Conditions: Malaria
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: yes

Brief summary:
A single-centre Phase 1b study to assess the safety, tolerability, pharmacokinetic profile, and antimalarial activity of single doses of coadministered artefenomel (OZ439) and piperaquine phosphate (PQP) against early Plasmodium falciparum blood stage infection in healthy adult volunteers.

Detailed description:
This is a single-centre, open-label, adaptive, study using the P. falciparum induced blood stage malaria (IBSM) inoculum as a model to characterise the pharmacodynamic (PD) activity of combined single dose administration of OZ439 and PQP.

The study will be conducted in a maximum of three cohorts (up to 8 subjects per cohort) using up to 4 different doses of OZ439 and PQP in each cohort. Subjects will be malaria naïve healthy males or females, aged between 18-55 years old, who meet all of the inclusion criteria and none of the exclusion criteria.

The first cohort will be composed of 4 groups of 2 subjects each. Subjects will be randomised into one of 4 dose groups and administered single oral doses of OZ439 and PQP in combination The combined dose of OZ439 and PQP will be different for each of the 4 groups in this cohort as shown in Table 1.

Table 1 OZ439 and PQP Cohort 1 Dose Drug Dose group

1A 1B 1C 1D OZ439 (mg) 200 200 400 400 PQP (mg) 480 640 480 640

The data captured from this first cohort will be used to determine the relationship between OZ439 and PQP concentrations and parasitaemia levels. Based on safety and tolerability data up to Day 35 post-dose, and pharmacokinetic/pharmacodynamic (PK/PD) analysis outcomes (based on PD data up to Day 35 and PK data up to Day 28 post-dose) of the drugs given in combination, the dose(s) for the subsequent cohort will be determined. A similar analysis will be done at the end of cohort 2 combining cohorts 1 and 2 data to decide the dose(s) to be tested in cohort 3. This will be decided by the funding sponsor and the Principal Investigator following review of the data by the Safety and Data Review Team (SDRT) and scientific evaluation.

The doses used in all cohorts will not exceed the maximum acceptable doses predefined for this study (800 mg for OZ439 and 1440 mg for PQP) as determined in previous safety, pilot efficacy and phase 2 studies.

Each subject will be inoculated on Day 0 with approximately 2,800 viable parasites of P. falciparum-infected human erythrocytes administered intravenously. Subjects will be followed up daily via phone call or text message on Days 1 to 3 post-inoculation to solicit any AEs.

Subjects will then come to the clinical unit once daily from Day 4 until presence of asexual parasites is established by quantitative polymerase chain reaction (qPCR) targeting the 18S rRNA gene (referred to hereafter as malaria 18S qPCR). Once qPCR becomes positive and until OZ439 and PQP administration, subjects will come to the clinical unit twice-daily, separated by approximately 12 hours, for clinical evaluation and blood sampling.

Subjects will be admitted to the clinical unit for single dose administration of OZ439 and PQP 8 days after malaria inoculation or at Investigators discretion (i.e. as per parasitaemia levels). Subjects will be followed up as inpatients for at least 72 hours to ensure tolerance of the investigational treatments and clinical response, then if clinically well on an outpatient basis for safety and clearance of malaria parasites via qPCR.

After discharge from the clinical unit, subjects will be followed up regularly for safety assessments, PK sampling, clinical evaluation, and malaria qPCR blood sampling until 35 days after OZ439 and PQP administration. All subjects will receive a standard course of therapy with Riamet® (artemether-lumefantrine) 34 days after OZ439 and PQP administration, or earlier in the event of failure of clearance of parasitaemia or recrudescence of parasitaemia. The presence of gametocytes in subjects' blood will be determined by parasite lifecycle stage qRT-PCR or by the presence of stable low level parasitaemia. If gametocytes are present at the time of treatment with Riamet®, Primacin™ (primaquine) will also be administered as a single oral dose.

AEs (AEs) will be monitored via telephone, within the clinical unit, and on outpatient review after malaria challenge inoculation and antimalarial study drugs administration. Blood samples for safety evaluation, malaria monitoring, and red blood cell antibodies will be drawn at screening and/or baseline and at nominated times after malaria challenge.

Arms:
arm 1: 200mg of OZ439 and 480 mg PQP. (OZ439 + α-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension) and PQP. arm 2: 200mg of OZ439 and 640 mg PQP.

(OZ439 + α-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension) and PQP. arm 3: 400mg of OZ439 and 480 mg PQP.

(OZ439 + α-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension) and PQP. arm 4: 400mg of OZ439 and 640 mg PQP.

(OZ439 + α-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension) and PQP. arm 5: 800mg of OZ439 and 960 mg PQP. arm 6: 200mg of OZ439 and 320 mg PQP. arm 7: 800mg of OZ439 and 640 mg PQP

Interventions: intervention 1: 480 mg Piperaquine phosphate intervention 2: 640 mg Piperaquine phosphate intervention 3: 200 mg OZ 439 intervention 4: 400 mg OZ 439 intervention 5: 800 mg OZ 439 intervention 6: 960 mg PQP intervention 7: 320 mg PQP
Intervention descriptions: intervention 1: 480 mg Piperaquine is a bis 4-aminoquinoline and was used mainly in China from the 1960's to the 1980's as an antimalarial monotherapy. intervention 2: 640 mg Piperaquine is a bis 4-aminoquinoline and was used mainly in China from the 1960's to the 1980's as an antimalarial monotherapy. intervention 3: 200 mg OZ439 + α-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension intervention 4: 400 mg OZ439 + α-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension intervention 5: 800 mg OZ439 + α-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension intervention 6: 960 mg Piperaquine is a bis 4-aminoquinoline and was used mainly in China from the 1960's to the 1980's as an antimalarial monotherapy. intervention 7: 320 mg Piperaquine is a bis 4-aminoquinoline and was used mainly in China from the 1960's to the 1980's as an antimalarial monotherapy.

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
A single-centre Phase 1b study to assess the safety, tolerability, pharmacokinetic profile, 
and antimalarial activity of single doses of co-administered artefenomel (OZ439) and 
piperaquine phosphate (PQP) against early Plasmodium falciparum blood stage infection in 
healthy adult volunteers 
 
Protocol Identifying Number: QP17C19 
 
Principal Investigator: Prof. James McCarthy 
  
Study Sponsor: Medicines for Malaria Venture 
 
Local Sponsor: Clinical Network Services 
 
Version Number: Protocol 4.0  
 
27 August 2018 
 
CONFIDENTIALITY STATEMENT 
This document contains information that
 is privileged or confidential. As such, it may not be 
disclosed unless specific prior permission is granted in writing by 
Medicines for Malaria Venture
 
or such disclosure is required by federal or other laws or regulatio
ns. Persons to whom any of this 
information is to be disclosed mus
t first be informed that the information is confidential.
 These 
restrictions on disclosure will apply equally to all future information supplied, which is indicated 
as privileged or confidential
.


 
 
i 
 
CONTENTS  
LIST OF ABBREVIATION S ......................................................................................................... 1 
STATEMENT OF COMPLIANCE ......................................................................................................... 4 
PROTOCOL SUMMARY ..................................................................................................................... 6 
SCHEMATIC OF STUDY D ESIGN  ............................................................................................ 13 
1 
KEY ROLES  ...................................................................................................................... 15 
2 
INTRODUCTION: BACKGR
OUND INFORMATION AND  SCIENTIFIC RATIONALE
 
18 
2.1 
BACKGROUND INFORMATION .............................................................................................. 18 
2.2 
RATIONALE .................................................................................................................................... 19 
2.3 
POTENTIAL RISKS AND BENEFITS ...................................................................................... 20 
2.3.1 
KNOWN POTENTIAL RISKS .................................................................................. 20 
2.3.2 
KNOWN POTENTIAL BENEFITS ......................................................................... 25 
3 
OBJECTIVES AND PURPO SE ......................................................................................... 26 
4 
STUDY DESIGN AND ENDPOINTS  ................................................................................ 27 
4.1 
DESCRIPTION OF THE STUDY DESIGN .............................................................................. 27 
4.2 
STUDY ENDPOINTS ..................................................................................................................... 29 
4.2.1 
PRIMARY ENDPOINT .............................................................................................. 29 
4.2.2 
SECONDARY ENDPOINTS ..................................................................................... 29 
4.2.3 
EXPLORATORY ENDPOINTS ................................................................................ 30 
5 
STUDY ENROLLMENT AND  WITHDRAWAL ............................................................... 31 
5.1 
Subject Inclusion Criteria ..................................................................................................................... 31 
5.2 
Subject Exclusion Criteria .................................................................................................................... 32 
5.3 
Contraception ....................................................................................................................................... 37 
5.4 
Strategies for Recruitment and Retention ............................................................................................. 37 
5.5 
Subject Withdrawal or termination ...................................................................................................... 39 
5.5.1 
Reasons for Withdrawal or Termination ........................................................................... 39 
5.5.2 
Handling of Subject Withdrawals or termination ............................................................. 39 
5.6 
Premature Termination or Suspension of Study ................................................................................... 39 
6 
STUDY AGENT  ................................................................................................................. 40 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION .......................................................... 40 
6.1.1 
ACQUISITION ............................................................................................................. 40 
6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING .......... 41 
6.1.3 
PRODUCT STORAGE AND STABILITY ............................................................. 42 
6.1.4 
PREPARATION ........................................................................................................... 43 
6.1.5 
DOSING AND ADMINISTRATION ....................................................................... 44 
6.1.6 
ROUTE OF ADMINISTRATION ............................................................................. 45 
6.1.7 
STARTING DOSE AND DOSE ESCALATION SCHEDULE .......................... 46 
6.1.8 
DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS ...................................... 46 
6.1.9 
Duration of Therapy ......................................................................................................... 46 
6.1.10 
 Tracking of Dose ............................................................................................................. 46 
6.2 
Study agent Accountability Procedures ................................................................................................ 47 
7 
STUDY PROCEDURES AND  SCHEDULE  ...................................................................... 47 
7.1 
STUDY PROCEDURES/EVALUATIONS ................................................................................ 47 
7.1.1 
STUDY SPECIFIC PROCEDURES ......................................................................... 47 
7.1.2 
STANDARD OF CARE STUDY PROCEDURES ................................................ 51 


 
 
ii 
 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ................................................................. 51 
7.2.1 
CLINICAL LABORATORY EVALUATIONS ..................................................... 51 
7.2.2 
Other Assays or Procedures .............................................................................................. 54 
7.2.3 
SPECIMEN PREPARATION, HANDLING, AND STORAGE ......................... 56 
7.2.4 
SPECIMEN SHIPMENT ............................................................................................. 56 
7.3 
STUDY SCHEDULE ....................................................................................................................... 56 
7.3.1 
SCREENING ................................................................................................................. 56 
7.3.2 
ELIGIBILITY CONFIRMATION VISIT ............................................................... 58 
7.3.3 
FOLLOW-UP ................................................................................................................ 59 
7.3.4 
END OF STUDY VISIT (EOS) ................................................................................ 63 
7.3.5 
EARLY TERMINATION VISIT .............................................................................. 64 
7.3.6 
UNSCHEDULED VISIT ............................................................................................. 64 
7.3.7 
SCHEDULE OF EVENTS TABLE .......................................................................... 64 
7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES ............................................................. 69 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ................... 69 
7.5.1 
PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES
 
69 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ......................... 69 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES .................. 70 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES ................................... 70 
7.9 
SUBJECT ACCESS TO STUDY AGENT AT STUDY CLOSURE ..................................... 70 
8 
ASSESSMENT OF SAFETY .............................................................................................. 70 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ..................................................................... 70 
8.1.1 
DEFINITION OF AES (AE) ...................................................................................... 70 
8.1.2 
DEFINITION OF SERIOUS AES (SAE) ............................................................... 72 
8.1.3 
DEFINITION OF AES OF SPECIAL INTEREST (AESI) ................................. 73 
8.2 
CLASSIFICATION OF AN AE ................................................................................ 74 
8.2.1 
SEVERITY OF EVENT .............................................................................................. 74 
8.2.2 
RELATIONSHIP TO STUDY AGENT ................................................................... 75 
8.2.3 
EXPECTEDNESS......................................................................................................... 76 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP
 
77 
8.4 
REPORTING PROCEDURES ....................................................................................................... 77 
8.4.1 
AE REPORTING .......................................................................................................... 77 
8.4.2 
SERIOUS AE REPORTING ...................................................................................... 79 
8.4.3 
UNANTICIPATED PROBLEM REPORTING ...................................................... 80 
8.4.4 
AES OF SPECIAL INTEREST (AESI) .................................................................. 80 
8.4.5 
REPORTING OF PREGNANCY .............................................................................. 80 
8.5 
STUDY HALTING RULES ........................................................................................................... 80 
8.6 
SAFETY OVERSIGHT .................................................................................................................. 81 
9 
CLINI CAL MONITORING .................................................................................................. 81 
10 
STATISTICAL CONSIDER ATIONS  ................................................................................ 82 
10.1 
STATISTICAL ANALYSIS PLAN ............................................................................................. 82 
10.2 
ANALYSIS DATASETS ................................................................................................................ 82 
10.3 
DESCRIPTION OF STATISTICAL METHODS ..................................................................... 82 
10.3.1 
GENERAL APPROACH ............................................................................................. 82 
10.3.2 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) .......................... 83 


 
 
iii 
 
10.3.3 
ANALYSIS OF THE SECONDARY ENDPOINT(S) .......................................... 83 
10.3.4 
SAFETY ANALYSES ................................................................................................. 84 
10.3.5 
ADHERENCE AND RETENTION ANALYSES .................................................. 85 
10.3.6 BASELINE DESCRIPTIVE STATISTICS .................................................................................. 85 
10.3.7 
PLANNED INTERIM ANALYSES ......................................................................... 85 
10.3.8 
ADDITIONAL SUB-GROUP ANALYSES ............................................................ 85 
10.3.9 
MULTIPLE COMPARISON/MULTIPLICITY ..................................................... 86 
10.3.10 TABULATION OF INDIVIDUAL RESPONSE DATA ......................................................... 86 
10.3.11 EXPLORATORY ANALYSES ..................................................................................................... 86 
10.4 
SAMPLE SIZE ................................................................................................................................. 86 
10.5 
MEASURES TO MINIMIZE BIAS ............................................................................................. 86 
10.5.1 
ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES ............... 86 
10.5.2 
EVALUATION OF SUCCESS OF BLINDING .................................................... 86 
10.5.3 
BREAKING THE STUDY BLIND/SUBJECT CODE ......................................... 86 
11 
SOURCE DOCUMENTS AND  ACCESS TO SOURCE DAT A/DOCUMENTS  ............... 87 
12 
QUALITY ASSURANCE AN D QUALITY CONTROL  .................................................... 87 
13 
ETHICS/PROTECTION OF
 HUMAN SUBJECTS  .......................................................... 87 
13.1 
ETHICAL STANDARD ................................................................................................................. 88 
13.2 
ETHICAL REVIEW ........................................................................................................................ 89 
13.3 
INFORMED CONSENT PROCESS ............................................................................................ 90 
13.3.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
PROVIDED TO SUBJECTS ......................................................................................................................... 90 
13.3.2 
CONSENT PROCEDURES AND DOCUMENTATION ..................................... 90 
13.4 
SUBJECT AND DATA CONFIDENTIALITY ......................................................................... 91 
13.4.1 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA
 
91 
13.5 
FUTURE USE OF STORED SPECIMENS ................................................................................ 91 
14 
DATA HANDLING AND RE CORD KEEPING  ................................................................ 92 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ................................ 92 
14.2 
STUDY RECORDS RETENTION ............................................................................................... 92 
14.3 
PROTOCOL DEVIATIONS .......................................................................................................... 93 
14.4 
PUBLICATION AND DATA SHARING POLICY ................................................................. 93 
15 
STUDY ADMINISTRATION  ............................................................................................ 95 
15.1 
STUDY LEADERSHIP .................................................................................................................. 95 
15.2 
LIABILITY/INDEMNITY/INSURANCE .................................................................................. 95 
16 
CONFLICT OF INTEREST
 POLICY  ............................................................................... 95 
17  
LITERATURE REFERENCE
S ......................................................................................... 95 
APPENDIX .................................................................................................................................... 100 
 
 


 
 
1 
 
LIST OF ABBREVIATION S 
ACPR 
Adjusted Adequate Clinical and Parasitological Response 
ACT 
Artemisinin Combination Therapy 
AE 
AE 
AESI 
AE of Special Interest 
ALT 
Alanine Aminotransferase  
ANZCTR 
Australia New Zealand Clinical Trial Registry 
anti-HBc Ab 
Anti-Hepatitis B Core Antibodies 
anti-HCV 
Anti-Hepatitis C Virus 
anti-HIV1 
Anti-Human Immunodeficiency Virus 1 
anti-HIV2 
Anti-Human Immunodeficiency Virus 2 
AST 
Aspartate Aminotransferase  
AUC 
Area Under the Curve 
AUCinf 
AUC Curve to Infinite Time 
AUClast 
AUC Curve to Last Quantifiable Concentration 
BDI 
Beck Depression Index 
Blood Service  
Australian Red Cross Blood Service 
CRP 
C-Reactive Protein  
Cmax 
Maximum Plasma Concentration  
CNS 
Clinical Network Services 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for AEs 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
EC50 
Half maximal effective concentration 
EOS 
End of Study 
Emax 
Maximum effective concentration 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
FQ 
Ferroquine 
G6PD 
Glucose-6-Phosphate Dehydrogenase 
GCP  
Good Clinical Practice  
GI 
Gastrointestinal  
GMP  
Good Manufacturing Practice  
GPDI 
General Pharmacodynamic Interaction 
HAV 
Hepatitis A Virus 
HBs Ag 
Hepatitis B surface antigen 
HCV  
Hepatitis C Virus  
HEV 
Hepatitis E Virus 
HDL 
High Density Lipoprotein 
HIV  
Human Immunodeficiency Virus  
HPLC 
High-Performance Liquid Chromatography System 
HREC 
Human Research Ethics Committee  


 
 
2 
 
IB 
Investigators Brochure 
IBSM 
Induced Blood Stage Malaria  
ICH  
International Conference on Harmonization 
IMM 
Independent Medical Monitor  
IMP  
Investigational Medicinal Product  
IV 
Intravenous 
LC MS  
Liquid Chromatography–Mass Spectrometry 
LFT 
Liver Function Test 
LLOQ 
Lower Limit of Quantification 
MAP 
Modelling Analysis Plan 
MCB 
Master Cell Bank 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFA 
Membrane Feeding Assay 
MIC 
Minimum Inhibitory Concentration 
MMV 
Medicines for Malaria Venture 
MPC 
Minimal Parasiticidal Concentration  
NHMRC  
National Health and Medical Research Council 
NLME 
Non-linear mixed effect 
NTF 
Note To File 
OZ439 
Artefenomel 
PD 
Pharmacodynamic  
PK 
Pharmacokinetic 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PQP 
Piperaquine Phosphate 
PRR 
Parasite Reduction Ratio 
Pt ‰ 
Parasite clearance half-life  
QIMR Berghofer 
Queensland Institute of Medical Research Berghofer  
qPCR 
Quantitative Polymerase Chain Reaction 
qRT-PCR 
Quantitative Reverse Transcription Polymerase Chain Reaction 
QTc 
Corrected QT 
RBC 
Red Blood Cell 
Rh 
Rhesus Antibody 
SAE  
Serious AE  
SAP 
Statistical Analysis Plan 
SDRT 
Safety and Data Review Team  
SERC 
Single Exposure Radical Cure 
SOP 
Standard Operating Procedures 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
t1/2 
Terminal Half-Life 
TEAE                            
Treatment-Emergent AE 
TGA 
Therapeutic Goods Administration 
Tmax 
Time taken to reach Cmax 
TPGS 
α-tocopherol polyethylene glycol 1000 succinate 


 
 
3 
 
TPP 
Target Product Profile 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization  
WOCBP 
Women of Childbearing Potential 


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STATEMENT OF COMPLIA
NCE  
Investigator  declaration  
I have read the protocol and agree that it contains all necessary details for carrying out the study 
as described. I will conduct this protocol as outlined herein and will make a reasonable effort to 
complete the study within the time designated. 
I agree to personally conduct or supervise the described study. 
The study will be conducted in accordance with the following: 
 World Medical Association Declaration of Helsinki – Ethical Principles for Medical 
Research Involving Human Subjects (Fortaleza, Brazil 2013). 
 NHMRC National Statement on Ethical Conduct in Human Research (2007, updated May 
2015). 
 Note for Guidance on Good Clinical Practice (GCP) – Annotated with Therapeutic Goods 
Administration (TGA) Comments (CPMP/ICH/135/95), as adopted by the Australian TGA 
(July 2000). 
 Current ethics approved Clinical Trial Protocol. 
I agree to inform all subjects that the study drugs are being used for investigational purposes and 
I will ensure that the requirements related to obtaining informed consent are in accordance with 
International Council of Harmonisation (ICH) Guidelines for GCP Section 4.8 and local 
requirements. 
I agree to report AEs that occur in the course of the study to the Sponsor in accordance with ICH 
Guidelines for GCP Section 4.11 and local requirements. 
I have read and understand the information in the Investigator’s Brochures, including the potential 
risks and side effects of the study drugs. 
I agree to promptly report to the Human Research Ethics Committee (HREC) all changes in the 
research activity and all unanticipated problems involving risk to subjects. I will not make any 
changes to the conduct of the study without HREC and Sponsor approval, except when necessary 
to eliminate apparent immediate harm to subjects. 
I agree to maintain adequate and accurate records and make those records available in accordance 
with ICH Guidelines for GCP Section 4.11 and local requirements. 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study 
are informed about their obligations in meeting the above commitments. 
I understand that the study may be terminated or enrolment suspended at any time by the Sponsor, 
with or without cause, or by me if it becomes necessary to protect the best interest of the subjects. 
 
