga/L 
 
Basophils
High (adults)
> 0.1 Giga/L
Eosinophils


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High 
> 0.5 Giga/L or > 
ULN 
(if ULN ≥ 0.5 
Giga/L) 
> 0.5 Giga/L or > ULN (if ULN > 0.5 Giga/L) 
Glucose
Low 
≤ 3.9 mmol/L and < 
LLN 
<2.7 mmol/L 
High 
≥11.1 mmol/L 
(unfasted) 
≥7 mmol/L (fasted)
≥10.0 mmol/L (unfasted) 
≥7 mmol/L (fasted after >12 hours of fast) 
Albumin
Low (adults)
≤25 g/L
Creatine Kinase
High, all grades
> 3 ULN 
≥3 ULN
At least grade 1 (adults)
> 3 ULN 
At least grade 2 (adults)
> 10 ULN
Sodium 
Low 
< 3 mmol/L 
Birth/0 to 27 days old: ≤3.0 mmol/L 
28 days/1 month to 16/18 years old: ≤3.5 mmol/L 
High 
≥ 5.5 mmol/L 
Birth/0 to 27 days old: ≥7.0 mmol/L 
28 days/1 month to 23 months old: ≥6.0 mmol/L 
24 months/2 years to 16/18 years old: ≥5.5 mmol/L 
Creatinine 
High 
≥ 150 µmol/L 
Birth/0 to <6 years old: >53 µmol/L 
6 years to <12 years old: >90 µmol/L 
12 years to 16/18 years old: >132 µmol/L 
Increase from baseline
 
At least grade 1 (adults) 
≥ 30% change from 
baseline
 
At least grade 2 (adults) 
≥ 100% change 
from baseline
 
Creatinine Clearance 
Low, all grades 
< 90 mL/min* 
Birth/0 to 27 days old: < 25 ml/min/1.73m² ** 
28 days/1 month to 23 months old: < 45 ml/min/1.73m² **  
From 2 years old: < 60 ml/min/1.73m² ** 
Mild (adults) 
[60 – 90[ 
mL/min*
 
Moderate (adults) 
[30 – 60[ 
mL/min*
 
Severe (adults) 
[15 – 30[ 
mL/min*
 
End stage (adults)
< 15 mL/min*
 
*MDRD or 
Cokcroft-Gault 
equation 
**GFR Bedside Schwartz Formula 
Based on normal ranges: 20 to 50 (<8 days), 25 to 80 (8 days to 1 
month), 30 to 90 (1-6 months), 40 to 115 (6-12 months), 60 to 190 
(12-23 months), 90 to 165 (2-12 years), 80-120 (After 12 years)
BUN


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High 
≥ 17 mmol/L 
Birth/0 to 27 days old: ≥4.3 mmol/L 
28 days/1 month to 16/18 years old: ≥6.4 mmol/L
Alanine Aminotransferase
High, at least grade 1
> 3 ULN
≥3 ULN
High, at least grade 2
> 5 ULN
≥5 ULN
High, at least grade 3
> 10 ULN
≥10 ULN
High, at least grade 4
> 20 ULN
≥20 ULN
Aspartate Aminotransferase
High, at least grade 1
> 3 ULN
≥3 ULN
High, at least grade 2
> 5 ULN
≥5 ULN
High, at least grade 3 
> 10 ULN
≥10 ULN
High, at least grade 4 
> 20 ULN
≥20 ULN
Alkaline phosphatase
High
> 1.5 ULN
≥1.5 ULN
Total Bilirubin
High, all grades
> 1.5 ULN
≥1.3 ULN
At least grade 1 (adults)
> 1.5 ULN
At least grade 2 (adults)
> 2 ULN 
Alanine Aminotransferase and total bilirubin
High 
ALT > 3 ULN and 
TBILI > 2 ULN
ALT ≥ 3 ULN and TBILI ≥ 2 ULN 
Direct bilirubin and total bilirubin 
High 
BILDIR >35% 
TBILI and 
TBILI >1.5 ULN
BILDIR >35% TBILI and TBILI≥1.3 ULN 
References: 
-for adults: Criteria for Potentially Significant Abnormalities – for Phase 2/3 studies (oncology excepted) - Version 3.0 – 
21-MAY-2014 
-for children: Criteria for Potentially Clinically Significant Abnormalities for Studies in Children - Version 3.0 - 21-MAY-2014 
PCSA DEFINITION FOR ECG PARAMETERS 
ECG parameter 
PCSA criteria
Adults 
Children 
Heart Rate 
Low, at least grade 1 (adults) 
<50 bpm 
 