___________________________________         Date: _____________________________ 
Professor James McCarthy, Principal Investigator 


OZ439 and PQP Protocol 
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Signat ories 
The undersigned parties agree that the protocol was written in accordance with the World Medical 
Association Declaration of Helsinki – Ethical Principles for Medical Research Involving Human 
Subjects (Fortaleza, Brazil 2013), the NHMRC National Statement on Ethical Conduct in Human 
Research (2007, updated May 2015), and the Note for Guidance on Good Clinical Practice – 
Annotated with TGA Comments (CPMP/ICH/135/95), as adopted by the Australian Therapeutic 
Goods Administration (July 2000). 
Name  
Signature  
Date  
Protocol Writer: 
Dr Rebecca W ebster PhD 
Clinical Trials Project Manager 
QIMR Berghofer Medical Research Institute 
 
 
 
This clinical trial protocol has been reviewed and approved by the Sponsor.
 
Name  
Signature  
Date  
Sponsor Medical Director:  
Stephan Chalon , MD, PhD 
Medicines for Malaria Venture 
 
 
Sponsor Project Director: 
Jörg Möhrle PhD
 
Medicines for Malaria Venture 
 
 
 
 
 
 


OZ439 and PQP Protocol 
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PROTOCOL SUMMARY  
 
Title:  
A single-centre Phase 1b study to assess the safety, tolerability, 
pharmacokinetic profile, and antimalarial activity of single doses of co-
administered artefenomel (OZ439) and piperaquine phosphate (PQP) 
against early Plasmodium falciparum blood stage infection in healthy 
adult volunteers. 
Study 
Description : 
This is a single-centre, open-label, adaptive, study using the P. falciparum 
induced blood stage malaria (IBSM) inoculum as a model to characterise 
the pharmacodynamic (PD) activity of combined single dose 
administration of OZ439 and PQP.  
The study will be conducted in a maximum of three cohorts (up to 8 
subjects per cohort) using up to 4 different doses of OZ439 and PQP in 
each cohort.  Subjects will be malaria naïve healthy males or females, aged 
between 18-55 years old, who meet all of the inclusion criteria and none 
of the exclusion criteria. 
The first cohort will be composed of 4 groups of 2 subjects each. Subjects 
will be randomised into one of 4 dose groups and administered single oral 
doses of OZ439 and PQP in combination The combined dose of OZ439 
and PQP will be different for each of the 4 groups in this cohort as shown 
in Table 1.   
Table 1 OZ439 and PQP Cohort 1 Dose  
Drug  
Dose group  
1A 
1B 
1C 
1D 
OZ439 (mg) 
200 
200 
400 
400 
PQP     (mg) 
480 
640 
480 
640 
 
The data captured from this first cohort will be used to determine the 
relationship between OZ439 and PQP concentrations and parasitaemia 
levels. Based on safety and tolerability data up to Day 42–2 and 
pharmacokinetic/pharmacodynamic (PK/PD) analysis outcomes (based on 
PD data up to Day 42–2 and PK data up to Day 35–2), the dose(s) for the 
subsequent cohort will be determined.  


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After review of the PK/PD and safety data from Cohort 1 by the Safety 
and Data Review Team (SDRT) it was determined that, the second cohort 
will be composed of 2 dose groups of 4 subjects each. Subjects will be 
randomised into one of 2 dose groups and administered single oral doses 
of OZ439 and PQP in combination. The combined dose of OZ439 and PQP 
will be different for each group in this cohort as shown in Table 2.   
Table 2 OZ439 and PQP Cohort 2 Dose 
Drug  
Dose group  
2A 
2B 
OZ439 (mg) 
800 
200 
PQP     (mg) 
960 
320 
 
A similar analysis will be done at the end of cohort 2 combining cohorts 1 
and 2 data to decide the dose(s) to be tested in cohort 3. This will be 
decided by the funding sponsor and the Principal Investigator following 
review of the data by the SDRT and scientific evaluation.  
 
The doses used in all cohorts will not exceed the maximum acceptable 
doses predefined for this study (800 mg for OZ439 and 1440 mg for PQP) 
as determined in previous safety, pilot efficacy and phase 2 studies.  
Each subject will be inoculated on Day 0 with approximately 2,800 viable 
parasites of P. falciparum-infected human erythrocytes administered 
intravenously. Subjects will be followed up daily via phone call or text 
message on Days 1 to 3 post-inoculation to solicit any AEs.  
Subjects will then come to the clinical unit once daily from Day 4 until 
presence of asexual parasites is established by quantitative polymerase 
chain reaction (qPCR) targeting the 18S rRNA gene (referred to hereafter 
as malaria 18S qPCR). Once qPCR becomes positive and until OZ439 and 
PQP administration, subjects will come to the clinical unit twice-daily, 
separated by approximately 12 hours, for clinical evaluation and blood 
sampling.  
Subjects will be admitted to the clinical unit for single dose administration 
of OZ439 and PQP 8 days after malaria inoculation or earlier if a subject 
has a malaria clinical score >6 or at Investigators discretion. Subjects will 


OZ439 and PQP Protocol 
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be followed up as inpatients for at least 72 hours to ensure tolerance of the 
investigational treatments and clinical response, then if clinically well on 
an outpatient basis for safety and clearance of malaria parasites via qPCR.  
After discharge from the clinical unit, subjects will be followed up 
regularly for safety assessments, PK sampling, clinical evaluation, and 
malaria qPCR blood sampling until Day 42–2 (34 days after OZ439 and 
PQP administration). All subjects will receive a standard course of therapy 
with Riametﬁ (artemether -lumefantrine) on Day 42–2, or earlier in the 
event of failure of clearance or recrudescence of parasitaemia or at 
Investigators discretion based on subject safety. For guidance, the 
definitions for failure of parasite clearance and recrudescence are defined.  
– Failure of clearance: defined as failure to clear parasitaemia by at 
least 10-fold at 72 hours post-IMP administration  
– Recrudescence: defined as ≥5 000 blood stage parasites/mL and a 
2-fold parasitaemia increase within 48 hours, or re-occurrence of 
malaria symptoms with a malaria clinical score >6).  
The presence of gametocytes in subjects’ blood will be determined by 
parasite lifecycle stage qRT-PCR or by the presence of stable low level 
parasitaemia. If gametocytes are present at the time of treatment with 
Riametﬁ, Primacin™ (primaquine) will also be administered as a single 
oral dose.  
AEs (AEs) will be monitored via telephone, within the clinical unit, and 
on outpatient review after malaria challenge inoculation and antimalarial 
study drugs administration. Blood samples for safety evaluation, malaria 
monitoring, and red blood cell antibodies will be drawn at screening and/or 
baseline and at nominated times after malaria challenge.   
 
 


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Objectives:  
 
Primary: 
The primary study objectives are:  
a. To characterise the PK/PD relationship between OZ439 and PQP 
plasma concentrations and blood stage asexual parasitaemia in 
healthy subjects following P. falciparum IBSM infection.  
 
b. To evaluate the safety and tolerability of OZ439 and PQP when co-
administered as single doses in healthy subjects following 
P. falciparum IBSM infection. 
Secondary: 
The secondary study objectives are:  
a. To describe the PK of OZ439 and PQP when co-administered as 
single doses in healthy volunteers under fasted conditions.  
 
b. To characterize the PD effect of co-administered single doses of 
OZ439 and PQP on clearance of P. falciparum asexual blood stage 
parasites from the blood of healthy subjects in the IBSM model. 
Exploratory: 
The exploratory study objectives are:  
a. To characterise specific cell subsets and immune signatures 
associated with control of parasite burden and pathogenicity 
following first exposure to P. falciparum, to identify specific cells, 
immunomodulatory molecules and immune pathways to target for 
therapeutic intervention. 
b. To investigate the role of RBC complement regulatory proteins and 
anti-phosphatidylserine antibodies in malarial anaemia. 
c. To investigate the association between serum complement 
activation, 
complement 
activating 
antibodies, 
and 
RBC 
complement regulatory protein expression. 
 
 


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Endpoints:  
Primary: 
Primary study endpoints:  
a. The PK/PD relationship between OZ439 and PQP plasma 
concentrations and blood stage asexual parasitaemia will be 
determined by: 
 Effect of OZ439 on Emax and EC50 of PQP 
 Effect of PQP on Emax and EC50 of OZ439 
 
b. The incidence, severity and relationship to OZ439 and PQP of 
observed and self-reported AEs up to trial Day 42–2 after the co-
administration of single doses of OZ439 and PQP to healthy 
subjects inoculated with IBSM 
 
Secondary: 
Secondary study endpoints: 
a. Estimation of OZ439 and PQP PK parameters up to trial Day 42–2 
of single doses using non-compartmental methods: AUC0-168h, 
AUClast, AUC0-inf, Cmax, tmax, t1/2, tlag, C168h, CL/F, Vz/F 
and λinf.  
 
b. The effect of co-administered single oral doses of OZ439 and PQP 
on clearance of P. falciparum blood stage parasites from the blood 
of inoculated subjects as measured by qPCR up to trial Day 42–2. 
Parasite clearance will be assessed by the following parameters: 
 Parasite clearance half-life (Pt ‰),  
 Parasite reduction ratio (PRR), 
 Percentage of subjects with recrudescence of parasitaemia, 
defined as ≥5 000 blood stage parasites/mL and a 2-fold 
increase within 48 hours, or re-occurrence of malaria 
symptoms with a malaria clinical score >6).   
 
 


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Exploratory: 
a. Identification of immune checkpoint molecules. 
b. The level of expression of complement regulatory proteins (CD35, 
CD55 and CD59) and phosphatidylserine on RBC. 
c. The level of complement activating antibodies and anti-
phosphatidylserine antibodies.  
Population:  
A total of up to 24 subjects will be enrolled in this study (up to 3 cohorts 
of 8 subjects each). Subjects will be malaria naïve healthy males or 
females, aged between 18-55 years old, who meet all of the inclusion 
criteria and none of the exclusion criteria. 
In each cohort, if more than, 2 discontinuations due to non-safety related 
reasons occur; additional subjects may be recruited to replace the 
discontinued subjects on agreement with the study sponsor. 
Subjects eligible for inclusion of the study will be further invited to 
participate in optional exploratory components that will require additional 
blood samples to be taken at scheduled time-points during the study. 
Details regarding these optional study components will be provided in a 
separate Participant Information Sheet and subjects agreeing to participate 
in these components will provide specific written consent for this. Refusal 
to participate in the optional study components will not jeopardise a 
subjects’ participation in the main study.   
Phase:  
Phase 1b 
Number of sites 
enrolling 
subjects:  
The study is planned to be performed in one investigational site: 
Q-Pharm Pty Ltd 
Level 5, 300C Herston Rd and  
Level 6, Block 8, Royal Brisbane and Women’s Hospital 
Herston QLD 4006, Australia 
Additional sites in Australia may be added if necessary. 
 
Description 
of 
study agents:  
Malaria challenge agent:  
P. falciparum 3D7 blood stage challenge agent 


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The P. falciparum 3D7 master cell bank (MCB) was produced from blood 
collected from a donor with clinical manifestation of malaria. Each 3D7 
inoculum dose will be prepared aseptically from an aliquot of the  
P. falciparum 3D7 MCB. Each subject administered 3D7 will be 
inoculated intravenously with a dose of approximately 2,800 viable  
P. falciparum 3D7-infected RBCs in 2 mL of saline for injection. 
Investigational medicinal products:
 
OZ439 
OZ439 + α-tocopherol polyethylene glycol 1000 succinate (TPGS) 
granules for oral suspension, in 200 mg and 400 mg dosages and provided 
with sucrose. 
 
PQP  
Piperaquine phosphate (PQP), 160 mg tablets. 
 
Antimalarial rescue medications:
 
Artemether/lumefantrine 
Riametﬁ (20 mg artemether and 120 mg lumefantrine) will be 
administered to all subjects beginning on approximately Day 42–2 (34 
days after administration of OZ439 and PQP), or earlier in the event of 
failure of clearance or recrudescence of parasitaemia or at Investigators 
discretion based on subject safety. A course of treatment comprises 6 doses 
of 4 tablets administered orally over a period of 60 hours (total course of 
24 tablets). Each dose of tablets should be taken with food or drinks rich 
in fat (e.g., milk).  
Primaquine (if required)  
Subjects may receive a single oral dose of Primacin™ equivalent to 45 mg 
primaquine (6 tablets, each containing primaquine phosphate 13.2 mg, 
equivalent to 7.5 mg of primaquine) to ensure complete clearance of 
gametocytes. 
 
Artesunate (if required) 
Treatment of subjects with intravenous artesunate will only occur in the 
event that subjects are unable to complete oral treatment with Riametﬁ (e.g. 
the subject is vomiting). Treatment with artesunate would be done at the 
recommended dose regimen of 2.4 mg/kg at approximately 0, 12, 24, 48 
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Duration of Study  It is estimated that the clinical portion of the study will be completed in 
approximately 10 months.  
Duration subject 
participation:  
Approximately 2.5 months (74 days) for each subject, including a 
screening period of up to 28 days, a period of observation following 
inoculation of approximately 8 days, and a follow-up period after 
administration of OZ439 and PQP of 37 days.  
 
 
SCHEMATIC OF STUDY D ESIGN  
 


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1 
KEY ROLES  
 
Principal Investigator 
Prof. James McCarthy, MBBS 
Q-Pharm Pty Ltd (visiting Medical Officer) and  
QIMR Berghofer Medical Research Institute 
Level 5, 300C Herston Rd  
Herston QLD 4006, Australia 
Tel: +61(0)7 3845 3647 or +61 (0)7 3845 3636 
Mobile : +61 4144204659 
Email: j.mccarthy@uq.edu.au 
Co-Investigator/s 
Dr Paul Griffin MBBS FRACP FRCPA  
Q-Pharm Pty Ltd  
Level 5, 300C Herston Road  
Herston QLD 4006, Australia  
Tel: +61 (0)7 3845 3647  
Fax: +61 (0)7 3845 3637  
Email: paul.griffin@infectiousdiseasesqld.com.au   
 
Dr Anand Odedra MBBS 
Q-Pharm Pty Ltd (visiting Medical Officer) and  
QIMR Berghofer Medical Research Institute 
Level 5, 300C Herston Road  
Herston QLD 4006, Australia  
Tel: +61 (0)7 3845 3636  
Email: Anand.Odedra@qimrberghofer.edu.au  
 
Dr Bridget Barber MBBS, DTM&H, MPH, FRACP, PhD  
Q-Pharm Pty Ltd (visiting Medical Officer) and  
QIMR Berghofer Medical Research Institute 
Level 5, 300C Herston Road  
Herston QLD 4006, Australia  
Tel: +61 424 737 153 
Email: Bridget.Barber@qimrberghofer.edu.au 
Local Sponsor/s 
Clinical Network Services (CNS) Pty Ltd  
Level 4, 88 Jephson St  
Toowong QLD 4066, Australia  
Tel: +61 (0)7 3719 6000 
Sponsor Medical Director 
Stephan Chalon, MD, PhD 
Medicines for Malaria Venture 
Route de PrØ-Bois 20 
1215 Geneva 15 


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Switzerland 
Email: chalons@mmv.org 
Sponsor Project Director 
Jörg Möhrle , PhD 
Medicines for Malaria Venture 
Route de PrØs-Bois 20 
1215 Geneva 15 
Switzerland 
Tel: +41 22 555 0330 
Email: moehrlej@mmv.org 
Sponsor Clinical Scientist 
Myriam El Gaaloul, PharmD 
Medicines for Malaria Venture 
Route de PrØ-Bois 20 
1215 Geneva 15 
Switzerland 
Tel: +41 22 555 0377 
Email: elgaaloulm@mmv.org 
Medical Monitor 
Dr. med. Michael Marx MD  
Medical Director 
ICON Clinical Research 
Internal Tel: 7123 1568 
External Tel : +49 6103 904 1568 
Mobile : (+49) 172 677 7401 
Email: Michael.Marx@iconplc.com 
Medical Malaria Expert 
Prof. Dennis Shanks 
Australian Army Malaria Institute  
Gallipoli Barracks  
Enoggera QLD 4051, Australia  
Tel: +61 (0)7 3332 4931  
Email: Dennis.SHANKS@defence.gov.au 
Institutional Ethics 
Committee 
QIMR Berghofer Medical Research Institute Human Research 
Ethics Committee (QIMR Berghofer HREC; EC00278) 
Locked Bag 2000, Royal Brisbane and Women’s Hospital 
Brisbane QLD 4029, Australia 
Tel: +61 (0)7 3362 0117 
Sponsor Pharmacometrician 
Nathalie Gobeau, PhD 
Medicines for Malaria Venture 
Route de PrØ-Bois 20 
1215 Geneva 15 
Switzerland 
Address 
Tel: +41 22 555 03 64 


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Email: gobeaun@mmv.org 
Regulatory, Site Monitoring 
and 
Data Management Functions: 
Jolien Visser 
Clinical Network Services (CNS) Pty Ltd  
Level 4, 88 Jephson St  
Toowong QLD 4066, Australia  
Tel: +61 7 3719 6000 
Email: Jolien.visser@clinical.net.au 
Clinical Study Centre 
Q-Pharm Pty Ltd 
Level 5, 300C Herston Rd and  
Level 6, Block 8, Royal Brisbane and Women’s Hospital 
Herston, QLD 4006, Australia 
Tel: +61  (0)7 3845 3636 
Clinical Laboratories 
Clinical laboratory measurements 
Ms Marie-Claire Keogh 
Sullivan Nicolaides Pathology Central Laboratory (SNP) 
24 Hurworth Street  
Bowen Hills, QLD  4006, Australia 
Tel: +61 (0)7 3377 8782 
Email: marie-clarie_keogh@snp.com.au 
 
Parasite quantification in blood samples 
Ms Jane Gaydon 
Queensland Paediatric Infectious Diseases Laboratory (QPID), 
SASVRC, Level 8, Centre for Children’s Health Research 
62 Graham Street,  
South Brisbane, QLD 4101, Australia 
Tel: +61 (0)7 3069 7464 
Email: j.gaydon@uq.edu.au 
 
Investigational drug quantification in blood samples 
Dr. Christoph Siethoff 
CEO 
Swiss BioQuant AG,  
Kägenstrasse 18  
4153 Reinach, Switzerland 
Email: Christoph.Siethoff@swissbioquant.com 
mail@swissbioquant.com 
T  +41 (0) 617 1698 12         
Serious AE and AESI 
reporting 
Prime vigilance 
Email : mmv@primevigilance.com 
Tel: +44 800 471 5694 
 
 


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2 
INTRODUCTION: BACKGR
OUND INFORMATION AND  SCIENTIFIC 
RATIONALE  
 
2.1 
BACKGROUND INFORMATION  
 
Malaria is the second most prevalent infectious disease in the world and threatens half of the 
world’s population. In accordance with the latest estimates by the World Health Organisation 
(WHO), there were an estimated 216 million new cases of malaria worldwide and 445,000 deaths 
in 2016 [1].  The majority of these deaths were due to infection with P. falciparum.  The WHO 
has declared malaria control a global development priority and has changed their recommendation 
from control programs to eradication programs.  
  
Malaria drug resistance is a major hurdle to achieving malaria eradication. Resistance has been 
developed not only to conventional monotherapies such as chloroquine, amodiaquine and 
sulfadoxine/pyrimethamine but also to the gold standard treatment for uncomplicated 
P. falciparum malaria, artemisinin combination therapy (ACT). Resistance to ACT’s has been 
reported across the Greater Mekong Sub region in South-East Asia [2, 3] and the inevitable spread 
of artemisinin resistance to Africa is of great concern. Artemisinin resistance has been linked to 
mutations in the propeller domain of the P. falciparum Kelch13 gene [4]. Artemisinin-resistant 
isolates are not completely resistant to artemisinin, but instead have a slow parasite clearance 
phenotype compared to artemisinin-sensitive isolates. This can lead to reduced clearance of young 
ring-stage parasites, and therefore further maturation and sequestration of parasites leading to 
increased morbidity and mortality. As such, a continual generation of new compounds and drug 
combinations are needed to avoid a dangerous shortage of potential future treatment options. 
To achieve eradication of malaria, long-lasting, single-dose treatments that completely clear 
malaria parasites from the body and provide a period of protection following the treatment are 
required. These ideal types of medicines are referred to as single encounter radical cures (SERC). 
The WHO and Medicines for Malaria Venture (MMV) have identified the key properties that a 
SERC must have. These properties are defined by Burrows et al. (2017) in the antimalarial target 
product profile (TPP) [5]. A key requirement of a target product is the inclusion of two or more 
active molecules with different mechanisms of action. The aim of including two or more active 
compounds is to achieve an increased barrier to resistance by using drugs with different 
mechanisms of action, forcing the parasite to develop multiple simultaneous mutations in order to 
become resistant. Furthermore, in a combination therapy, one of the two active compounds should 
have a rapid onset of action, killing most of the parasite load. Both active compounds should 
maintain plasma concentrations levels above the minimal parasiticidal concentration (MPC) for 
approximately the same time and ensure complete elimination of all parasites [5].  


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Artefenomel (OZ439), is a novel trioxolane, and a front-runner candidate for inclusion in a new 
antimalarial combination. It is a synthetic ozonide with potency comparable to artemisinin, with a 
rapid parasite clearance rate of approximately 3.6 h in P. falciparum. Additionally, OZ439 has a 
substantially longer half-life than artemisinin (46 - 62 h as opposed to 1-3 h for artemisinin [6]). 
For these reasons, clinical studies in which artefenomel is combined with a companion drug with 
a different mechanism of action are being planned, or are currently in progress.  
 
Piperaquine is a bis 4-aminoquinoline and was used mainly in China from the 1960’s to the 1980’s 
as an antimalarial monotherapy. In the 1980’s, it became clear that parasite resistance had 
developed to PQP monotherapy. PQP is characterised by slow absorption and a long elimination 
half-life (4–5 weeks) and is now widely used in combination with dihydroartemisinin as a fixed 
dosed ACT.  The successful paring of PQP with an artemisinin, together with its long biological 
half-life, means PQP is potentially a good drug partner for OZ439.  
 
The safety, tolerability and PK profiles for OZ439 and PQP are well-established in healthy subjects 
and in patients. The antimalarial activity of the drugs individually has been demonstrated in IBSM 
studies in healthy subjects and in patients with uncomplicated malaria. A Phase IIb study of a 
single-dose regimen of OZ439 800 mg in combination with 3 doses of PQP (640 mg, 960 mg, and 
1440 mg) in adults and children with uncomplicated P. falciparum malaria has been performed in 
Africa and Asia. In this study, none of the dose arms of the study met the protocol-defined efficacy 
threshold of ≥95% based on the primary endpoint of polymerase chain reaction (PCR)-adjusted 
adequate clinical and parasitological response (ACPR) outcome on Day 28 in the per protocol 
analysis set. Therefore, an IBSM study assessing the antimalarial effect of OZ439 and PQP in a 
single dose combination could allow further understanding of the observed outcome of the OZ439 
and PQP Phase IIb trial where treatment was also administered as a single dose combination.  
 
Cumulatively, an estimated 1250 subjects have received OZ439 either alone or in combination 
with piperaquine phosphate (PQP), ferroquine (FQ), mefloquine, DSM265, or Cobicistat in 
clinical trials globally since the Development International Birth Date until 29 March, 2018). 
 
2.2 
RATIONALE  
 
This study aims to evaluate the antimalarial activity of co-administered single doses of OZ439 and 
PQP in the IBSM model, and enable characterisation of the exposure-response relationship 
between OZ439 and PQP PK and blood stage asexual parasitaemia. Previous research has shown 
that the IBSM model is a good predictive model for real world antimalarial drug activity with 
single drug administration [7]. However, it is yet to be determined if the model is an effective 
predictive tool when two or more drugs are administered in combination.  


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We hypothesise that data obtained in a controlled disease-like setting (Phase 1 drug combination 
IBSM model) can be used to effectively predict the outcome of Phase 2 studies in patients with 
uncomplicated malaria. To evaluate this hypothesis, we will assess if the outcome of this trial can 
be used to predict what was observed in patients with uncomplicated malaria in the 
MMV_OZ439_13_003 Phase 2b combination trial [8].  
The doses chosen for use in Cohort 1 are based on the PK/PD relationships from the IBSM 
monotherapy studies and potential PD interaction effects of the combination based on the phase 
IIb study. Several doses will be tested in Cohort 1, which should achieve parasite reduction but 
not complete cure, such that, parasite regrowth can be observed, allowing an initial estimation of 
the PK/PD parameters of the 2 drugs when combined. The results of the first cohort will then be 
used to guide dose selection for Cohort 2 and 3 maximising the information on the PD interaction 
effect.   
 
2.3 
POTENTIAL RISKS AND BENEFITS  
 
2.3.1 KNOWN POTENTIAL RISKS  
Potential risks have been identified through review of previous clinical studies conducted to date 
using the IBSM model with P. falciparum isolates, as well as a review of the literature. P. 
falciparum 3D7 has been used to challenge 312 healthy subjects in 25 IBSM Phase 1 clinical trials, 
18 of which were successfully undertaken at QIMR Berghofer/Q-Pharm [9-34].  
IBSM model risks  
Risk management of blood borne infections
 
In this study, P. falciparum 3D7 inoculum will be used. This contains a very small amount of 
donor blood. However, the risk of infection from a possible blood borne virus from the blood 
transfused in this study extremely low for a number of reasons. Firstly, the donors were screened 
and tested negative for the presence of active blood borne infections. Secondly, white blood cells 
were removed from the donor blood by the Australian Red Cross Blood Service (Blood Service), 
which lowers the risk of transfusion transmitted infections. Thirdly, the volume of blood used in 
the IBSM model for transmitting malaria is many thousands of times smaller than in a transfused 
unit, thus reducing the risk of infection. As part of the safety monitoring, all subjects will have 
serum stored for testing of blood borne virus infections before and after the study (Section 7.2.1). 
To date, no blood borne infections have been reported in any of the 312 subjects who have received 
the P. falciparum 3D7 inoculum in IBSM studies.  
Risk management of reaction to the blood sample
 
The risk of developing red blood cell (RBC) alloantibodies in this study is considered extremely 
low since the donor blood used to produce the inoculant was blood group O Rh (D) Negative. 


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People with this blood group are generally considered “universal donors”, as recipients of their 
blood have minimal risk of developing RBC alloantibodies when given much larger volumes of 
blood than is used in the IBSM model. However, it is possible that subjects could suffer a 
transfusion reaction after they receive the inoculum, or develop alloantibodies to the donor RBCs 
that may make blood transfusion more difficult in the future. To date, one subject has developed 
an antibody response to a minor Rh antigen (anti-E antibody) following inoculation with P. 
falciparum 3D7 [35]. However, there was no laboratory evidence to indicate that the specific Rh 
phenotype of the donor RBCs in the inoculum provoked production of this allo anti-E antibody. 
Subjects will be monitored for signs and symptoms in the period immediately after administration 
of the inoculum to further assess the risk of the inoculum in causing a transfusion reaction. Subjects 
will also be tested for RBC alloantibodies at screening and at the end of the study as part of their 
safety monitoring (Section 7.2.1).  
Women of childbearing potential (WOCBP) have a small additional risk of developing RBC 
alloantibodies that could cause problems during pregnancy. WOCBP have participated in several 
IBSM trials with P. falciparum isolate 3D7 with no known issues to date. Specific strict 
contraception requirements will be requested for this population during the study (Section 5.1). 
Including WOCBP in the trial enhances the generalisability of the study results. 
Risk management of malaria infection
 
The number of viable blood stage parasites used to infect the subjects in this study (~2,800) is 
substantially lower than the parasitaemia reached after the bite of a single malaria-infected 
mosquito, where approximately 30,000 parasites are released into the blood when they break 
out of a single infected liver cell [36]. In this study, parasite growth and malaria symptoms will 
be closely monitored in subjects following administration of the challenge agent. The threshold 
for commencement of antimalarial drug treatment defined for this study (Day 8) has been selected 
since it is prior to the time-point at which advanced clinical symptoms of malaria are likely to 
occur, as observed in the previous 25 clinical trials performed with the 3D7 challenge agent.  
Risk m anagement of liver function abnormalities  
Transient, asymptomatic liver function test (LFT) abnormalities including rare cases of alanine 
aminotransferase/aspartate aminotransferase elevations >10 fold the upper limit of normal (× ULN) 
have been reported in several subjects in IBSM studies [35, 37]. However, no changes in bilirubin 
were reported except for in one subject with unappreciated pre-existing liver disease [35, 37]. The 
LFT derangements did not require treatment, and resolved by the end of the studies. A few cases 
of the LFT elevations were considered as serious AEs (SAEs) by two Pharma sponsors due to 
internal processes for SAE notifications. Following an independent review involving drug-induced 
liver injury experts, it was found that these LFT elevations are most likely a direct consequence of 
the malaria infection, rather than reflecting a direct drug-induced liver injury caused by an 
investigational antimalarial drug. As a precaution all subjects in this study will undergo regular 


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safety monitoring to assess for asymptomatic LFT abnormalities. Subjects are required to reduce 
intake of possibly hepatotoxic substances, such as alcohol and paracetamol, during the course of 
the study (see Sections 5.2 & 7.6). Drugs of abuse are not permitted under any circumstance.  
Risk management of cardiac AEs 
To our knowledge, 3 cardiac SAEs have been reported in healthy subjects in the Netherlands 
participating in malaria challenge studies using sporozoites i.e. direct feeds by infected mosquitoes 
rather than IBSM infection. Refer to the P. falciparum 3D7 Investigator’s Brochures for further 
details [35]. No cardiac SAEs caused by the inoculum have been reported in IBSM studies. As a 
precaution, people at significant risk of cardiovascular disease will be excluded from participating 
in IBSM studies, and regular safety monitoring including physical examination and 
electrocardiogram (ECG) recordings will take place for all subjects.  
Investigational Medical Product (IMP) risks
 
OZ439 risks  
To date, OZ439 administered either as a monotherapy or in combination with a partner anti-
malarial, has been generally well tolerated in malaria patients and in healthy subjects. In a 
monotherapy Phase IIa study of OZ439 doses of 200, 400, 800 and 1200 mg in malaria patients, 
increased blood creatine phosphokinase was the most frequently reported AE (AE); a dose 
relationship was not seen for this AE and no clinically relevant muscular AE were reported.  
Gastrointestinal (GI) AEs, including vomiting, abdominal pain, diarrheoa, and nervous system 
disorders, including dizziness and headache, were reported more frequently with 1200 mg OZ439 
compared to the other dose cohorts. None of these AEs were SAEs.  
One case of vaso-vagal syncope considered related to therapy was reported in association with 
sinus arrest and orthostatic hypotension. Two SAEs of atrial fibrillation were reported in healthy 
volunteers. One case occurred at day 35 post dose and was identified as not related to the study 
drug. The second case was moderate atrial fibrillation, considered as possibly related to the study 
drug in a subject who had received OZ439 and FQ. The event occurred in context of symptomatic 
orthostatic hypotension and resolved spontaneously without medical treatment.  
In a Phase IIb study, where OZ439 was evaluated in combination with PQP, in patients with 
uncomplicated P. falciparum malaria, malaria and electrocardiogram (ECG) QTc prolongation 
were the most frequently reported AEs. Malaria was reported with a higher incidence in the OZ439 
800 mg:PQP 960 mg and in the OZ439 800 mg:PQP 640 mg treatment arms than in the OZ439 
800 mg:PQP 1440 mg treatment arm. The ECG QTc prolongation was reported with a higher 
incidence in the OZ439 800 mg:PQP 1440 mg and the OZ439 800 mg:PQP 960 mg treatment arms 
than in the OZ439 800 mg:PQP 640 mg treatment arm. Concentration-related QTc prolongation 


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has been widely documented with PQP. Diarrheoa and vomiting were the most frequently reported 
AEs of the GI system in patients treated with both OZ439 and PQP. None of these AEs were SAEs. 
 
The AE profile for OZ439 in healthy subjects was similar to the AE profile in malaria patients. 
Gastrointestinal AEs, including nausea, vomiting, and diarrhea, were the most frequently reported 
AEs in healthy subjects treated with OZ439 alone or OZ439 in combination with either PQP, MQ, 
or FQ. A tendency for a dose-response relationship was seen for GI events. These AEs were 
generally mild in intensity. 
 
Eight subjects treated with OZ439, including 6 malaria patients and 2 healthy volunteers, have had 
SAEs, including P. vivax relapse, pyelonephritis, increased alanine aminotransferase (ALT), 
increased aspartate aminotransferase (AST), decreased neutrophil count, anemia, febrile 
convulsion and decreased hemoglobin in malaria patients; and atrial fibrillation and a gunshot 
wound in healthy subjects. Five SAEs reported in malaria patients (increased ALT, increased AST, 
decreased neutrophil count, anemia and decreased hemoglobin) were assessed as related to study 
drug by the Investigator. 
 
An AE of vomiting led to study drug discontinuation in 1 malaria patient treated with OZ439. Ten 
healthy subjects treated with OZ439 discontinued a Phase Ia study due to an AE. Vomiting (5 
subjects) was the most frequently reported AE leading to study discontinuation in the 10 healthy 
subjects. Except for a few cases observed with α-tocopherol polyethylene glycol 1000 succinate 
(TPGS) formulation, vomiting is not reported in healthy subjects at doses < 800 mg OZ439. 
 
No Hy’s law cases have been observed. However, mild to severe and reversible increases in ALT 
and AST were seen in OZ439-treated malaria patients; these increases did not appear to be dose-
dependent. Decreases in hemoglobin, neutrophils, and platelets were also seen in OZ439-treated 
malaria patients; however, these decreases were consistent with those observed in acute malaria. 
Close monitoring of liver function is required in the clinical studies. 
In the clinic, a significant effect on placebo-corrected change from baseline QTcF was not 
demonstrated for OZ439. In healthy subjects the effect of OZ439 800 mg alone on QTc was 
minimal, with a maximum mean QTcF increase from baseline and placebo of 8.5 ms 
(Study MMV_OZ439_12_002). In Study MMV_OZ439_12_003, 1 healthy subject with an 
undisclosed history of mitral and tricuspid regurgitation was discontinued from the study due to 
asymptomatic supraventricular/junctional tachycardia after dosing with 120 mg OZ439. QTc 
prolongations (both QTcB and QTcF) were seen when OZ439 was administered in combination 
with PQP to malaria patients and healthy subjects. Most of the prolongations were in the range of 
>30 ms but <60 ms; however, prolongations >60 ms were observed in malaria patients, with QTcF 
values that exceeded 500 ms in 2 patients (1 hypokalemic patient). Reversible right bundle branch 
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sinus bradycardia (1 patient) were also observed in malaria patients treated with OZ439. Close 
monitoring of cardiac function is required in the clinical studies. 
In healthy subjects treated with OZ439 alone or OZ439 in combination with PQP, gastrointestinal 
(GI) symptoms which include nausea, vomiting, and diarrhea, are the most commonly reported 
AEs and these AEs have been reported to be generally mild in intensity. OZ439 was clinically well 
tolerated in two previous IBSM studies (QP12C10 and QP14C12) where the highest dose tested 
was 500 mg. In a Phase Ib IBSM study QP12C10 in healthy subjects infected with P. falciparum, 
most of the AEs reported were assessed as probably related to the inoculum (i. e., malaria). There 
were no events considered probably related to OZ439. In another Phase Ib/IBSM study QP14C12, 
healthy subjects infected with P. falciparum received OZ439 in combination with another 
investigational antimalarial, DSM265. No new clinically relevant safety signals were observed. 
OZ439 may be contraindicated in persons with known hypersensitivity to artemisinin-based 
compounds or to any components of the product formulation. Carcinogenicity studies have not 
been performed with OZ439. OZ439 has shown in vivo embryo-fetal toxicity in the rat.  Therefore, 
OZ439 should not be administered to pregnant or breastfeeding women. However, OZ439 can be 
administered to women of child bearing potential (WOCBP) with the use of a strict double method 
of contraception in well controlled clinical trials and under medical supervision. Healthy male and 
female subjects participating in studies of OZ439 must agree to use a double method of 
contraception for a duration defined in section 5.1 (inclusion criteria) of this protocol.  
No deaths have been reported in any of the clinical studies. 
Additional information on non-clinical and clinical studies conducted with OZ439 is provided in 
the IB [38]. 
Piperaquine phosphate (PQP) risks  
PQP as a combination antimalarial with dihydroartemisinin is well tolerated in both adults and 
children, with the main AEs reported being GI disturbances such as diarrhoea [39, 40]. Studies 
with dihydroartemisinin/PQP demonstrated corrected QT (QTc) interval prolongation during 
treatment [41, 42]. Very few individual patients have been observed to have a prolongation that 
could be regarded as clinically significant (>60 msec); of note, the QTc prolongation induced by 
PQP has not been reported to be associated with clinically relevant cardiovascular events, which 
would suggest a lack of pro-arrhythmic effect. Therefore, although statistically significant, the 
QTc prolongation observed following PQP therapy is unlikely to be of clinical concern. European 
regulatory authorities have advised that Eurartesimﬁ (dihydroartemisinin/PQP) not be 
administered with food to reduce PQP peak concentrations, and caution that prior and post-
electrocardiographic monitoring be undertaken, and avoidance of concomitant recent exposure to 
drugs at risk of QTc prolongation [18, 42, 43]. Therefore, during this study, subjects will receive 
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PQP has been clinically well tolerated in previous IBSM studies using this drug [34]. In these 
studies, PQP treatment demonstrated a robust safety profile in doses up to 960 mg when used for 
the treatment of uncomplicated P. falciparum malaria infection. 
Details on the safety and efficacy of PQP as part of the combination product Eurartesimﬁ, may be 
found in the European Medicines Agency (EMA) European Public Assessment Report. 
Rescue Medication risks  
Riametﬁ, Primacin™ and Artesunate risks are detailed in their respective approved manufacturer’s 
prescribing information (Appendix 1). Primacin™ may cause severe haemolytic anaemia in 
subjects with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Subjects will be tested for 
G6PD deficiency at screening to ensure the safety of Primacin™. The G6PD status will determine 
how the subject is treated with Primacin™. 
General risk management
 
The risk to subjects in this study will also be minimised as follows: 
 Adherence to the inclusion/exclusion criteria to ensure that only subjects who are not at 
any perceived risk are enrolled in the study. 
 Close clinical and laboratory monitoring to ensure the safety and well-being of the subjects. 
 Subjects will be prescribed curative therapy for malaria (Riametﬁ with the addition of 
Primacin™ if required) for final parasite clearance during or at the end of the study. 
 The total volume of blood drawn from each subject enrolled into the study (including 
optional exploratory research sampling) will not exceed a standard unit of blood 
(approximately 450 mL) over any 30-day period.  
 In the rare event that a subject requires hospitalisation at the request of the Principal 
Investigator or his representative, this will be done at the Infectious Diseases Unit, Royal 
Brisbane and Women’s Hospital. Emergency procedures are in place at the Q-Pharm 
clinics for dealing with any unforeseen clinical emergencies which may arise. 
With these safety provisions, the overall risk to the subjects in the study is considered to be minimal 
and acceptable, and the potential of future improved treatment for malaria is considered to 
outweigh these potential risks.  
2.3.2 KNOWN POTENTIAL BENEFITS  
There is no expected clinical benefit for the healthy subjects that will participate in this study. 
Overall, on the basis of the available non-clinical and clinical data, and prior knowledge, the risk-
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3 
OBJECTIVES AND PURPO SE 
Primary:  
a) To characterize the PK/PD relationship between OZ439 and PQP plasma concentrations 
and blood stage asexual parasitaemia in healthy subjects following P. falciparum IBSM 
infection.  
 
b) To evaluate the safety and tolerability of OZ439 and PQP when co-administered as single 
doses in healthy subjects following P. falciparum IBSM infection. 
Secondary: 
a) To describe the PK of OZ439 and PQP when co-administered as single doses in healthy 
subjects under fasted conditions. 
 
b) To characterize the PD effect of co-administered single doses of OZ439 and PQP on 
clearance of P. falciparum asexual blood stage parasites from the blood of healthy subjects 
in the IBSM model. 
Exploratory: 
The exploratory study objectives are:  
a. To characterise specific cell subsets and immune signatures associated with control of 
parasite burden and pathogenicity following first exposure to P. falciparum, to identify 
specific cells, immunomodulatory molecules and immune pathways to target for 
therapeutic intervention. 
b. To investigate the role of RBC complement regulatory proteins and anti-
phosphatidylserine antibodies in malarial anaemia. 
c. To investigate the association between serum complement activation, complement 
activating antibodies, and RBC complement regulatory protein expression. 
 
 


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4 
STUDY DESIGN AND ENDPOINTS  
 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
This is a single-centre, open-label, adaptive, study using the P. falciparum IBSM inoculum as a 
model to characterise the PD activity of combined administration of OZ439 and PQP.  
The study will be conducted in a maximum of three cohorts (up to 8 subjects per cohort) using up 
to 4 different doses of OZ439 and PQP in each cohort.  Subjects will be malaria naïve healthy 
males or females, aged between 18-55 years old, who meet all of the inclusion criteria and none 
of the exclusion criteria. Additionally, the study includes optional, exploratory 
components, 
which require separate informed consent for subjects agreeing to participate in these.   
The first cohort will comprise 4 groups of 2 subjects each. Subjects will be administered single 
oral doses of OZ439 and PQP in combination. The dose of OZ439 and PQP will be different for 
each group in Cohort 1, and subjects will be randomised into one of the dose groups listed in Table 
1.   
Table 1 OZ439 and PQP Cohort 1 Dose  
Drug  
Dose group  
1A 
1B 
1C 
1D 
OZ439 (mg) 
200 
200 
400 
400 
PQP (mg) 
480 
640 
480 
640 
 
The data captured from this first cohort will be used to determine the relationship between OZ439 
and PQP concentrations and parasitaemia levels. Based on safety and tolerability data up to Day 
42–2 and PK/PD analysis outcomes (based on PD data up to Day 42–2 and PK data up to Day 
35–2), of the drugs given in combination the dose(s) for the subsequent cohort 2 will be 
determined.  
After review of the PK/PD and safety data from Cohort 1 by the SDRT it was determined that, the 
second cohort will be composed of 2 dose groups of 4 subjects each. Subjects will be randomised 
into one of 2 dose groups and administered single oral doses of OZ439 and PQP in combination. 
The combined dose of OZ439 and PQP will be different for each group in this cohort as shown in 
Table 2.   
 