Low, at least grade 2 (adults) 
<40 bpm
 
Low, at least grade 3 (adults) 
<30 bpm
 
Low and decrease from baseline, all 
grades 
<50 bpm and decrease from 
baseline ≥20 bpm 
Birth/0 to 27 days old: ≤ 90 bpm and decrease 
from baseline ≥20 bpm 
28 days/1 month to 23 months old: ≤ 80 bpm and 
decrease from baseline ≥20 bpm 
24 months/2 years to <6 years old: ≤ 75 bpm and 
decrease from baseline ≥20 bpm 
6 to <12 years old: ≤ 50 bpm and decrease from 
baseline ≥20 bpm 


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12 to 16/18 years old: ≤ 50 bpm and decrease 
from baseline ≥20 bpm 
At least grade 1 (adults) 
<50 bpm and decrease from 
baseline ≥20 bpm
 
At least grade 2 (adults) 
<40 bpm and decrease from 
baseline ≥20 bpm
 
At least grade 3 (adults) 
<30 bpm and decrease from 
baseline ≥20 bpm
 
High, at least grade 1 (adults)
>90 bpm
High, at least grade 2 (adults)
>100 bpm
 
High, at least grade 3 (adults)
>120 bpm
 
High and increase from baseline, all 
grades 
>90 bpm and increase from 
baseline ≥20bpm 
Birth/0 to 27 days old: ≥ 190 bpm and increase 
from baseline ≥20 bpm 
28 days/1 month to 23 months old: ≥ 175 bpm 
and increase from baseline ≥20 bpm 
24 months/2 years to <6 years old: ≥ 140 bpm and 
increase from baseline ≥20 bpm 
6 to <12 years old: ≥ 120 bpm and increase from 
baseline ≥20 bpm 
12 to 16/18 years old: ≥ 120 bpm and increase 
from baseline ≥20 bpm 
At least grade 1 (adults) 
>90 bpm and increase from 
baseline ≥20bpm
 
At least grade 2 (adults) 
>100 bpm and increase from 
baseline ≥20bpm
 
At least grade 3 (adults)  
>120 bpm and increase from 
baseline ≥20bpm
 
PR
High, all grades  
>200 ms  
Birth/0 to 27 days old: ≥ 120 ms 
28 days/1 month to 23 months old: ≥ 140 ms 
24 months/2 years to <6 years old: ≥ 160 ms 
6 to <12 years old: ≥ 170 ms 
12 to 16/18 years old: ≥ 180 ms 
At least grade 1 (adults)
>200 ms
At least grade 2 (adults)
>220 ms
At least grade 3 (adults)
>240 ms
High and increase from baseline (adults)
At least grade 1
>200 ms and increase from 
baseline ≥25%
 
At least grade 2
>220 ms and increase from 
baseline ≥25%
 
At least grade 3
>240 ms and increase from 
baseline ≥25%
 
QRS
High, all grades
>110 ms
Birth/0 to 27 days old: ≥ 85 ms 
28 days/1 month to 23 months old: ≥ 85 ms 
24 months/2 years to <6 years old: ≥ 95 ms 
6 to <12 years old: ≥ 100 ms 


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12 to 16/18 years old: ≥ 110 ms 
At least grade 1 (adults)
>110 ms
At least grade 2 (adults)
>120 ms
High and increase from baseline (adults)
At least grade 1
>110 ms and increase from 
baseline ≥25%
 