 


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Table 2 OZ439 and PQP Cohort 2 Dose 
Drug  
Dose group  
2A 
2B 
OZ439 (mg) 
800 
200 
PQP     (mg) 
960 
320 
 
A similar analysis will be done at the end of cohort 2 combining cohorts 1 and 2 data to decide the 
dose(s) to be tested in cohort 3. This will be decided by the funding sponsor and the Principal 
Investigator following SDRT and scientific evaluation.  
The doses used in all Cohorts will not exceed 800 mg for OZ439 and 1440 mg for PQP as 
determined in previous safety, pilot efficacy and phase 2 studies. Each subject will be inoculated 
on Day 0 with approximately 2,800 viable parasites of P. falciparum-infected human erythrocytes 
administered intravenously. Subjects will be monitored daily via phone call or text message on 
Days 1 to 3 post-inoculation to solicit any AEs.  
Then, subjects will come to the clinical unit on a daily basis from Day 4 until the presence of 
asexual parasites is established by qPCR targeting the 18S rRNA gene (referred to as malaria 18S 
qPCR). Once qPCR becomes positive and until OZ439 and PQP administration, subjects will 
attend the clinical unit for twice-daily visits, separated by approximately 12 hours, for clinical 
evaluation and blood sampling.  
Subjects will be admitted to the clinical unit for single dose administration of OZ439 and PQP 8 
days after malaria inoculation or earlier if a subject has a malaria clinical score >6 or at 
Investigators discretion. An intravenous cannula will be placed and preliminary blood samples 
collected. The participants will then be administered the IMP in a fasting state immediately. 
Subjects in the first cohort may all be dosed on the same day, since these exposures have been 
documented in previous studies and shown to be well tolerated.  
Once single dose co-administration of OZ439 and PQP occurs, subjects will be followed up as 
inpatients for at least 72 hours to monitor for safety and tolerability of the treatment and to ensure 
adequate clinical and parasitological response. Blood samples will be collected pre-dose and 
following OZ439 and PQP treatment to measure plasma concentrations of OZ439 and PQP. 
Wherever possible, PK sampling will coincide with post-dose blood collection for monitoring of 
parasitaemia. 
After 72 hours, if clinically well, subjects will be discharged from the clinical unit and will be 
followed up regularly for safety assessments, PK sampling, clinical evaluation and malaria qPCR 
blood sampling until Day 42–2. All subjects will receive a standard course of therapy with 


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Riametﬁ (artemether -lumefantrine) on Day 42–2 or earlier in the event of failure of clearance of 
parasitaemia defined as failure to clear parasitaemia by at least 10-fold at 72 hours post-IMP 
administration. Riamet will also be administered in the event of recrudescence of parasitaemia 
(defined as ≥5 000 blood stage parasites/mL and a 2-fold increase within 48 hours, or a malaria 
clinical score >6) or at Investigators discretion.  If indicated by the presence of gametocytes at the 
time of treatment with Riamet®, Primacin™ 45 mg will also be administered as a single oral dose. 
Subjects participating may optionally consent to be included in the exploratory components of the 
study which require additional blood samples to be collected at specified time-points throughout 
the study. These time-points coincide with those already scheduled as part of the main study 
assessments. If any of the main study time-points change the exploratory study time-points will 
change to match. Details of the exploratory components and analyses are provided in Section 7.2.2. 
A review by the SDRT of data from each cohort will be conducted prior to dosing the subsequent 
cohort. Safety and tolerability data up to Day 42–2 and PK/PD analysis outcomes (based on PD 
data up to Day 42–2 and PK data up to Day 35–2), from all subjects who received treatment with 
OZ439 and PQP will be required for the review. A similar analysis will be done at the end of 
cohort 2 combining cohorts 1 and 2 data to decide the dose(s) to be tested in cohort 3. This will be 
decided by the funding sponsor and the Principal Investigator following review of the data by the 
SDRT and scientific evaluation.  
The doses used in all cohorts will not exceed the maximum acceptable doses predefined for this 
study (800 mg for OZ439 and 1440 mg for PQP) as determined in previous safety, pilot efficacy 
and phase 2 studies.  
4.2 
STUDY ENDPOINTS 
 
4.2.1 PRIMARY ENDPOINT 
 The PK/PD relationship between OZ439 and PQP plasma concentrations and blood stage 
asexual parasitaemia will be determined by: 
o Effect of OZ439 on Emax and EC50 of PQP 
o Effect of PQP on Emax and EC50 of OZ439 
 
 The safety and tolerability of a single combined dose of OZ439 and PQP will be evaluated 
by the incidence, severity and relationship of observed and self-reported AEs up to trial 
Day 42–2 after the co-administration of single doses of OZ439 and PQP to subjects 
inoculated with IBSM.  
4.2.2 SECONDARY ENDPOINTS 


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 Estimation of OZ439 and PQP PK parameters up to trial Day 42–2 after co-administration 
of single doses using non-compartmental methods: AUC0-168h, AUClast, AUC0-inf, Cmax, tmax, 
t1/2, tlag, C168h, CL/F, Vz/F and λinf. 
 
 The effect of co-administered single oral doses of OZ439 and PQP on clearance of 
P. falciparum blood stage parasites from the blood of inoculated subjects as measured by 
qPCR up to trial Day 42–2 after co-administration of OZ439 and PQP. Parasite clearance 
will be assessed by the following parameters: 
o Parasite clearance half-life (Pt ‰).  
o Parasite reduction ratio (PRR). 
o Percentage of subjects with recrudescence of parasitaemia, defined as ≥5 000 blood 
stage parasites/mL and a 2-fold increase within 48 hours, or re-occurrence of 
malaria symptoms with a malaria clinical score >6).   
 
4.2.3 EXPLORATORY ENDPOINTS 
 
 Identification of immune checkpoint molecules. 
 The level of expression of complement regulatory proteins (CD35, CD55 and CD59) and 
phosphatidylserine on RBC. 
 The level of complement activating antibodies and anti-phosphatidylserine antibodies. 


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5 
STUDY ENROLLMENT AND  WITHDRAWAL  
 
5.1 
SUBJECT INCLUSION CRITERIA 
Subjects eligible for inclusion in this study must fulfil all of the following criteria: 
Demography  
1. Adult (male and female) subjects between 18 and 55 years of age inclusive, who do not live 
alone (from inoculation day until at least the end of the Riametﬁ treatment) and will be 
contactable and available for the duration of the trial and contactable up to 2 weeks following 
the End of Study visit (approximately 8.5 weeks).  
2. Body weight minimum 50 kg, body mass index between 18 and 32 kg/m2, inclusive. 
Health status  
3. Certified as healthy by a comprehensive clinical assessment (detailed medical history, 
complete physical examination and special investigations). 
4. Vital signs after 5 minutes resting in supine position: 
 90 mmHg ≤ systolic blood pressure (SBP) ≤ 140 mmHg, 
 40 mmHg ≤ diastolic blood pressure (DBP) ≤ 90 mmHg, 
 40 bpm ≤ heart rate (HR) ≤ 100 bpm. 
5. Must have QTcF ≤450 ms, QTcB ≤450 ms for male subjects, QTcF ≤470 ms, QTcB ≤470 ms 
for female subjects and PR interval ≤210 ms at screening and at pre-inoculation on inoculation 
day. 
6. Heterosexual women of childbearing potential should be surgically sterile or using an 
insertable, injectable, transdermal or combination oral contraceptive approved by the TGA 
combined with a barrier contraceptive for the duration of the study, and have negative results 
on a urine pregnancy test done before inoculation. Abstinent, heterosexual female subjects 
must agree to start a double method if they start a sexual relationship during the study. 
Adequate contraception does not apply to subjects of childbearing potential with same sex 
partners (abstinence from penile-vaginal intercourse), when this is their preferred and usual 
lifestyle. Female subjects with same sex partners must not be planning in vitro fertilisation 
within the required contraception period. 
Women of non-childbearing potential who will not require contraception during the study are 
defined as: post-menopausal (spontaneous amenorrhoea for ≥ 12 months, or spontaneous 


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amenorrhoea for 6-12 months and follicle-stimulating hormone (FSH) ≥ 40 IU/mL; either 
should be together with the absence of oral contraceptive use for > 12 months). 
Male subjects participating must agree to use a double-barrier method of contraception 
including condom plus diaphragm or condom plus intrauterine device or condom plus stable 
oral/transdermal/injectable hormonal contraceptive by the female partner from the time of 
informed consent through to 90 days after the last dose of OZ439 and PQP. Abstinent male 
subjects must agree to start a double-barrier method if they begin sexual relationships during 
the study and up to 90 days after the last dose of study drug.  
Male subjects with female partners that are surgically sterile, or male subjects who have 
undergone sterilisation and have had testing to confirm the success of the sterilisation may also 
be included.   
Regulations  
7. Having given written informed consent prior to undertaking any study-related procedure. 
8. Must be willing and able to communicate and participate in the whole study. 
5.2 
SUBJECT EXCLUSION CRITERIA 
Subjects fulfilling any of the following criteria will not be eligible for inclusion in this study: 
Medical history and clinical status
 
1. 
Haematology, clinical chemistry, coagulation or urinalysis results at screening or on 
admission prior to Inoculation or IMP administration that are outside of Sponsor-approved 
clinically acceptable laboratory ranges documented in the laboratory manual or are 
considered clinically relevant. 
2. 
Any history of malaria or participation in a previous malaria challenge study. 
3. 
Must not have travelled to or lived (>2 weeks) in a malaria-endemic region during the past 
12 months or planned travel to a malaria-endemic region during the course of the study (for 
endemic regions see https://map.ox.ac.uk/country-profiles/#!/). Bali is not considered a 
malaria-endemic region. 
4. 
Participation in any investigational product study within the 12 weeks preceding IMP 
administration. 
5. 
Has evidence of increased cardiovascular disease risk (defined as >10%, 5-year risk for those 
greater than 35 years of age, as determined by the Australian Absolute Cardiovascular 
Disease Risk Calculator (http://www.cvdcheck.org.au/)). Risk factors include sex, age, 


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systolic blood pressure (mm/Hg), smoking status, total and HDL cholesterol (mmol/L), and 
reported diabetes status. 
6. 
Symptomatic postural hypotension at screening on two consecutive readings, irrespective of 
the decrease in blood pressure, or asymptomatic postural hypotension defined as a decrease 
in systolic blood pressure ≥20 mmHg within 2-3 minutes when changing from supine to 
standing position. 
7. 
History of splenectomy. 
8. 
History or presence of diagnosed (by an allergist/immunologist) or treated (by a physician) 
food or known drug allergies (including but not limited to allergy to any of the antimalarial 
rescue medications to be used in the study), or history of anaphylaxis or other severe allergic 
reactions. Note. Subjects with seasonal allergies/hay fever, house dust mite or allergy to 
animals that are untreated and asymptomatic at the time of dosing can be enrolled in the 
study 
9. 
History of convulsion (including intravenous drug or vaccine-induced episodes) Note. A 
medical history of a single febrile convulsion during childhood is not an exclusion criterion.   
10. 
Presence of current or suspected serious chronic diseases such as cardiac or autoimmune 
disease (HIV or other immuno-deficiencies), insulin-dependent and non-insulin dependent 
diabetes (excluding glucose intolerance if exclusion criterion 4 is met), progressive 
neurological disease, severe malnutrition, acute or progressive hepatic disease, acute or 
progressive renal disease, porphyria, psoriasis, rheumatoid arthritis, asthma, epilepsy, or 
obsessive-compulsive disorder. 
11. 
History of malignancy of any organ system (other than localised basal cell carcinoma of the 
skin or in situ cervical cancer), treated or untreated, within 5 years of screening, regardless 
of whether there is evidence of local recurrence or metastases. 
12. 
Subjects with history of schizophrenia, bi-polar disease, or other severe (disabling) chronic 
psychiatric diagnosis including depression or receiving psychiatric drugs or who has been 
hospitalised within the past 5 years prior to enrolment for psychiatric illness, history of 
suicide attempt, or confinement for danger to self or others. 
13. 
History of serious psychiatric condition that may affect participation in the study or preclude 
compliance with the protocol, including but not limited to past or present psychoses, 
disorders requiring lithium, a history of attempted or planned suicide, more than one 
previous episode of major depression, any previous single episode of major depression 
lasting for or requiring treatment for more than 6 months, or any episode of major depression 
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The Beck Depression Inventory (Appendix 4) will be used as an objective tool for the 
assessment of depression at screening. In addition to the conditions listed above, subjects 
with a score of 20 or more on the Beck Depression Inventory and/or a response of 1, 2 or 3 
for item 9 of this inventory (related to suicidal ideation) will not be eligible for participation. 
These subjects will be referred to a general practitioner or medical specialist as appropriate. 
Subjects with a Beck score of 17 to 19 may be enrolled at the discretion of the Investigator 
if they do not have a history of the psychiatric conditions mentioned in this criterion and 
their mental state is not considered to pose additional risk to the health of the subject or to 
the execution of the study and interpretation of the data gathered. 
14. 
History of recurrent headache (e.g. tension-type, cluster or migraine) with a frequency of ≥2 
episodes per month on average and/or severe enough to require medical therapy. 
15. 
Presence of acute infectious disease or fever (e.g. sublingual temperature ≥38.5°C) within 
the 5 days prior to inoculation with malaria parasites. 
16. 
Evidence of acute illness within the 4 weeks prior to screening that the Investigator deems 
may compromise subject safety. 
17. 
Significant inter-current disease of any type, in particular liver, renal, cardiac, pulmonary, 
neurologic, rheumatologic, or autoimmune disease by history, physical examination, and/or 
laboratory studies including urinalysis. 
18. 
Subject has a clinically significant disease or any condition or disease that might affect drug 
absorption, distribution or excretion (e.g. gastrectomy, diarrhoea). 
19. 
Blood donation of any volume within 1 month before inclusion, or participation in any 
research study involving blood sampling (more than 450 mL/unit of blood), or blood 
donation to Australian Red Cross Blood Service (Blood Service) or other blood bank during 
the 8 weeks prior to the treatment drug dose in the study. 
20. 
Subject unwilling to defer blood donations to the Blood Service for at least 6 months. 
21. 
Medical requirement for intravenous immunoglobulin or blood transfusions. 
22. 
Subject who has ever received a blood transfusion. 
23. 
History or presence of alcohol abuse (alcohol consumption more than 40 g/4 units/4 standard 
drinks per day) or drug habituation, or any prior intravenous usage of an illicit substance. 
24. 
Tobacco use of more than 5 cigarettes or equivalent per day, and unable to stop smoking for 
the duration of the clinical unit confinement. 
25. 
Female subject who is breastfeeding. 


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Interfering substances  
26. 
Any vaccination within the last 28 days. 
27. 
Any corticosteroids, anti-inflammatory drugs, immunomodulators or anticoagulants. Any 
subject currently receiving or having previously received immunosuppressive therapy 
(including systemic steroids, adrenocorticotrophic hormone or inhaled steroids) at a dose or 
duration associated with hypothalamic-pituitary-adrenal axis suppression (e.g. 1 mg/kg/day 
prednisone, chronic use of inhaled high potency corticosteroids such as budesonide 800 
μg/day or fluticasone 750 μg, or equivalent). 
28. 
Any recent (<6 weeks) or current systemic therapy with an antibiotic or drug with potential 
antimalarial activity (e.g. chloroquine, piperaquine phosphate, benzodiazepine, flunarizine, 
fluoxetine, tetracycline, azithromycin, clindamycin, doxycycline etc.). 
29. 
Ingestion of any poppy seeds within the 24 hours prior to the screening blood test (subjects 
will be advised by phone not to consume any poppy seeds in this time period). 
30. 
Excessive consumption of beverages or food containing xanthine bases including Red Bull, 
chocolate, coffee etc. (more than 400 mg caffeine per day, equivalent to more than 4 cups of 
coffee per day). 
31. 
Unwillingness to abstain from consumption of grapefruit or Seville oranges from inoculation 
day until end of the study. 
32. 
Unwillingness to abstain from consumption of quinine containing foods/beverages such as 
tonic water and lemon bitter, from inoculation day until end of Riametﬁ treatment. 
33. 
Use of prescription drugs or non-prescription drugs or herbal supplements (such as St John’s 
Wort), within 14 days or 5 half-lives (whichever is longer) prior to the malaria inoculation. 
As an exception, ibuprofen (preferred) may be used at doses of up to 1.2 g/day or 
paracetamol at doses of up to 4 g/day after discussion with the Investigator. Limited use of 
other non-prescription medications or dietary supplements, not believed to affect subject 
safety or the overall results of the study, may be permitted on a case-by-case basis following 
approval by the Sponsor in consultation with the Investigator. Subjects are requested to 
refrain from taking non-approved concomitant medications from recruitment until the 
conclusion of the study. 
General conditions  
34. 
Any subject who, in the judgment of the Investigator, is likely to be non-compliant during 
the study, or is unable to cooperate because of a language problem or poor mental 
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35. 
Any subject in the exclusion period of a previous study according to applicable regulations. 
36. 
Any subject who is the Principal Investigator or any sub-Investigator, research assistant, 
pharmacist, study coordinator, or other staff thereof, directly involved in conducting the 
study. 
37. 
Any subject without a good peripheral venous access. 
Biological status  
38. 
Positive result on any of the following tests: hepatitis B surface antigen (HBs Ag), anti-
hepatitis B core antibodies (anti-HBc Ab), anti-hepatitis C virus (anti-HCV) antibodies, anti-
human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab). 
39. 
Positive urine drug test. Any drug listed in Section 7.2.1 in the urine drug screen unless there 
is an explanation acceptable to the Investigator (e.g., the subject has stated in advance that 
they consumed a prescription or over-the-counter product which contained the detected 
drug) and/or the subject has a negative urine drug screen on retest by the pathology 
laboratory. Any subject testing positive for acetaminophen (paracetamol) at screening may 
still be eligible for study participation, at the Investigator’s discretion. 
40. 
Positive alcohol breath test.  
Specific to the study  
41. 
Cardiac/QT risk: 
 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. 
 History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia. 
 Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia, or hypomagnesaemia. 
 ECG abnormalities in the standard 12-lead ECG (at screening or at pre-inoculation on 
inoculation day) which in the opinion of the Investigator is clinically relevant or will 
interfere with the ECG analyses. 
42. 
Known hypersensitivity to artesunate or any of its excipients, artemether or other artemisinin 
derivatives, 
piperaquine 
phosphate, 
proguanil/atovaquone, 
primaquine, 
or 
4-
aminoquinolines. 
Healthy subjects who do not fulfil all the inclusion criteria, and/or fulfil any of the exclusion 
criteria should not be enrolled into the study without exception. In case of doubt, the Investigator 
is to confer with the medical monitor for agreement. Waivers for inclusion of volunteers that are 
not meeting all eligibility criteria will not be granted. 


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Subjects who are excluded from participation on study days for any of the above reasons may be 
eligible to participate on a postponed schedule, if the Investigator considers this appropriate. 
5.3 
CONTRACEPTION 
 
Male and female subjects who are sexually active must use, with their partner, 2 approved methods 
of highly effective contraception from the time of informed consent until 90 days after the last 
dose of OZ439 and PQP. 
Two or more of the following methods are acceptable and must include at least 1 barrier method:  
 
 Surgical sterilisation (vasectomy (male), tubal ligation (female))  
 Placement of an intrauterine device or intrauterine system  
 Hormonal contraception (implantable, patch, oral, injectable)  
 Barrier methods (this must be a condom or their partner’s use of an occlusive cap 
[diaphragm or cervical/vault caps] with spermicidal foam/gel/film/cream/suppository)  
Alternatively, true abstinence is acceptable when it is in line with the subject’s preferred and usual 
lifestyle. If a subject is usually not sexually active but becomes active, they, with their partner, 
must comply with the contraceptive requirements detailed above. 
Adequate contraception does not apply to subjects of childbearing potential with same sex partners 
(abstinence from penile-vaginal intercourse), when this is their preferred and usual lifestyle. 
Female subjects with same sex partners must not be planning in vitro fertilisation within the 
required contraception period. 
Women of non-childbearing potential who will not require contraception during the study are 
defined as: post-menopausal (spontaneous amenorrhoea for ≥ 12 months, or spontaneous 
amenorrhoea for 6-12 months and follicle-stimulating hormone (FSH) ≥ 40 IU/mL; either should 
be together with the absence of oral contraceptive use for > 12 months) or permanently sterilised 
(e.g. hysterectomy, bilateral salpingectomy). 
Adequate contraception is also not required for male subjects with female partners that are 
permanently sterilised or male subjects who have undergone sterilisation and have had testing to 
confirm the success of the sterilisation.   
 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Up to 24 subjects are planned to be enrolled in the study. It is estimated that approximately 75 
subjects may need to be screened to complete enrolment. Four reserve subjects will be required at 
each inoculation day to ensure 8 subjects are dosed for each cohort.  


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Subjects will be recruited from the QIMR Berghofer Human Research Ethics Committee (QIMR 
Berghofer HREC) approved database of healthy subjects maintained by Q-Pharm, or by a general 
or study specific advertisement via print, radio or poster media to students of Queensland 
universities or to the general community, as approved by the QIMR Berghofer HREC. No 
restrictions will apply for ethnic or racial categories; the expected population may include all 
Australian racial categories.  
Subjects who complete the study up to Day 45–2/EOS will be paid $3,865 compensation for their 
participation. Subjects who withdraw or are withdrawn from the study will be compensated on a 
fractional basis for their involvement unless they are withdrawn as a consequence of their 
misconduct. Reserve subjects who do not participate in the study will be paid $150 compensation 
(per inoculation day) for the inconvenience associated with their attendance for screening and for 
their attendance on the inoculation day, in case they are required to participate. Volunteers who 
fail screening due to an underlying medical condition previously unknown to them will be 
reimbursed $75 for their time, and provided with the appropriate referrals for guidance and 
counselling for their condition. 
 


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5.5 
SUBJECT WITHDRAWAL OR TERMINATION 
 
5.5.1 REASONS FOR WITHDRAWAL OR TERMINATION 
Subjects are free to withdraw from the study at any time. A subject may be considered withdrawn 
if he/she states an intention to withdraw, fails to return for scheduled protocol visits for any reason, 
or becomes lost to follow-up. Subjects may also be withdrawn by the Investigator. Possible reasons 
for withdrawal by the Investigator include the occurrence of an SAE, failure by the subject to 
comply with the requirements of the protocol, or for any other reason at the Investigator’s 
discretion. 
5.5.2 HANDLING OF SUBJECT WITHDRAWALS OR TERMINATION 
If a subject is withdrawn from the study, the funding Sponsor will be informed immediately. If 
there is a medical reason for withdrawal, the subject will remain under the supervision of the 
Principal Investigator until satisfactory health has returned. 
The Investigator will make every effort to determine the primary reason for a subject’s withdrawal 
from the study and record this information in the electronic case report form (eCRF). For subjects 
who are lost to follow-up, the Investigator will demonstrate due diligence by documenting all steps 
taken to contact the subject (e.g. dates of phone calls, registered letter, home visit, etc.) in the 
source documents. If earlier withdrawal from further study procedures occurs, the subject will be 
asked to complete the antimalarial rescue treatment. The subjects will also be asked to complete 
the early termination evaluation as described in Section 7.3.5. 
If the subject is withdrawn from the study procedures or follow-up for any reason, with the 
subject’s permission, medical care will be provided for any SAEs that occurred during 
participation in the study until the symptoms of any SAEs are resolved and the subject’s condition 
becomes stable. Follow-up for AEs is described in Section 8.3. 
If a subject is withdrawn due to a study drug-related AE or due to termination of the study, the 
early-termination subject will not be replaced. If a subject does not complete the study for reasons 
other than safety, the early termination subject may be replaced after mutual agreement between 
the funding Sponsor and the Investigator. The decision regarding the replacement of subjects will 
be documented. 
5.6 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
The Sponsor, Principal Investigator, QIMR Berghofer HREC and Regulatory Authorities 
independently reserve the right to discontinue the study at any time for safety or other reasons. 
This will be done in consultation with the Sponsor where practical. In the event of premature trial 
termination or suspension, the above-mentioned parties will be notified in writing by the 


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terminator/suspender stating the reasons for early termination or suspension (with the exception of 
the Sponsor’s responsibility for notifying the Regulatory Authorities). After such a decision, the 
Sponsor and the Principal Investigator will ensure that adequate consideration is given to the 
protection of the subjects’ interests and safety. The Investigator must review all subjects as soon 
as practical and complete all required records. 
In addition to the classic assessment of SAEs and the occurrence/severity of other AEs by the 
Sponsor and the Investigator, after exploring potential confounding factors, the following criteria 
should be considered as guidance for the decision to stop inoculation of further subjects:  
 A subject experiences an SAE that is related to the inoculum.  
 There is insufficient response to OZ439 and PQP. 
 The Investigator and Sponsor may decide to stop inoculation based on other safety signals 
not described in the above criteria.  
6 
STUDY AGENT  
 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
 
6.1.1 ACQUISITION 
Challenge Agent  (hereafter referred to as inoculum) 
 
P. falciparum 3D7  
The P. falciparum 3D7 master cell bank (MCB) was produced from a person with O Rh(D) 
Negative blood who was infected with the parasite by mosquito bite. The 3D7 MCB was 
cryopreserved, aliquoted into cryovials and stored in liquid nitrogen under controlled conditions. 
Refer to the P. falciparum 3D7 Investigator’s Brochure for more details [35]. A 3D7 MCB 
cryovials will be retrieved from storage, thawed, and used to aseptically prepare the 3D7 inoculum 
at Q-Gen. 
Study Drug  
OZ439 
OZ439 granules + α-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral 
suspension (200 mg and 400 mg strengths of OZ439) will be provided in aluminium sachets. Food 
grade sucrose will be provided by Q-Pharm pharmacy. The drug product will be shipped either 
directly to Q-Pharm, or via Pharmaceutical Packaging Professionals Pty Ltd (Victoria, Australia). 
Import will be facilitated by MMV and the TGA will be notified using the Clinical Trial 
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Piperaquine phosphate (PQP)  
Piperaquine phosphate, 160 mg will be provided from a stock at Pharmaceutical Packaging 
Professionals Pty Ltd and shipped directly to Q-Pharm. 
Antimalarial Rescue Medications  
Riametﬁ and PrimacinTM (if required) 
Riametﬁ and PrimacinTM will be acquired by Q-Pharm, labelled according to identity, brand or 
source, and batch number. The supplies will be held in appropriate locked storage conditions at Q-
Pharm until required. The contents of the label for the drug to be administered to the subjects will 
be in accordance with all applicable regulatory requirements. The inoculum strain (P. falciparum 
3D7) used in the challenge model has been proven to be sensitive to the rescue medications. 
Artesunate (if required) 
If a subject vomits or cannot tolerate oral drugs, then artesunate will be administered intravenously 
as described in Section 6.1.5. This drug is the recommended parenteral treatment for malaria in 
Australia. Currently, it is a Special Access Scheme drug, and has been sourced from Guilin 
Pharmaceutical (Shanghai) Co., Ltd. Import was facilitated by MMV. The manufacture of 
intravenous (IV) artesunate is undertaken in a WHO Pre-Qualified GMP facility 
(http://www.mmv.org/access/access-portfolio/artesun-injectable-artesunate ). 
The rescue drugs, i.e., Riametﬁ, PrimacinTM, and artesunate will be inventoried prior to the 
beginning of trial enrolment on trial accountability logs in regards to condition upon receipt, 
including lot numbers. The Investigator or qualified designee will ensure that the received drugs 
are the specified formulation. The site pharmacist or qualified designee is responsible for 
maintaining an accurate inventory and accountability record of drug supplies for this trial.  
6.1.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
Inoculum  
P. falciparum 3D7  
Each 3D7 inoculum dose will contain parasitised and unparasitised RBCs, resuspended in 0.9% 
Sodium Chloride Intravenous Infusion, in a total volume of 2 mL in syringes. The syringes will be 
double contained following preparation and labelled in accordance with GCP guidelines and the 
Access to Unapproved Therapeutic Goods - Clinical Trials in Australia [44].  
 
 


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Study Drug  
OZ439  
OZ439 is available as OZ439 + α-tocopherol polyethylene glycol 1000 succinate (TPGS) granules 
for oral suspension dosage form. OZ439 granules and TPGS granules are co-packaged in a 2-
compartment sealed sachet. The OZ439 granules and TPGS granules are physically separated in 
the sachet packaging. Dose strengths of 200 mg and 400 mg OZ439 are available. The OZ439 and 
TPGS granules for oral suspension are mixed with water to form an oral suspension, and sucrose 
is added prior to administration to the subject. The sucrose is added to make the oral suspension 
palatable. Reconstitution steps will be described in the Pharmacy Manual. The contents of the label 
for drug to be administered to the subjects will be in accordance with all applicable regulatory 
requirements. 
Piperaquine phosphate (PQP)  
PQP is formulated as tablets (160 mg per tablet). PQP will be labelled according to identity, brand 
or source, and batch number. The contents of the label for drug to be administered to the subjects 
will be in accordance with all applicable regulatory requirements. 
Antimalarial Rescue Medications
 
Riametﬁ and Primacin™ and Artesunate 
Riametﬁ tablets (20 mg artemether/120 mg lumefantrine) are yellow, round, flat tablets marked 
with N/C and a score line on one side and CG on the other side. Each carton contains 24 tablets.  
Primacin™ tablets (primaquine phosphate) are round, flat, orange uncoated tablets. Primacin™ 
tablets are available in bottles of 28 or 56 tablets. Primacin™ will be labelled according to identity, 
brand or source, and batch number. The contents of the label for the drug to be administered to the 
subjects will be in accordance with all applicable regulatory requirements. 
Artesunate for I/V administration is presented as a powder for reconstitution (60 mg artesunic 
acid) in a vial. 
6.1.3 PRODUCT STORAGE AND STABILITY 
Inoculum   
P. falciparum 3D7  
The inoculum is prepared at Q-Gen on inoculation day (Day 0). The time between preparation of 
the 3D7 inoculum and administration to each subject will be a maximum of 2 hours, during which 


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time all inocula will be stored on ice. The Q-Pharm pharmacist will document receipt conditions 
and time restrictions of use.  
Study Drug  
OZ439 
OZ439 + TPGS granules for oral suspension drug products should be stored between 15-30°C. 
Food grade sucrose is to be stored at room temperature.   
Piperaquine phosphate (PQP)  
PQP tablets are to be stored at 15 to 25C. 
Antimalarial Rescue Medications
 
Riametﬁ and Primacin™ 
 Riametﬁ is to be stored below 30°C and protected from moisture (dispersible tablets).   
 Primacin™ is to be stored below 25°C. 
 Artesunate: store in tightly closed containers, protected from light. 
All drugs will be held in appropriate locked storage conditions at the clinical unit until required. 
6.1.4 PREPARATION 
Inoculum   
P. falciparum 3D7  
The inocula will be prepared aseptically at Q-Gen (QIMR Berghofer), from a frozen cryovial of 
the P. falciparum 3D7 MCB, by nominated QIMR Berghofer staff members under the guidance 
of the Investigator. The infected RBCs will be thawed, washed, resuspended in saline, diluted in a 
final volume of 2 mL of clinical grade saline, and dispensed into syringes [35]. Any remaining 
unused infected RBCs will be discarded as per approved standard operating procedures. 
Study Drug  
OZ439 
The OZ439 and TPGS granules for oral suspension are mixed with water to form an oral 
suspension and sucrose is added prior to administration to the subject. The sucrose is added to 
make the oral suspension palatable. The OZ439 will be drunk and then the cup rinse water will be 
used to swallow the PQP tablets. The reconstitution procedure will be described in the Pharmacy 
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Piperaquine phosphate (PQP)  
PQP is available as tablets and no preparation is required. The tablets will be swallowed with the 
water that is used to rinse the OZ439 suspension cup with.  
OZ439 and PQP will be administered at the same time. Subjects will be fasted for 6 hours pre- and 
post-dose.  
Antimalarial Rescue Medications
 
Riametﬁ and Primacin™ 
Riametﬁ and Primacin™ are available as tablets and no preparation is required. 
6.1.5 DOSING AND ADMINISTRATION 
Inoculum   
P. falciparum 3D7  
An inoculum dose, containing an estimated ~2,800 viable P. falciparum 3D7 parasite-infected 
RBCs in a volume of 2 mL, will be administrated intravenously to each subject on Day 0. The 
actual number of parasites inoculated will take into account the loss of viability resulting from 
cryopreservation, storage and thawing. On inoculation day, subjects may have food until at least 
half an hour prior to inoculation. Subjects will undergo intravenous cannulation with an 
appropriate gauge cannula. Placement and patency will be checked by flushing the vein with 5-10 
mL of clinical grade saline. The inoculum will be injected, and the cannula again flushed with 5-
10 mL of clinical grade saline. The cannula will then be removed, and haemostasis ensured by use 
of an appropriate dressing. All subjects will be inoculated intravenously within 60 minutes of each 
other. See Section 6.1.3 for stability information. An extra syringe will be prepared to quantify the 
parasite count of the inocula by malaria 18S qPCR.  
Study Drug  
OZ439 and piperaquine phosphate (PQP)  
Subjects will be admitted to the clinical unit for single dose administration of OZ439 and PQP, 8 
days after malaria inoculation or earlier if a subject has a malaria clinical score >6 or at 
Investigators discretion. The doses to be administered to subjects in Cohort 1 and 2 are shown in 
Tables 1 and 2 respectively (Section 4.1). Subsequent doses for subsequent cohorts will be 
determined by the SDRT following safety, tolerability and PK/PD review.  Subjects will be fasted 
for ≥6 hours pre and post OZ439 and PQP administration. The OZ439+TPGS granules will be 
mixed with water to form a suspension. Sucrose will be added to the suspension to assist with 
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with the OZ439 cup rinse water. The reconstitution procedure will be described in the Pharmacy 
Manual. 
Antimalarial Rescue Medications
 
Riametﬁ and Primacin™ 
All subjects will receive compulsory treatment with Riametﬁ on trial Day 42–2, or at failure of 
OZ439 and PQP to clear parasitaemia, or at evidence of recrudescence (defined as ≥5 000 blood 
stage parasites/mL and a 2-fold increase within 48 hours, or a malaria clinical score >6), or at the 
Investigators discretion. Riametﬁ tablets containing 20 mg artemether and 120 mg lumefantrine 
will be administered as 6 doses of 4 tablets (total course of 24 tablets) given over a period of 60 
hours (total dose of 480 mg artemether and 2.88 g lumefantrine). Each dose of tablets administered 
orally should be taken with food or drinks rich in fat (e.g., milk). Subjects will be reminded of the 
potential side effects of Riametﬁ and given the Consumer Medicine Information for Riametﬁ 
(Appendix 1). 
Subjects may also be treated with Primacin™ at the time of Riametﬁ treatment if gametocytaemia 
is suspected from parasite lifecycle stage qRT-PCR or by the presence of stable low level 
parasitaemia, or at the Investigator’s discretion, to ensure complete clearance of gametocytes. If 
needed, subjects will take 6 Primacin™ tablets, each containing 13.2 mg primaquine phosphate 
equivalent to 7.5 mg primaquine (the total primaquine dose will be 45 mg). Primacin™ for oral 
use will be taken as a single dose with food. Subjects will be reminded of the potential side effects 
of Primacin™ and given the Consumer Medicine Information for Primacin™ (Appendix 1). 
IV artesunate may be used as a rescue medication if a subject vomits or cannot tolerate oral drugs. 
See artesunate section above. 
 
6.1.6 ROUTE OF ADMINISTRATION 
Inoculum  
P. falciparum 3D7  
Intravenous 
Study Drug  
Artefenomel (OZ439)  
Oral administration 
Piperaquine phosphate (PQP)  


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Oral administration 
Antimalarial Rescue Medications
 
Riametﬁ and Primacin™ 
 
Oral administration 
Artesunate 
If a subject vomits or cannot tolerate oral drugs, then artesunate will be administered intravenously 
as described in Section 6.1.5. 
6.1.7 STARTING DOSE AND DOSE ESCALATION SCHEDULE 
Dosing with the malaria inoculum and rescue drugs is presented in Section 6.1.5. No dose 
escalation will be performed.  
Study Drug  
Dosing with OZ439 and PQP will be performed as described in section 4.1. The doses of OZ439 
and PQP for subjects enrolled in cohort 1 are shown in Table 1 of the Protocol Summary. Subjects 
will be randomised to one of the four groups that comprise Cohort 1. The doses of OZ439 and 
PQP for subjects enrolled in cohort 2 are shown in Table 2 of the Protocol Summary.. Subjects 
will be randomised to one of the two groups that comprise Cohort 2. The OZ439 and PQP doses 
to be evaluated in subsequent cohorts will be determined at the SDRT meeting based on the safety 
and tolerability data up to Day  42–2, and PK/PD analysis outcomes (based on PD data up to Day 
42–2 and PK data up to Day 35–2) of the drugs given in combination in previous Cohort(s). 
The doses used in all Cohorts will not exceed 800 mg for OZ439 and 1440 mg for PQP as 
determined in previous safety, pilot efficacy and phase 2 studies. 
6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
Not applicable. 
6.1.9 DURATION OF THERAPY 
See Section 6.1.5 for dose information. 
6.1.10  TRACKING OF DOSE 
The P. falciparum challenge agent, OZ439 and PQP, and if required Primacin™ will be 
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Riametﬁ on site for initial dosing followed by monitoring, either in the clinic or by phone for 3 
days to ensure adherence to Riametﬁ therapy. 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
The Q-Pharm pharmacist or delegate, as nominated by the Principal Investigator, is responsible 
for maintaining accurate study agent accountability records throughout the study. Study agents 
include the challenge agents (OZ439 and PQP), and the rescue medications. Dispensing, 
accountability and documentation will be in accordance with Q-Pharm standard procedures. All 
products will be inventoried upon receipt by the Q-Pharm pharmacist. The condition of the 
products at the time of receipt by the pharmacist will be documented, as will the time restrictions 
of use for the syringes containing the challenge agents and the time restrictions of use for the oral 
suspension of OZ439 and TPGS. The lot numbers and expiry dates of the inoculum and 
antimalarial drugs will be documented. The Q-Pharm pharmacist or delegate will ensure that the 
received products are the specified formulation.  
The storage, handling and the disposal of the challenge agents will be in accordance with approved 
procedures. All dosages prescribed and dispensed to the subjects and all dose changes during the 
study must be recorded in the eCRFs. All drug supplies are to be used only in accordance with this 
protocol, and not for any other purpose. All used medications will be fully documented. Used and 
unused drug containers must be destroyed at the site once drug accountability is final and has been 
checked by the Sponsor or its delegate, and written permission for destruction has been obtained 
from the Sponsor. 
Study products and study accountability logs will be available to the Sponsor or their 
representative as part of the study monitoring procedures. Upon completion of the study, copies of 
all study drug management records will be provided to the Sponsor. Original records will be 
maintained at the clinical site with the rest of the study records. 
7 
STUDY PROCEDURES AND  SCHEDULE  
 
7.1 
STUDY PROCEDURES/EVALUATIONS 
 
7.1.1 STUDY SPECIFIC PROCEDURES  
Medical history 
Medical history will be elicited at screening as described below.  
Past Medical/Surgical History Includes:  
History of all known allergies  
Current medications, including over-the-counter and herbal preparations  


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History of substance abuse and recreational drug use  
History of depression, anxiety, mental illness, emotional problems, use of psychiatric medications and 
Surgical procedures and results  
Physical examination 
Complete Physical Examination Includes: 
Weight (Screening only)  
Height  (Screening only)   
Review of systems excluding genitourinary examination and including the following:  
Head, neck (including thyroid), ears, eyes, nose and throat  
Heart/circulation  
Chest  
Lungs  
Abdomen  
Skin  
Neurological exam  
Abbreviated Physical Examination: an abbreviated physical examination will be performed at Day 
0 (inoculation day) and Day 8 (OZ439/PQP dosing day). The examination will include; 
heart/circulation, chest, lungs and abdomen.  
Symptom-Directed Physical Examination: physical examinations will be symptom-directed at 
specified time points. Body systems will be reviewed only if clinically indicated at the discretion 
of the Investigator (see Appendix 3 for a list of symptoms and signs of malaria).  
Beck Depression Inventory 
All subjects will be required to complete the Beck Depression Inventory at screening. This is a 
validated questionnaire used as an objective tool for the assessment of depression (See Appendix 
4).  
Vital signs/12-lead ECG and Safety Laboratory Sample Allowed Time Windows  
Time point  
Tolerance window 
 
 
Vital Signs/ 12-Lead Electrocardiogram/Safety Laboratory Sample 
In confinement 
Pre-dose 
- 90 min to 0 h 
0-4 hours inclusive after IMP  
– 10 min 
4-12 hours inclusive after IMP 
– 10 min 
16-72 hours inclusive after IMP 
– 40 min 
 
 
Out patient 


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72-120 hours inclusive  
– 120 min 
168-EOS inclusive 
– 48 hours 
 
Vital signs 
Vital signs (temperature, heart rate, respiratory rate and blood pressure) will be measured at 
screening after the subject has rested in the supine position for at least 5 minutes and in the standing 
position within 2-3 minutes when changing from the supine to standing position (blood pressure 
and heart rate only). At all other time-points, vital signs will be measured after the subject has 
rested in the seated position for at least 5 minutes. Tympanic temperature will be taken at the 
clinical unit. 
The normal ranges for vital signs once on study are: 
Parameter 
Range 
Systolic blood pressure             
90-140 mmHg 
Diastolic blood pressure           
50-90 mmHg 
Heart rate                                 
50 -100 bpm 
Temperature                             
35.0-37.5°C  
Respiratory rate                        
10-25 breaths/min 
Peripheral O2 Saturation          
>=95% 
Electrocardiograms 
Triplicate 12-lead ECG will be recorded after resting in supine for at least 5 minutes. The same 
body position will be assumed by the subject for each recording. ECG tracings will be retained 
and labelled as per standard procedures at the CRU and the mean of the three values will be 
recorded in the eCRF. Any clinically, significant findings will be discussed with the Medical 
Monitor and Sponsor and documented as adverse events. The Investigator will sign and date each 
ECG as evidence of their review. 
The normal ECG ranges once on study are: 
Parameter 
Range 
PR interval             
<= to 210 ms 
QRS           
>50 to < = to120 ms 
QT interval                                 
>200 to < 500 
QTcB/QTcF                            
Males: ≤ 450 msec 
QTcB/QTcF                           
Females ≤470 msec 
 