At least grade 2 
>120 ms and increase from 
baseline ≥25%
 
QTc Fridericia and QTc Bazett 
Increase from baseline, Grade 1 
Increase from baseline ]30-60] ms
All age classes: Increase from baseline ]30-60] ms 
Increase from baseline, Grade 2
Increase from baseline >60 ms
All age classes: Increase from baseline >60 ms
References: 
-for adults: Criteria for Potentially Significant Abnormalities – for Phase 2/3 studies (oncology excepted) - Version 3.0 – 
21-MAY-2014 
-for children: Criteria for Potentially Clinically Significant Abnormalities for Studies in Children - Version 3.0 - 21-MAY-2014 
PCSA DEFINITION FOR VITAL SIGNS PARAMETERS 
Vital signs parameter 
PCSA criteria
Adults 
Children 
Systolic blood pressure supine
Low and decrease 
from baseline 
≤95 mmHg and decrease from 
baseline ≥20 mmHg 
Birth/0 to 27 days old: ≤ 60 mmHg and decrease from 
baseline ≥20 mmHg 
28 days/1 month to 23 months old: ≤ 70 mmHg and 
decrease from baseline ≥20 mmHg 
24 months/2 years to <6 years old: ≤ 70 mmHg and 
decrease from baseline ≥20 mmHg 
6 to <12 years old: ≤ 80 mmHg and decrease from 
baseline ≥20 mmHg 
12 to 16/18 years old: ≤ 90 mmHg and decrease from 
baseline ≥20 mmHg 
High and increase from 
baseline 
≥160 mmHg and increase from 
baseline ≥20 mmHg 
Birth/0 to 27 days old: ≥ 85 mmHg and increase from 
baseline ≥20 mmHg 
28 days/1 month to 23 months old: ≥ 98 mmHg and 
increase from baseline ≥20 mmHg 
24 months/2 years to <6 years old: ≥ 101 mmHg and 
increase from baseline ≥20 mmHg 
6 to <12 years old: ≥ 108 mmHg and increase from 
baseline ≥20 mmHg 
12 to 16/18 years old: ≥ 119 mmHg and increase from 
baseline ≥20 mmHg 
Diastolic blood pressure supine 
Low and decrease from 
baseline 
≤45 mmHg and decrease from 
baseline ≥10 mmHg 
Birth/0 to <6 years old: ≤ 34 mmHg and decrease from 
baseline ≥10 mmHg 
6 to <12 years old: ≤ 48 mmHg and decrease from 
baseline ≥10 mmHg 


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12 to 16/18 years old: ≤ 54 mmHg and decrease from 
baseline ≥10 mmHg 
High and increase from 
baseline  
≥110 mmHg and increase from 
baseline ≥10 mmHg 
Birth/0 to 27 days old: ≥ 50 mmHg and increase from 
baseline ≥10 mmHg 
28 days/1 month to 23 months old: ≥ 54 mmHg and 
increase from baseline ≥10 mmHg 
24 months/2 years to <6 years old: ≥ 59 mmHg and 
increase from baseline ≥10 mmHg 
6 to <12 years old: ≥ 72 mmHg and increase from 
baseline ≥10 mmHg 
12 to 16/18 years old: ≥ 78 mmHg and increase from 
baseline ≥10 mmHg 
Heart rate supine (adults)
Low and decrease 
from baseline
≤50 bpm and decrease from 
baseline ≥20 bpm
 
Low and decrease from 
baseline
≥120 bpm and increase from 
baseline ≥20 bpm
 
References: 
-for adults: Criteria for Potentially Significant Abnormalities – for Phase 2/3 studies (oncology excepted) - Version 3.0 – 
21-MAY-2014 
-for children: Criteria for Potentially Clinically Significant Abnormalities for Studies in Children - Version 3.0 - 21-MAY-2014 
 
 
 


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APPENDIX 4. 
POWER AND SAMPLE SIZE 
The below table shows the power for different sample size and success rate hypotheses. 
Sample size 
Hypothesis on success rate 
Powera 
140 
0.92 
6.3% 
140 
0.94 
25.9% 
140 
0.95 
44.6% 
140 
0.96 
67.2% 
140 
0.964 
75.9% 
140 
0.97 
87.1% 
150 
0.92 
8.1% 
150 
0.94 
31.7% 
150 
0.95 
52.3% 
150 
0.96 
74.7% 
150 
0.964 
82.5% 
150 
0.97 
91.7% 
160 
0.92 
10.0% 
160 
0.94 
37.4% 
160 
0.95 
59.3% 
160 
0.96 
80.7% 
160 
0.964 
87.5% 
160 
0.97 
94.7% 
a probability that the lower bound of the exact (Clopper-Pearson) 95% two-sided confidence interval for success rate is strictly 
greater than 0.9.