Blood sampling 


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Main Study- Blood will be collected for clinical laboratory evaluations including haematology, 
biochemistry, serology, pregnancy testing and/or FSH testing (see Section 7.2.1). Blood samples 
will also be collected to monitor malaria parasitaemia and to quantify plasma drug concentrations 
for PK analysis (see Section 7.2.2).  
Optional exploratory components- Blood will be collected to characterise specific cell subsets with 
an aim to identify immune-regulatory pathways initiated during malaria infection that can be 
targeted for clinical advantage. Blood samples will also be collected to investigate early changes 
to RBC that leads to malaria induced anaemia.   
The estimated blood volume required for both the main study and optional exploratory components 
is listed in Appendix 2. The total volume of blood drawn from each subject will not exceed 450 
mL in any given 30-day period. The total blood volume at day 30, for both the main study and 
optional exploratory components, will be approximately 404 mL and by EOS at day 45, for both 
the main study and optional exploratory components, will be approximately 485 mL.  
This volume provides an allowance for unscheduled safety laboratory assessments that may be 
required at the discretion of the Principal Investigator or the Sponsor to ensure subject safety.  
Urine sample collection 
Urine will be collected for urinalysis and drug screening (see Section 7.2.1).  
AE recording 
AEs will be recorded as described in Section 8.  
Malaria Clinical Score 
The following 14 signs/symptoms frequently associated with malaria will be graded by the Study 
nurse or doctor using a 4-point scale (absent: 0; mild: 1; moderate: 2; severe: 3) and summed to 
generate a total Malaria Clinical Score (maximum total score possible is 42). Individual scores 
for each symptom as well as the total score will be recorded. 
Headache 
Anorexia 
Myalgia (muscle ache) 
Nausea 
Arthralgia (joint ache) 
Vomiting 
Fatigue/lethargy 
Abdominal discomfort 
Malaise (general discomfort/uneasiness) 
Fever 
Chills/Shivering/Rigors 
Tachycardia 
Sweating/hot spells 
Hypotension 
Medical Diary 


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Provide subjects with diary cards and instruct subjects to record symptoms and concomitant 
medications during the study. 
Temperature Self Recording 
Provide subjects with thermometers to record any temperature readings during the study in the 
event of symptoms of fever, sublingual temperature will be taken by subjects at home for practical 
reasons. 
7.1.2 STANDARD OF CARE STUDY PROCEDURES  
Not applicable.  
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
 
7.2.1 CLINICAL LABORATORY EVALUATIONS  
Any significant deviations from results obtained during screening will be followed until resolution 
or investigated fully, or until the subject is referred to a general practitioner. The Investigator will 
document the clinical significance of all results falling outside of the normal reference ranges. All 
abnormal laboratory test results judged as being clinically significant will be recorded as AEs. 
The estimated blood volume required for these tests is listed in Appendix 2. 
Haematology  
Full blood count (FBC) with differential 
 
White blood cell count (WBC)  
WBC differential (diff)  
A manual blood smear should be reviewed if there are immature/abnormal cells detected on the 
automated differential or if an automated differential was not able to be performed.  
Neutrophils (NEUT) 
Lymphocytes (LYM) 
Monocytes (MON) 
Eosinophils (EOS) 
Basophils (BAS) 
Red blood cell count (RBC) 
Mean corpuscular volume (MCV)  
Haemoglobin (HGB)  
Haematocrit (HCT)  
Platelet count (PLAT)  
Reticulocyte count (RETI) (screening and EOS or early termination visit only)
 
Blood Group and Rh(D) tests (Screening only)  


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RBC alloantibodies testing 
Blood for RBC alloantibodies testing will be collected at screening and Day 45–2 or early 
termination visit. 
G6PD testing 
Blood for G6PD testing will be collected at screening only. G6PD deficiency is not an exclusion 
criterion but will be determined at screening to ensure the safety of Primacin™. 
Coagulation testing 
Blood for PT, APTT and INR will be collected at screening visit. 
Biochemistry and CRP biomarker 
Sodium (SODIUM) 
 
Alkaline phosphatase (ALP) 
Potassium (K) 
Alanine aminotransferase (ALT, SGPT) 
Chloride (CL) 
Aspartate aminotransferase (AST, SGOT) 
Bicarbonate (BICARB) 
Calcium corrected 
Glucose (GLUC) 
Phosphate (PHOS) 
Urea  
Lactate dehydrogenase (LDH) 
Creatinine (CREAT) 
Magnesium (Screening only)  
Urate 
Cholesterol (Screening only)  
Albumin (ALB) 
Triglycerides (Screening only)  
Globulin  
HDL (Screening only)  
Total protein  
Estimated glomerular filtration rate (eGFR) 
Total bilirubin (BILI)  
C-Reactive Protein (CRP) (Not included at 
Screening ) 
Direct (conjugated) bilirubin (BILDIR) 
 
Urinalysis 
Urine will be tested by dipstick at the clinical unit. If there are any abnormalities considered 
clinically significant in blood, leucocytes or protein, the urine will be sent for formal laboratory 
urinalysis per the clinical unit standard procedure. 
Glucose (GLUC) 
Bilirubin (BILI) 
Ketone (KETONES) 
Specific gravity (SPGRAV) 
Blood  
pH  
Protein (PROT) 


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Urobilinogen (UROBIL) 
Nitrite  
Leukocytes (WBC)  
Formal laboratory urinalysis (if required)  
Urine drug screens and alcohol breath tests 
If the results of the urine drug screens or alcohol breath tests are positive, subjects will not be 
enrolled in the clinical study.  
All subjects will be questioned about concomitant medications and use of recreational drugs. The 
urine drug screen may be repeated if the potential subject denies usage of any of these agents and 
the test result is believed to be a false positive. 
Subjects testing positive for paracetamol at screening and/or inoculation day may still be eligible 
for study participation, at the Investigator’s discretion. Subjects requiring paracetamol on a daily 
basis would not be eligible to enrol in the study, as the use of any over-the-counter medication 
during the study is restricted and potential subjects should not discontinue their usual medications 
in order to participate in the study. 
Urine drug screens:  
Amphetamines 
Opiates 
Methamphetamines 
Phencyclidine 
Barbiturates 
Tetrahydrocannabinol (cannabis) 
Benzodiazepines 
Tricyclic antidepressants 
Cocaine  
Acetaminophen (paracetamol) 
Methadone 
 
Alcohol breath test  
Serology 
HIV 1/2 (anti-HIV1 and anti-HIV2 Ab) 
Hepatitis B (HBs Ag, anti-HBc (IgG + IgM if IgG  is positive)) 
Hepatitis C (anti-HCV) 
Hepatitis A (anti-HAV) (IgM) - performed from stored sample for testing, at Investigator ’s discretion 
Hepatitis E (anti-HEV) (IgM) - performed from stored sample for testing, at Investigator ’s discretion 
Epstein-Barr virus - performed from stored sample for testing, at Investigator ’s discretion 
Cytomegalovirus - performed from stored sample for testing, at Investigator ’s discretion 
Safety serum storage 
Blood for serum storage as safety retention samples will be collected at times outlined in Section 
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7.2.2 OTHER ASSAYS OR PROCEDURES 
The estimated blood volume required for these tests is listed in Appendix 2.  
PK/PD Allowed Time Windows  
Time point  
Tolerance window 
Pharmacokinetic/pharmacodynamic 
In confinement 
Pre-dose 
- 60 min to 0 h 
0-4 hours inclusive after IMP  
– 2 min 
4-12 hours inclusive after IMP 
– 5 min 
16-72 hours inclusive after IMP 
– 30 min 
 
 
Out patient 
72-120 hours inclusive  
– 120 min 
168-EOS  
– 48 hours 
Malaria monitoring  
Blood will be collected to monitor parasitaemia using qPCR targeting the 18S rRNA gene. 
Additional blood (up to approximately 2.5 mL per time-point) may be collected for parasite 
lifecycle stage qRT-PCR at the Investigator’s discretion. This is to evaluate for the presence of 
sexual parasite stages (gametocytes) and other parasite lifecycle stages in the blood. This blood 
may also be used for research into various aspects of parasite biology e.g. gametocytes, parasite 
lifecycle stages, recrudescence, commitment etc. The qRT-PCR may target genes including but 
not limited to: the female gametocyte-specific transcript pfs25, the male gametocyte-specific 
transcript pfMGET, and the ring-stage transcript pfSBP-1 as appropriate. The samples may be taken 
at time points indicated by malaria 18S qPCR, or at the Investigator’s discretion.  
Microscopic examination for evidence of parasitaemia or gametocytaemia may be conducted at 
the Investigator’s discretion.  
Malaria monitoring will continue until a minimum of one negative 18S qPCR is detected post 
rescue therapy.   
PK blood collection and processing 
Blood sampling for PK analysis will be performed at scheduled time points from immediately 
before dosing with OZ439 and PQP until 816 hours post-dose, (allowed time-windows as 
described above). 
 
Blood samples will be collected either by direct venepuncture or via an indwelling cannula inserted 
in a forearm vein. Details of the volume of blood collected are listed in Appendix 2. 


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A description of the required lab procedures will be described in the Laboratory Manual. 
The actual sample collection date and time will be entered in the PK blood collection section of 
the eCRF. Any sampling problems will be documented in the eCRFs. 
Pharmacokinetic analytical methods 
Plasma concentrations of OZ439 and PQP will be quantified by LC MS/MS in the selected reaction 
monitoring mode using heated electrospray ionization in positive ion mode.  
OZ439: Plasma samples will be precipitated with five volume equivalents of a mixture of 
acetonitrile/methanol (4/1, v/v) containing the internal standard. After centrifugation, the samples 
will be diluted with a mixture of water/acetonitrile (1/1, v/v). An aliquot of 2 µL of the sampl e will 
be injected onto the High-performance liquid chromatography system (HPLC). 
PQP: Plasma samples will be precipitated with ten volume equivalents of acetonitrile containing 
the internal standard. After centrifugation and dilution with one equivalent of water, an aliquot of 
25.0 µL of the supernatant will be injected onto the HPLC system. 
Optional exploratory components 
Blood sampling for immune cell characterisation and complement regulatory protein analysis will 
be performed at scheduled time points as detailed in Section 7.3. The time-points for the 
exploratory components are scheduled to coincide with blood collection time-points of the main 
study. If time-points of the main study change the exploratory study time-points will change to 
match to ensure subject comfort and convenience.   
Blood samples will be collected either by direct venepuncture or via an indwelling cannula inserted 
in a forearm vein. Details of the volume of blood collected are listed in Appendix 2. 
Optional exploratory components analytical methods 
Specific cell subsets will be sorted from blood collected on Days 0 (prior to malaria inoculation), 
4, 8 (prior to OZ439 and PQP administration), 15 and at EOS. The host immune response generated 
by these sorted cells will be investigated at the DNA, RNA and protein levels with an integrative 
high dimensional multi-omics strategy. DNA, RNAs, including mRNA, microRNA and long-non-
coding RNA (lncRNA), and proteins will be extracted from the same sample and samples will be 
assayed in a high dimensional biology approach. mRNA, miRNAs, and lncRNA will be profiled 
using NanoString, RNAseq, and/or whole transcriptome analysis. Comprehensive panels of 
molecules involved in T cell activation, function, and exhaustion will be evaluated using multi-
parametric flow cytometry. Proteogenomics will also be investigated, whereby data from high-
resolution mass-spectrometers (e.g. QTRAP) will generate fingerprints for peptides which are 
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Expression of complement regulatory proteins (CD35, CD55, and CD59) and phosphatidylserine 
on RBC will be assessed by flow cytometry and will be quantified by commercial ELISA from 
blood samples collected on Day 0 (prior to malaria inoculation), Day 8 (prior to OZ439 and PQP 
administration), Days 10, 12, 13, 15, 18 and at EOS.   
7.2.3 SPECIMEN PREPARATION, HANDLING, AND STORAGE 
Q-Pharm’s standard work instructions will apply to the allowed time windows for study procedures 
and sample collection. If the observation time and blood sampling time coincide, for precision of 
timing, blood collection will take precedence over other procedures scheduled at the same time.  
Blood will be collected into tubes containing the appropriate anticoagulant. Samples will be 
processed according to the laboratory requirements. 
Biological samples will be retained for the time required for assessment for analysis, and may then 
be discarded. Safety serum samples will be stored indefinitely with the permission of the subjects 
for any retrospective safety assessments. 
7.2.4 SPECIMEN SHIPMENT 
 
Samples collected will be shipped to nominated local or international laboratories for assessment 
(Section 1). The site staff will be responsible for shipment of samples to analytical laboratories for 
testing. Samples must be packed securely together with completed shipment forms in shipping 
containers together with sufficient dry ice as per Shipper procedures. 
 
7.3 
STUDY SCHEDULE 
 
7.3.1 SCREENING 
A screening visit will be scheduled after an initial phone interview conducted by clinical unit staff 
has occurred to review background information. For the screening visit, potential subjects will be 
asked to come to the clinical unit after an overnight fast of ≥8 hours. During this initial screening 
visit, an Investigator will discuss the details of the study with the potential subject, and the potential 
subject will read the Participant Information Sheet and be encouraged to ask questions.  
Subjects will be fully informed of the nature of the study at this time, and advised of the 
requirement to repeat some screening tests during the Day -3 to Day -1 safety visit (if required) 
and/or on inoculation day to determine their continuing eligibility. Subjects must confirm that they 
will not be living alone from inoculation day until the end of the Riametﬁ treatment. 
Individuals willing to be considered for inclusion may sign the Consent Form during the screening 
visit, or return to the clinical unit after further consideration. The subject will be given a copy of 
the Participant Information Sheet and signed Consent Form for their records. The signed and dated 


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originals will be held on file by the clinical unit. Participation consent must be obtained from all 
subjects prior to screening tests. 
The consenting process will take place with one of the Q-Pharm medical staff or Investigators and 
will include the following: 
1. Provide the Participation Information Sheet and Informed Consent Form and give the 
subject sufficient time to review the contents. 
2. Explain the study via the Participation Information Sheet and gain informed consent from 
the subject, if they are willing to consent.  
3. Ensure the subject and member of staff taking consent have signed and dated the Informed 
Consent Form and received a signed copy.  
Once the potential subject has provided written consent to participate, the pre-study screening may 
be initiated. The screening will be conducted within 4 weeks prior to the inoculation day and will 
include: 
1. A screening number will be assigned to each subject. 
2. Elicit a complete medical history and use of medications.  
3. Elicit a social history including recreational drug, alcohol and tobacco use.  
4. Perform alcohol breath test. 
5. Perform a drugs of abuse screen.  
6. Perform complete physical examination. 
7. Ask subject to complete the Beck Depression Inventory. 
8. Assess the cardiovascular disease risk as per exclusion criterion 4.  
9. Record vital signs. 
10. Obtain a 12-lead ECG in triplicate.  
11. Collect urine for urinalysis.  
12. Collect blood samples for haematology, biochemistry, RBC alloantibodies, G6PD testing, 
and serology (viral hepatitis B and C and HIV). 
13. Collect blood for coagulation profile 
14. Perform serum β-hCG pregnancy test for all female subjects and follicle stimulating 
hormone test (FSH) for post-menopausal females. 
15. Verify subject meets inclusion/exclusion criteria. 
Subjects who complete all screening procedures and satisfy all entry criteria will be considered 
eligible to participate in this study. To be eligible for study entry, laboratory values at screening 
must not be outside the range of the normal values at a level deemed to be clinically significant 
according to Sponsor-approved criteria. For eligibility parameters, a repeat may be requested to 
exclude laboratory error. Re-screening will not be allowed unless the Investigator considers the 
cause of the initial pre-screening failure to be of an acute and completely reversible nature. 


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If screening laboratory results are abnormal, e.g. HIV testing, the subject will be referred for 
appropriate counselling. If any clinically significant abnormalities are detected during screening, 
the subject will be referred for follow-up tests to a general practitioner or medical specialist as 
appropriate. 
7.3.2 ELIGIBILITY CONFIRMATION VISIT 
Day -3 to Day -1 safety visit  
Subjects (including approximately 4 reserve subjects as mentioned in Section 5.4) will report to 
the clinical unit between Day -3 to Day -1 for the following baseline assessments, unless screening 
laboratory assessments were conducted within this period, in which case repeat sampling will not 
be required.  
This visit will include: 
1. Collect blood samples for haematology, biochemistry (including CRP biomarker) and 
serum β-hCG pregnancy test for all female subjects.  
2. Collect urine for urinalysis. 
The timing of these assessments is to ensure that results are available for review by the Investigator 
prior to inoculation on inoculation day. Subjects with clinically significant laboratory findings at 
this stage will not be eligible for inoculation. 
Malaria inoculation day (Day 0 )  
Each subject (and approximately 4 reserve subjects) will report to the clinical unit on the morning 
of Day 0. The Investigator will review the subjects’ screening and eligibility confirmation visit 
results prior to their enrolment into the study and subsequent inoculation. The Investigator will 
emphasise the requirement to return to the clinical unit for malaria drug treatment after the malaria 
inoculation and confirm that they will not be living alone from Day 0 until the end of the study by 
checking housemates contact details recorded at screening visit.  
On admission to the clinical unit, subjects will be required to undertake further procedures to 
determine whether they remain eligible to be enrolled. A reserve subject may be asked to replace 
a subject who does not continue to meet eligibility. These reserves will be compensated for the 
study visit even if not inoculated, as described in the Participant Information and Consent Form.  
The procedures that will be undertaken prior to inoculation on Day 0 include: 
1. Verify that all applicable eligibility criteria have been met.  
2. Elicit information regarding any new medical conditions, illnesses and medication use 
since screening. 
3. Perform alcohol breath test and urine drug screen.  
4. Perform urine β-hCG pregnancy test for WOCBP subjects 


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5. Conduct abbreviated physical examination.  
6. Record vital signs.  
7. Obtain 12-lead ECG in triplicate.  
8. Cannulate subjects with an indwelling intravenous cannula for the malaria inoculum, and 
record which arm is utilised.  
9. Collect blood samples for malaria qPCR and safety serum storage.  
10. Collect optional blood samples for immune cell characterisation and complement 
regulatory proteins (if consented separately). 
11. Perform Malaria Clinical Score. 
 
Administration of the malaria inoculum: 
1. Administer the malaria inoculum of ~2 800 viable P. falciparum 3D7 infected human 
RBCs intravenously in the morning (approximately 9:00 AM).  
2. Observe for a minimum of 60 minutes after inoculation to evaluate for immediate adverse 
reactions.  
3. Educate subjects on signs and symptoms of malaria (Appendix 3).  
4. Emphasise to subjects the importance of returning on the nominated day (approximately 
Day 8), or as advised by the clinical unit staff, for IMP antimalarial treatment.  
5. Provide subjects with diary cards and thermometers to record any temperature readings 
during the study in the event of symptoms of fever. Subjects will also record symptoms 
and concomitant medications on the diary cards during the study.  
6. Record AEs and concomitant medications.  
7. Record vital signs prior to leaving the clinical unit (approximately 60 minutes after 
inoculation).  
8. Record malaria clinical score prior to leaving the clinical unit (malaria clinical score 
baseline sample; see Section 7.1.1). 
7.3.3 FOLLOW-UP  
Malaria monitoring via phone (Days 1
-3) 
During this period, subjects are expected to be asymptomatic. A daily phone call or text message 
will be made to the subjects by clinical unit staff to monitor subject well-being and to solicit any 
AEs. 
Daily visits to the clinical unit  for malaria monitoring (Day 4 AM until qPCR positive for 
malaria)  
Follow-up from Day 4 until qPCR becomes positive will be undertaken through daily visits 
(approximately 8:00 AM) to the clinical site. 


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The following procedures will occur during these visits:  
1. Perform symptom-directed physical examination when signs or symptoms of malaria are 
identified and it is clinically indicated (Appendix 3).  
2. Elicit information regarding any new medical conditions, illnesses and medication use 
since screening  
3. Record vital signs.  
4. Collect blood sample for malaria 18S qPCR.  
5. Collect optional blood samples for immune cell characterisation, Day 4 (if consented 
separately). 
6. Record malaria clinical score. 
7. Record AEs and use of concomitant medications.  
8. Check subject diaries. 
 
Day when qPCR p ositive until treatment day (Day 8) 
Follow-up from the day that malaria 18S qPCR becomes positive until treatment day will be 
undertaken through twice daily (AM & PM) visits to the clinical site separated by approximately 
12 hours (i.e. 06:00 – 11:00 and 18:00 – 23:00). The following procedures will occur during these 
visits:  
1. Perform symptom-directed physical examination.  
2. Elicit information regarding any new medical conditions, illnesses and medication use 
since screening  
3. Record vital signs.  
4. Collect blood sample for malaria 18S qPCR.  
5. Record malaria clinical score.  
6. Record AEs and use of concomitant medications.  
7. Check subject diaries. 
 
In-patient observation and 
IMP antimalarial treatment phase (Day 
8-Day 11) Subjects will 
be admitted to the clinical unit for 72 hours on the morning of Day 8 (or earlier if a subject has a 
malaria clinical score >6 or at Investigators discretion) for OZ439 and PQP treatment and 
monitoring of clinical symptoms of malaria.  
Admission 
The following procedures will occur at admission to the clinical unit: 
1. Perform abbreviated physical examination. 
2. Perform alcohol breath test and drug screen.  
3. Elicit information regarding any new medical conditions or illnesses. 


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4. Record vital signs. 
5. Obtain 12-lead ECG in triplicate. 
6. Collect urine for urinalysis.  
7. Perform urine β-hCG pregnancy test for WOCBP subjects. 
8. Cannulate subjects with an indwelling intravenous cannula.  
9. Collect blood samples for haematology, biochemistry (including CRP biomarker), malaria 
18S qPCR (parasite clearance baseline sample), and PK analysis (measurement of OZ439 
and PQP levels; PK baseline sample).  
NOTE: As these test results may not be available before the drug administration, the results of 
this time point will be used for future interpretation of study results. 
10. Collect optional blood samples for immune cell characterisation and complement 
regulatory proteins (if consented separately) 
11. Record malaria clinical score. 
12. Record AEs and use of concomitant medications. 
Treatment and observation  
The following procedures will occur during treatment and observation: 
1. Administer the appropriate doses of OZ439 and PQP to fasted (≥6 hours) subjects under 
direct observation, as described in (Section 6.1.5).  
2. Follow up subjects as in-patients for 72 hours to monitor safety and tolerability of the treatment 
and adequate clinical response. 
3. Perform symptom-directed physical examination when signs or symptoms of malaria are 
identified and it is clinically indicated. 
4. Obtain 12-lead ECG in triplicate at 4, 6, 8, 12, 24 and 72 (D4) hours post-OZ439 and PQP 
administration. 
5. Record vital signs 3 times a day whilst confined.  
6. Record malaria clinical score 3 times a day whilst confined. 
7. Collect blood samples for malaria 18S qPCR following treatment at 2, 4, 8, 12, 16, 20, 24, 
30, 36, 42, 48, 60, and 72 hours post-OZ439 and PQP administration as per allowed time 
windows.  
8. Collect blood samples for PK analysis of OZ439 and PQP at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 
24, 48, and 72 hours post-OZ439 and PQP administration as per allowed time windows.  
9. Collect optional blood samples for complement regulatory proteins (if consented 
separately) at approximately 48 hours post-OZ439 and PQP treatment.  
10. Record AEs and use of concomitant medications. 
 
Prior to exit from the clinical unit 


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Subjects will be allowed to leave the clinical unit 72 hours post-OZ439 and PQP treatment at the 
Investigator’s discretion. 
The following procedures will occur prior to discharge from the clinical unit: 
1. Perform symptom-directed physical examination at Investigators discretion.  
2. Record vital signs.  
3. Collect blood samples for haematology, biochemistry (including CRP biomarker), PK 
analysis and malaria 18S qPCR (~72 hours post-OZ439 and PQP dosing).  
4. Obtain 12-lead ECG in triplicate. 
5. Record AEs and use of concomitant medications. 
Out -patient monitoring post -OZ439 and PQP  treatment  (Day 12 up to Day 42–2) 
Follow-up at either AM (approximately 08:00) or AM and PM (if necessary, approximately 12 
hours apart) will be undertaken on an out-patient basis through visits post-confinement for clinical 
evaluation and blood sampling.  
The following procedures will take place during these visits: 
1. Elicit information regarding any new medical conditions or illnesses. 
2. Collect a blood sample for malaria 18S qPCR in the morning and in the evening on days 
12 and 13 and then three times weekly or at Investigators discretion based on parasitaemia 
until Day 42–2.  
3. Collect blood samples for parasite lifecycle stage qRT-PCR at the Investigator’s discretion 
(Section 7.2.2). 
4. Collect blood samples for PK analysis of OZ439 and PQP at 96–2, 168–48, 240–48, 
336–48, 504–48, 672–48 and 840–48 hours after OZ439 and PQP administration.  
5. Collect blood samples for haematology and biochemistry (including CRP biomarker) and 
urine for urinalysis at 336–48, 504–48 and 672–48 hours post-OZ439 and PQP 
administration or at the Investigator’s discretion. 
6. Collect optional blood samples for complement regulatory proteins (if consented 
separately) at 96–2, 120–48, 168–48, 240–48 hours post-OZ439 and PQP. 
7. Collect optional blood samples for immune cell characterisation (if consented separately) 
at 168–48 hours post-OZ439 and PQP. 
8. Perform symptom-directed physical examination when signs or symptoms of malaria are 
identified and it is clinically indicated. 
9. Record vital signs.  
10. Record malaria clinical score if vital signs are abnormal or at the Investigator’s discretion. 
11. Record AEs and use of concomitant medications. 
12. Check subject diaries. 
 
Rescue treatment with Riamet ﬁ  


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All subjects will receive a standard course of therapy with Riametﬁ (artemether -lumefantrine) on 
trial Day 42–2 or earlier in the event of failure of clearance or recrudescence of parasitaemia or at 
Investigators discretion based on subject safety.  
– Failure of clearance: defined as failure to clear parasitaemia by at least 10-fold at 72 hours 
post-IMP administration  
– Recrudescence: defined as ≥5 000 blood stage parasites/mL and a 2-fold parasitaemia 
increase within 48 hours, or re-occurrence of malaria symptoms with a malaria clinical 
score >6).  
Subjects may take the doses at the clinical unit or at home, as determined by the Investigator. 
Subjects will receive a phone call or text message from clinical unit staff to check on symptoms 
and ensure compliance and completion of treatment following the doses taken at home. Primacin™ 
may also be administered at the time of Riametﬁ treatment (Section 6.1.5). 
The following procedures will be performed prior to Riametﬁ treatment: 
1. Elicit information regarding any new medical conditions or illnesses. 
2. Perform symptom-directed physical examination.  
3. Record vital signs. 
4. Collect blood samples for haematology, biochemistry (including CRP biomarker). 
5. Collect blood samples for malaria 18S qPCR, and parasite lifecycle stage qRT-PCR (if 
required). 
6. Collect blood samples for PK analysis of OZ439 and PQP (if Riametﬁ treatment occurs on 
trial Day 42–2.  
7. Record malaria clinical score if vital signs are abnormal or at the Investigator’s discretion. 
8. Record AEs and use of concomitant medications. 
9. Obtain 12-lead ECG in triplicate. 
10. Check subject diaries. 
 
Follow-up post r escue treatment if Riamet ﬁ is administered prior to Day 42–2 
For all subjects a follow-up visit will occur 3-days (+2-days) after initiation of Riamet treatment. 
The following procedures will be performed at this visit. 
1. Perform symptom-directed physical examination.  
2. Record vital signs. 
3. Collect blood samples for haematology, biochemistry (including CRP biomarker). 
4. Collect blood for malaria 18S qPCR (if the result is positive the subject will be followed up 
until a minimum of one negative qPCR is detected).  
 
7.3.4 END OF STUDY VISIT (EOS) 


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The following procedures will be performed at the EOS visit after completion of Riametﬁ 
treatment (Day 45–2): 
1. Elicit information regarding any new medical conditions or illnesses. 
2. Perform full physical examination. 
3. Record vital signs. 
4. Collect blood samples for haematology, biochemistry (including CRP biomarker),  
5. Collect blood for malaria 18S qPCR (if the result is positive the subject will be followed up 
until a minimum of one negative qPCR is detected).  
6. Collect blood for parasite lifecycle stage qRT-PCR (if required). 
7. Collect urine for urinalysis.  
8. Record malaria clinical score. 
9. Collect blood samples for RBC alloantibodies, serology and safety serum storage (2 serum 
samples). 
10. Collect optional blood samples for immune cell characterisation and complement regulatory 
proteins (if consented separately). 
11. Perform serum β-hCG pregnancy test for WOCBP subjects. 
12. Record AEs and use of concomitant medications. 
13. Obtain 12-lead ECG in triplicate. 
 
See Section 8.3 for follow-up procedures for ongoing AEs/SAEs.  
 
7.3.5 EARLY TERMINATION VISIT 
If withdrawal occurs at any stage of the study, the subject will be asked to complete an EOS 
evaluation. In addition, subjects are informed o
f the essential requirement to complete the 
antimalarial drug treatment for their safety, via the Participant Information Sheet.
 
Participation in an early termination evaluation by each subject is voluntary. Procedures during 
the early termination visit are the same as for the Day 45–2/EOS visit (Section 7.3.4).  
7.3.6 UNSCHEDULED VISIT 
Unscheduled visits for malaria 18S qPCR or safety monitoring may be required at the 
Investigator’s discretion based on parasitaemia, clinical symptoms or laboratory results. Subjects 
will be contacted by phone to arrange these visits. Where possible, visits will be arranged at a time 
that is both convenient for the subject and meets any clinical urgency as determined by the 
Investigator. Unscheduled visits will be documented in the source documents and eCRF. 
7.3.7 SCHEDULE OF EVENTS TABLE 


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The Schedule of Events Table summarises the procedures to be conducted as per this protocol 
during screening, confinement and post-confinement. Section 7.1 and 7.2 provide detailed 
information on the procedures.  
An experienced nurse will be in attendance at the clinical unit when subjects are on-site and the 
Investigator will be available within approximately 30 minutes call back if required.  
In the schedule of events, evaluation may be in the morning, between 6:00 AM to 11:00 AM, and 
in the afternoon, between 6:00 PM to 11:00 PM, therefore separated by approximately 12 hours. 
Some safety and laboratory evaluation days may vary –2 days based on qPCR counts and clinical 
unit visits at the Investigator’s discretion.  


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Table 2: Schedule of Events  
Procedure  
Screening  
D-28 to D-1 
Eligibility 
visita  
D-3 to D-1 
Malaria 
inoculation 
day  
D0   
 
Post-
inoculation 
phone 
contact  
D1 to D3 
 
Malaria 
monitoring b  
D4 to D7 
 
OZ439 and PQP 
treatment and 
clinical unit 
confinement   
D8 to D11 
Out -patient 
monitoring  
D12 to D42–2  
Rescue 
treatment 
with Riametﬁ 
D42–2 
or earlier if 
required 
EOS visit  
D45–2 
Informed consent & BDI 
X 
 
 
 
 
 
 
 
 
Medical history, eligibility & 
prior medications 
X 
 
X 
 
 
 
 
 
 
Drug & alcohol screen 
X 
 
X 
 
 
X 
 
 
 
Full physical examination 
X 
 
 
 
 
 
 
 
X 
Abbreviated physical examination 
 
 
X 
 
 
Xr 
 
 
 
Symptom-directed physical 
examinationc 
 
 
 
 
X 
X 
X 
X 
 
Vital sign assessment 
X 
 
X 
 
X 
X 
X 
X 
X 
ECG 
X 
 
X 
 
 
Xj 
 
X 
X 
Urinalysis 
X 
X 
 
 
 
Xk 
X 
 
X 
Haematology & biochemistry 
X 
X 
 
 
 
X 
X 
X 
X 
Coagulation profile e 
X 
 
 
 
 
 
 
 
 
G6PD testing 
X 
 
 
 
 
 
 
 
 
RBC alloantibody 
X 
 
 
 
 
 
 
 
X 
Serology 
X 
 
 
 
 
 
 
 
X 
Serum β-hCG pregnancy test 
Xd 
X 
 
 
 
 
 
 
X 
Urine β-hCG pregnancy test 
 
 
X 
 
 
X 
 
 
 
Safety serum storage 
 
 
X 
 
 
 
 
 
X 
AEs & concomitant medications 
 
 
X 
X 
X 
X 
X 
X 
X 
Malaria clinical score 
 
 
X 
 
X 
X 
Xl 
X 
X 
Malaria 18S qPCR blood 
sampling 
 
 
X 
 
X 
X 
Xm 
X 
X 
Parasite lifecycle stage qRT-PCR 
blood samplingf 
 
 
 
 
 
 
X 
X 
X 
OZ439 and PQP  concentration 
blood sampling 
 
 
 
 
 
X 
X 
Xs 
 
Phone call or text message 
 
 
 
 
 
 
 
Xn 
 
Malaria inoculum 
 
 
Xg 
 
 
 
 
 
 
OZ439 and PQP  treatment 
 
 
 
 
 
X 
 
 
 
Riametﬁ treatmenth 
 
 
 
 
 
 
 
X 
 
Primacin™ treatmenti  
 
 
 
 
 
 
 
X 
 


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Immune cell characterisation 
(optional) 
 
 
Xo 
 
XP 
Xq 
X 
 
X 
Complement regulatory proteins 
(optional) 
 
 
Xo 
 
 
Xq 
X 
 
X 
PQP: piperaquine phosphate; EOS: End of Study, BDI: Beck Depression Inventory; ECG: electrocardiogram; G6PD: glucose-6-
phosphate dehydrogenase, RBC: red blood cell, PK: pharmacokinetic, PD: pharmacodynamic, qPCR: quantitative polymerase chain 
reaction, qRT-PCR: reverse transcription qPCR.  
a An additional safety visit will occur between Day -3 and Day -1 to collect samples for haematology, biochemistry and urinalysis, 
unless screening laboratory assessments were conducted within this period.  
b Daily visits until qPCR positive, and then twice daily visits until OZ439 and PQP treatment. 
c Symptom-directed physical examinations will be performed only if clinically indicated at the discretion of the Investigator (see 
Appendix 3 for a list of symptoms and signs of malaria). 
d Perform follicle stimulating hormone test (post-menopausal females) at screening.  
e To be performed at screening visit.  
f May be performed at the Investigator’s discretion, most probably pre and post administration of rescue medication to measure the level 
of gametocytaemia. 
g Cannulate subjects with an indwelling intravenous cannula for the malaria inoculum, and record which arm is utilised. Cannulate 
subjects with an indwelling intravenous cannula for the malaria inoculum, and record which arm is utilised. Administer the malaria 
inoculum of ~2 800 viable P. falciparum 3D7 infected human RBCs intravenously in the morning (approximately 9:00 AM). Observe 
for a minimum of 60 minutes after inoculation to evaluate for immediate adverse reactions. Educate subjects on signs and symptoms of 
malaria (Appendix 3). Emphasise to subjects the importance of returning on the nominated day (approximately Day 8), or as advised by 
the clinical unit staff, for IMP antimalarial treatment. Provide subjects with diary cards and thermometers to record any temperature 
readings during the study in the event of symptoms of fever. Subjects will also record symptoms and concomitant medications on the 
diary cards during the study 
h Riametﬁ treatment will occur on Day 42–2, or earlier if there is failure of clearance defined as failure to clear parasitaemia by at least 
10-fold at 72 hours post-IMP administration or recrudescence of parasitaemia (defined as ≥5 000 blood stage parasites/mL and a 2-fold 
increase within 48 hours, or a malaria clinical score >6), or at the Investigator’s discretion. 
i Primacin™ treatment if required (Section 6.1.5). 
j ECG to be performed in triplicate at 4, 6, 8, 12, 24 and 72 hours post-OZ439 and PQP dosing, and prior to Riamet treatment or at the 
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k At the time of admission to clinical unit only. 
l Only if vital signs are abnormal, or at the Investigator’s discretion. 
m 18s malaria to be performed Day 12 (am & pm), Day 13 (am & pm) then 3x per week until EOS at Investigators discretion. 
n Phone call for 3 days to ensure adherence to Riametﬁ treatment. 
o Blood collection pre-inoculation 
p Blood collection Day 4 visit 
q Blood collection pre-OZ439 and PQP dosing 
r Abbreviated physical examination pre-OZ439 and PQP dosing 
s Blood collection for OZ439 and PQP PK at Day 42–2. If Riametﬁ treatment occurs prior to Day 42–2 the PK collection will continue 
as per scheduled time-points 
 
 
 


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7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
Not applicable.  
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES  
Concomitant medications, treatments and procedures are those occurring from malaria inoculation 
until the end of the study (last visit). Those occurring prior to inoculation are classified as prior 
medications, treatments and procedures. Medications taken within 28 days before the malaria 
inoculation will be recorded as prior medication. Prior and concomitant medications, treatments 
and procedures permitted in this study are outlined in the inclusion/exclusion criteria (Section 5.1 
and 5.2).  
On inoculation day, subjects will be questioned in relation to relevant aspects of compliance with 
the study protocol, including drug intake since their screening visit. Details of all other drugs taken 
(prescription and over-the-counter, systemic and topical administration) will be recorded at this 
time and appropriate action taken. The Investigator may permit the use of ibuprofen up to 1.2 g/day 
or paracetamol up to 4 g/day, for treatment of headache or other pain if required. Ibuprofen is the 
preferred treatment for headache or pain. To minimise the risk of liver enzyme elevation 
paracetamol is to be avoided if possible, however paracetamol may be required by some subjects 
and as such is not a prohibited substance.  Any medication taken from inoculation day to the end 
of the study (last visit), for treatment of a medical condition or AE is to be recorded in the 
concomitant medication pages in the eCRF. The exact dose and timing of each dose should be 
recorded. 
7.5.1 PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
Not applicable. 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
Subjects will be informed and reminded of the following restrictions during recruitment, the 
informed consent process, and during screening and other assessments: 
 Subjects should not consume grapefruit or Seville oranges from inoculation day until the end 
of the study. 
 Subjects should not consume quinine containing foods/beverages such as tonic water, lemon 
bitter, from inoculation day until the end of the Riametﬁ treatment. 
 Subjects should not eat any poppy seeds in the 24 hours before the following time-points: 
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 Subjects should not eat or drink any food or beverages that contain alcohol (e.g. beer, wine, 
and mixed drinks) during confinement at the clinical unit and also 24 hours prior to each 
alcohol breath test. Subjects should not drink more than 2 standard drinks per day from 24 
hours before inoculation until the end of the Riametﬁ treatment. 
 Subjects should not consume beverages that contain xanthine bases (e.g. Red Bull, coffee) 
during confinement at the clinical unit. Subjects should not consume more than 400 mg 
caffeine per day, equivalent to more than 4 cups of coffee, from inoculation until the end of 
the Riametﬁ treatment. 
 Subjects should not use tobacco during confinement at the clinical unit. Subjects should not 
smoke more than 5 cigarettes or equivalent per day from inoculation until the end of the 
Riametﬁ treatment. 
 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
Not applicable.  
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  
The rescue medications used in this study are Riametﬁ and Primacin™ (if required). See details in 
Section 6. If a subject vomits or cannot tolerate oral drugs, then artesunate will be administered 
intravenously as described in Section 6.1.5. 
7.9 
SUBJECT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
Not applicable.  
8 
ASSESSMENT OF SAFETY  
 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
Safety of a single combined dose of OZ439 and PQP will be evaluated by the incidence, severity 
and relationship of observed and self-reported AE’s, AESI’s and SAE’s. Other safety parameters 
monitored during this study include physical examination, vital signs, clinical biochemistry, 
haematology, urinalysis, triplicate ECG, serology, RBC alloantibody testing, and malaria clinical 
score. See Sections 7.1 and 7.2 for details of these procedures. All safety parameters will be 
recorded in the eCRF. Safety monitoring will be specified in a safety management plan. 
8.1.1 DEFINITION OF AES (AE) 
An AE is defined as any untoward medical occurrence, i.e., any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom or disease that occurs in a subject during the 


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course of the study and which does not necessarily have a causal relationship with this treatment 
(i.e., whether or not considered drug-related).  
A treatment-emergent AE (TEAE) is an event that emerges following treatment with the 
investigational medicinal products (IMPs; OZ439 and PQP), having been absent pre-treatment, or 
worsens relative to the pre-treatment state.  
AEs include, but are not limited to: 
 A new symptom, sign or medical condition. 
 A disease or medical condition detected or diagnosed during the course of the study even 
though it may have been present prior to the start of the study. 
 An exacerbation of a pre-existing medical condition or disease. 
 An increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 
 Continuous persistent disease or symptoms present at study start that worsen following the 
start of the study. 
 An abnormal assessment (e.g. change on physical examination, ECG findings) if it 
represents a clinically significant finding that was not present at study start or worsened 
during the course of the study. 
 An abnormal laboratory test result if it represents a clinically significant finding, 
symptomatic or not, which was not present at study start or worsened during the course of 
the study or led to dose reduction, interruption or permanent discontinuation of study 
treatment.  
Borderline abnormal laboratory findings and other objective assessments should NOT be routinely 
captured and reported as AEs, as they will be collected and analysed separately. However, 
abnormal laboratory findings or other objective measurements that meet the following criteria 
should be captured and reported in the AE section of the eCRF: 
 the result meets the criteria for reporting as an SAE, 
 the test result is associated with accompanying symptoms, and/or 
 it requires additional diagnostic testing or medical/surgical intervention, and/or 
 it leads to a change in trial dosing, or discontinuation from the trial, significant additional 
concomitant drug treatment, or other therapy, and/or 
 it is considered by the Investigator or Sponsor to be clinically significant or represent a 
clinically significant change from baseline. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not require 
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Surgical procedures themselves are not AEs; they are therapeutic measures for conditions which 
may, or may not, be AEs.  
Certain information, although not considered an AE, must be recorded, reported, and followed up 
as indicated for an SAE (see Section 8.4.2 Serious AE Reporting). This includes: 
 Pregnancy exposure to an IMP. If a pregnancy is confirmed, use of the IMP must be 
discontinued immediately. Information about pregnancy exposure includes the entire course 
of pregnancy and delivery, and perinatal and neonatal outcomes, even if there are no 
abnormal findings. Both maternal and paternal exposures are considered other reportable 
information. For exposure involving the female partner of a male subject, the necessary 
information must be collected from the subject, while respecting the confidentiality of the 
partner. 
 Lactation exposure to an IMP with or without an AE. 
 Overdose of an IMP as specified in this protocol with or without an AE. 
 Inadvertent or accidental exposure to an IMP with or without an AE 
8.1.2 DEFINITION OF SERIOUS AES (SAE) 
A serious AE (SAE) is defined as an AE which fulfils at least one of the following criteria: 
Results in death. 
Is life-threatening 
o The term "life-threatening" in the definition of "serious" refers to an event in which 
the subject was at immediate risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it was more severe. 
Requires inpatient hospitalisation or prolongs existing hospitalisation, unless this is for: 
o Elective or pre-planned treatment or standard monitoring for a pre-existing 
condition that is unrelated to the study and has not worsened since the start of the 
study. 
o Cosmetic surgery, or for social reasons, or respite care in the absence of any 
deterioration in the subject’s general condition. 
Results in persistent or significant disability/incapacity. 
Is a congenital abnormality or birth defect. 
Is considered medically important 
o Medical and scientific judgement should be exercised in deciding whether other 
AEs are to be considered serious, such as important medical events that may not be 
immediately life-threatening but may jeopardise the subject or may require 


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intervention to prevent one of the other outcomes listed in the definition above. 
Examples of such events are: intensive treatment in an emergency room or at home 
for allergic bronchospasm; blood dyscrasias; convulsions that do not result in 
hospitalisation; development of drug dependency or drug abuse. 
Constitutes a possible Hy’s Law case 
o Hy’s Law case is defined as a subject with any value of alanine or aspartate 
aminotransferase greater than 3 × ULN together with an increase in total bilirubin 
to a value greater than 2 ×ULN and not associated to an alkaline phosphatase value 
greater than 2 ×ULN (FDA Guidance on Drug Induced Liver Injury: Premarketing 
Clinical Evaluation [2009]). 
A Suspected Unexpected Serious Adverse Reaction (SUSAR)
 is any SAE where a causal 
relationship with the malaria inoculum (3D7) or the IMPs (OZ439 and PQP) is at least a reasonable 
possibility, and the event is not listed in the IB(s) and/or Summary of Product Characteristics. 
8.1.3 DEFINITION OF AES OF SPECIAL INTEREST (AESI)  
An AESI (serious or non-serious) is one of scientific and medical concern specific to the sponsor’s 
product or programme, for which ongoing monitoring and rapid communication by the 
Investigator to the sponsor could be appropriate. Such an event might require further investigation 
in order to characterise and understand it. Depending on the nature of the event, rapid 
communication by the trial sponsor to other parties (e.g., regulators) might also be warranted 
(CIOMS VI, ICH E2F, 2010). Any abnormalities listed below should be reported as AESI: 
Hepatic : 
 any ALT or AST above 5xULN 
 an elevation in bilirubin 2xULN 
 any AST or ALT above 2xULN and (TBL > 1.5x ULN or INR > 1.4) 
 any AST or ALT above 2xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (eosinophil percent or count above 
the ULN) 
Cardiac:  
 QTcB or QTcF at any time >480 msec, 
 bundle branch block (except right bundle branch block that was present prior to IMP 
administration) 
 any arrhythmia, except: 
 sinus bradycardia that is 
– clinically asymptomatic, and 
– not associated with any other relevant ECG abnormalities 
 sinus tachycardia that is 
– clinically asymptomatic, and 
– associated with a body temperature >38.0 °C, and 
– not associated with any other relevant ECG abnormalities 
 respiratory sinus arrhythmia, 


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 wandering atrial pacemaker, 
 isolated, single premature atrial/ventricular complex (i.e. no bigeminy, trigeminy, 
couplets, triplets or salvos) that does not occur more than once in a particular ECG 
tracing. 
Haematological:  
 HB drop >2.0 g/dL from baseline prior to inoculation 
 Absolute neutrophil count <500/µl.  
 Platelet count <75,000 /mm3 
Dermatological: * 
Clinical signs of possible cutaneous adverse reactions such as:  
 
dermatitis,  
 
rash,  
 
erythematous rash,  
 
macular rash,  
 
papular rash,  
 
maculopapular rash,  
 
pruritic rash,  
 
pustular rash,  
 
vesicular rash. 
* if one of these cutaneous reaction is observed and when feasible, pictures of the lesions should 
be obtained 
 
 
8.2 
CLASSIFICATION OF AN AE 
 
8.2.1 SEVERITY OF EVENT 
In addition to determining whether an AE fulfils the criteria for a SAE or not, the severity of AEs 
experienced by study subjects will be graded according to the Common Terminology Criteria for 
AEs v4.03 published 14 June 2010 (CTCAE v4.03). This guidance provides a common language 
to describe levels of severity, to analyse and interpret data, to scale the aggregate AE score, and to 
articulate the clinical significance of all AEs. 
The severity of AEs will be graded as follows:  
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living. 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalisation or 
prolongation of hospitalisation indicated; disabling; limiting self-care activities of daily living. 


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Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
A mild, moderate, or severe AE may or may not be serious (see Section 8.1.2). These terms are 
used to describe the intensity of a specific event. Medical judgment should be used on a case-by-
case basis.  
Seriousness, rather than severity assessment, determines the regulatory reporting obligations. 
For guidance for assigning severity of the malaria, the purpose-designed malaria clinical score will 
be used (Section 7.1.1). 
8.2.2 RELATIONSHIP TO STUDY AGENT 
The Investigator will decide if AEs are related to any of the study agents or procedures. Where 
possible, a distinction should be made between events considered related to the malaria challenge 
agent, the IMPs, rescue treatments, or other protocol-mandated procedures. The assessment of 
causality will be made using the following definitions:  
Unrelated  
This category is applicable to those AEs which are judged to be clearly and incontrovertibly due 
to extraneous causes (disease, environment, etc.) and do not meet the criteria for the relationship 
listed under unlikely, possible or probable.  
Unlikely  
In general, this category is applicable to an AE which meets the following criteria (must have the 
first two):  
1. It does not follow a reasonable temporal sequence from administration of any of the study 
agents.  
2. It may readily have been produced by the subject’s clinical state, environment or toxic 
factors, or other modes of therapy administered to the subject.  
3. It does not follow a known pattern of response to the study agents.  
4. It does not reappear or worsen when any of the study agents are re-administered.  
Possible  
This category applies to those AEs in which the connection with any of the study agents appears 
unlikely but cannot be ruled out with certainty. An AE may be considered possible if or when 
(must have the first two):  


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1. 
It follows a reasonable temporal sequence from administration of any of the study 
agents.  
2. 
It may have been produced by the subject’s clinical state, environment or toxic factors, 
or other modes of therapy administered to the subject.  
3. 
It follows a known pattern of response to any of the study agents.  
Probable  
This category applies to those AEs which are considered, with a high degree of certainty, to be 
related to the study agents. An AE may be considered probable if (must have the first three):  
1. 
It follows a reasonable temporal sequence from administration of any of the study 
agents.  
2. 
It cannot be reasonably explained by the known characteristics of the subject’s clinical 
state, environment or toxic factors, or other modes of therapy administered to the 
subject. 
3. 
It disappears or decreases on cessation or reduction in dose.  
4. 
It follows a known pattern of response to any of the study agents.  
5. 
It reappears on re-administration. 
 
8.2.3 EXPECTEDNESS  
An AE is regarded as an unexpected event if its nature or severity is not consistent with the 
applicable reference safety information (IBs or approved manufacturer’s prescribing information 
for marketed drugs). Events that add significant information on the specificity, severity or 
frequency of previously described reactions, are also regarded as unexpected.  
Expected AEs from the malaria infection are listed in Appendix 3 and the IB for the 3D7 inoculum 
[35]. Expected AEs from the antimalarial drugs used are listed in the OZ439 IB [38] and the EMA 
European Public Assessment Report for PQP, Riametﬁ Consumer Medicine Information, 
Primacin™ Consumer Medicine Information, and artesunate WHO Public Assessment Report 
2011 (see Appendix 1). 
 
 


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8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
All AEs must be documented and followed up by the Investigator until: 
• the event is resolved, or 
• no further medically relevant information in relation to the event can be expected, and 
• the Investigator considers it justifiable to terminate the follow-up. 
Events that are unresolved at the time of the subject’s last follow-up visit should continue to be 
followed up by the Investigator for as long as medically indicated. The Sponsor retains the right 
to request additional information for any subject with ongoing AE(s)/SAE(s) at the end of the 
study, if judged necessary. 
All AEs should be treated appropriately. The Investigator will decide upon the appropriate action 
to be taken in response to an AE, which may include one or more of the following: 
• No action taken (i.e. further observation only). 
• Dosing with the IMP is withheld and the subject withdrawn from the study. 
• Administration of a concomitant medication. 
• Hospitalisation or prolongation of current hospitalisation (event to be reported as an SAE). 
• Other. 
In a case of occurrence of SAEs, regardless of whether or not it is judged to be challenge agent- or 
antimalarial drug-related, the subject will receive appropriate care under clinical supervision until 
all the symptoms of the SAEs have diminished or resolved and the subject’s condition improved.  
For ongoing AEs, care will be provided for a period of time as specified in the clinical site work 
instruction protocols. However, if the nature of the ongoing AE is determined by the Investigator 
as not being inoculum- or antimalarial drug-associated, the subject will be advised to visit his/her 
own general practitioner for further clinical care that he might require. 
8.4 
REPORTING PROCEDURES 
 
8.4.1 AE REPORTING  
It is the Investigator’s responsibility to document and report all AEs occurring in the study whether 
spontaneously reported by the subject, observed by the Investigator (either directly or by 
laboratory or other assessments), or elicited by general questioning. The period of observation for 
collection of AEs extends from the time of inoculation up to the end of the study; these AEs must 
be recorded on specific AE pages of the eCRF. Events reported prior to this will be recorded as 
medical history, unless the symptoms worsen during the study.  
The following information should be recorded for all AEs: 


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 Description of the AE. 
 Dates and times of onset and resolution of the event. 
 Duration of the event in hours. 
 The time of onset relative to inoculum, or the OZ439 and PQP treatment and/or the 
antimalarial rescue drugs. 
 Seriousness of the AE (SAE or not). 
 Severity of the event. 
 Action taken in response to the event (including treatment required). 
 Outcome of the event. 
 Relationship of the event to the study agents or procedures (causality assessment), 
including inoculum, IMPs, rescue medication, or any other treatment or procedure 
conducted during the study.  
 Changes in the severity of an AE will be documented to allow assessment of the duration 
of the event at each level of severity.  
 AEs worsening in severity will be considered unresolved and those reducing in severity 
will be considered resolving.  
 AEs characterised as intermittent require documentation of onset and duration at each 
episode. 
 Only one AE is reported if there is a variation in intensity (with highest intensity for final 
CSR Tables): the description will also report the various severities over time, 
 If the AE resolves and then reoccur at a later date: then two AEs are reported 
 All malaria-specific AEs will be tabulated and results graded according to a purpose-
designed malaria clinical score table (Section 7.1.1). 
 
 


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8.4.2 SERIOUS AE REPORTING  
 
The Investigator will take immediate appropriate action in response to SAEs to ensure subject 
safety and in an attempt to identify the causes of the event. The Investigator will notify Prime 
Vigilance, of any SAE within 24 hours of becoming aware of the event. The notification should 
be in writing by email or fax, and documented on a standard SAE reporting form.  
 
Serious AE Reporting: 
Prime Vigilance  
Email: MMV@primevigilance.com 
Fax: +44 800 471 5694 
 
Medical Director 
Stephan Chalon, MD, PhD 
Medicines for Malaria Venture 
Route de PrØ-Bois 20 
1215 Geneva 15 
Switzerland 
Email: chalons@mmv.org Representative 
Medical Monitor: 
Dr. med. Michael Marx MD  
Medical Director 
ICON Clinical Research 
Internal Tel: 7123 1568 
External Tel : +49 6103 904 1568 
Mobile : (+49) 172 677 7401 
Email:STUDY-MA-DL-3037-0010-Blinded@iconplc.com  
The Investigator will complete a follow-up SAE report within 14 days of the SAE, unless no 
further information is available in which case the follow-up report will be provided as soon as new 
information becomes available. The follow-up SAE report will be sent to the same recipients as 
the initial report as described above. Other supporting documents may be requested by these parties 
and will be provided by the Investigator or a delegate as soon as possible. 
Any SAE that meets the criteria of a SUSAR (Section 8.1.2) will be reported to the TGA by the 
local sponsor CNS in accordance with the Sponsor’s reporting procedures. 
 


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8.4.3 UNANTICIPATED PROBLEM REPORTING  
Not applicable.  
8.4.4 AES OF SPECIAL INTEREST (AESI) 
All AESIs, including those that do not meet the definition of an SAE, must be notified to the 
Pharmacovigilance provider (Prime vigilance) within 24 hours of the Investigator becoming 
aware of the occurrence of the AESI. The notification should be in writing by email or fax 
(Prime vigilance contact details mentioned above in 8.4.2 section) and documented on a standard 
AESI reporting form. Within 1 business day of receipt of any safety reports (initial or follow-up 
reports), Prime vigilance will notify the medical monitor (with the Sponsor medical monitor in 
copy), the sponsor and the SDRT of the event and its follow-up and will include all available 
information. 
The notification of follow-up information will follow the same procedure and timelines as the 
initial report.  
 
8.4.5 REPORTING OF PREGNANCY  
 
Pregnancy in a female subject or in a male subject’s female partner during the study should be 
reported and followed as described beneath. Pregnancy does not constitute an AE as such and the 
pregnancy outcome will not be recorded in the eCRF unless it is considered to be an AE. 
The Investigator must notify Prime Vigilance, in an expedited manner of any pregnancy occurring 
from the date of informed consent signature until 90 days after administration of OZ439 and PQP. 
The same process as described for AEs and AESI as described in Section 8.4.2. should be followed. 
In all cases, the pregnancy must be followed until birth of the child, and the outcome of the 
pregnancy and birth reported as above by completing the appropriate section of the Pregnancy 
Report Form used for the initial notification. The timelines of the outcome reporting vary as 
follows: 
 Normal outcomes should be reported within 45 days of birth/delivery. 
 Abnormal outcomes should be reported in an expedited manner as described in 
Section 8.4.2.  
An additional SAE Report form must be completed if the subject or subject’s partner sustains a 
serious event. A Parent-Child/Foetus Report (PCFR) must be completed if the child/foetus sustain 
an event. 
 
8.5 
STUDY HALTING RULES  
See Section 5.5. 


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8.6 
SAFETY OVERSIGHT 
Safety oversight will be undertaken by the Principal Investigator and the Medical Monitor who 
will serve as an independent expert to advise on clinical safety specifically in the situation where 
expert external advice is required regarding the need for administration of alternative/rescue 
antimalarial treatment in the circumstance of suboptimal response. 
The SDRT will be responsible for decisions related to the safety of subjects and the continuation 
of the study. The role and composition of the SDRT is outlined in the study specific SDRT Charter. 
The SDRT will be composed of the Principal Investigator, Medical Monitor, and a physician with 
expertise in clinical trials or infectious diseases. The SDRT will review the clinical and laboratory 
safety data as well as the recorded AEs and SAEs. The SDRT makes recommendations to the 
Sponsor. These recommendations are approved by the SDRT Chair who signs a letter of 
recommendation that is sent to the Principal Investigator and the Sponsor.  
A review by the SDRT of data from each cohort will be conducted prior to dosing the subsequent 
cohort. Safety and tolerability data up to Day 42–2, and PK/PD analysis outcomes (based on PD 
data up to Day 42–2 and PK data up to Day 35–2) from all subjects who received treatment with 
OZ439 and PQP will be required for the review. A similar analysis will be done at the end of 
cohort 2 combining cohorts 1 and 2 data to decide the dose(s) to be tested in cohort 3. This will be 
decided by the funding sponsor and the Principal Investigator following review of the data by the 
SDRT and scientific evaluation.  
Additionally, the SDRT may meet to assess any events that trigger the stopping rules or as needed 
to provide a recommendation and findings to QIMR Berghofer HREC and the Principal 
Investigator, in accordance with the approved SDRT Charter.  
Whether at a scheduled or unscheduled meeting, the SDRT will consider safety signals to 
determine whether or not they can recommend that the study continue. 
The SDRT will also review the safety and tolerability data from the study after completion of the 
last cohort. 
9 
CLINI CAL MONITORING 
It will be the Sponsor’s responsibility to ensure that the study is monitored in accordance with the 
requirements of GCP. The conduct of the study will be reviewed internally by the clinical unit (Q-
Pharm) in accordance with their standard procedures and work instructions, and GCP guidelines. 
The study will be monitored according to the SOPs of the monitoring CRO appointed this task by 
the Sponsor and all protocol deviations will be reported to the Sponsor. Protocol deviations that 
impact subject safety or data integrity will also be reported to the QIMR Berghofer HREC.  


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During the study, appointed study monitor(s) (on behalf of the Sponsor) will visit the site to check 
completeness of subject records, accuracy of eCRF entries, adherence to the protocol and to GCP, 
progress of enrolment, and to ensure that study agents were stored, dispensed, and accounted for 
according to specifications. Key study personnel are required to be available to assist the study 
monitor during these visits.  
The Investigator will be required to give the monitor access to all relevant source documents to 
confirm their consistency with the eCRF entries. The Sponsor will require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of 
SAEs, and the recording of data that is used for all primary and safety variables. Additional checks 
of the consistency of the source data with the eCRFs will be performed according to the study-
specific monitoring plan. No information in source documents about the identity of the subjects 
will be disclosed.  
 
10 
STATISTICAL CONSIDER ATIONS  
 
10.1 STATISTICAL ANALYSIS PLAN 
The following sections describe the statistical analysis as it is foreseen when the study is being 
planned. A detailed Statistical Analysis Plan (SAP) will be finalised and approved prior to database 
lock and will provide details of all analyses to be performed as well as the format of listings and 
tables to be provided for completion of the Clinical Study Report (CSR). Any deviations from the 
SAP will be described and justified in the final CSR. 
For the safety primary endpoint, we hypothesise that inoculating with ~2 800 viable P. falciparum 
3D7 parasite-infected RBCs and treating with OZ439 and PQP on trial Day 8 will be safe and will 
result in no SAEs, and will not cause severe malaria symptoms.  
This study is not powered to compare IMP doses but rather to answer the primary objectives. 
10.2 ANALYSIS DATASETS 
The safety analysis dataset will include all subjects who receive the malaria inoculum. This 
population will be used to analyse all safety data as well as demographic and baseline data.  
The population(s) used for analysis of PK, PD and PK/PD analysis will be defined in the SAP.  
10.3 DESCRIPTION OF STATISTICAL METHODS 
 
10.3.1 GENERAL APPROACH 


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This is an adaptive dose finding study using the IBSM model to characterise the PK/PD 
relationship between OZ439 and PQP for the treatment of early P. falciparum blood stage 
infection. 
Continuous data will be summarised using descriptive statistics (mean and standard deviation, or 
median and interquartile range). Categorical data will be presented using the number (N) and 
percentage (%) (using the number of subjects without missing data in the calculation). 
10.3.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
A model-based analysis is foreseen to characterise the PK/PD relationship between QZ439 and 
PQP plasma concentrations and blood stage asexual parasitaemia. For assessing the contribution 
of each compound and their interaction effect, data of this combination therapy study, will be 
pooled with data from previous human challenge monotherapy studies for each compound, i.e. 
QP12C01 (OZ439) and QP13C05 (Piperaquine). 
The final PK/PD model will describe the time courses of plasma concentrations and of the parasite 
counts by a nonlinear mixed effects (NLME) modelling approach. The change in parasite count 
will be modelled as the joint effects of parasite growth and drug concentration. 
The model will be developed in step wise manner. First, a joint PK model for OZ439 and 
piperaquine will be established potentially taking PK drug-drug interaction into account. Second, 
the PD model will be developed using individual PK parameters as regressors. The effect of each 
compound on parasite clearance is described by a sigmoidal Emax model or related models that take 
into account time delays of the drug action if appropriate. PD interactions between OZ439 and 
PQP will be described using the General PD Interaction (GPDI) models. PD interaction scenarios 
to be tested with the GLDI model include a change in each drug’s EC50, Emax or EC50 and Emax 
caused by the other drug. 
Graphical displays will be given, where appropriate. Details of the modelling analysis will be 
described in the modelling analysis plan (MAP). 
10.3.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
The secondary endpoints are PD and PK parameters.  
PK parameters  
Estimation of OZ439 and PQP PK parameters over 28 days after co-administration of single doses 
using non-compartmental methods:  
The following pharmacokinetic parameters will be determined using non-compartmental methods 
from plasma concentration-time data from all cohorts: AUC0-168h, AUClast, AUC0-inf, Cmax, tmax, t1/2, 
tlag, C168h, CL/F, Vz/F and λinf. These data will be summarized descriptively by treatment and dose. 


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For calculation of descriptive statistics of blood concentrations, values below the LLOQ will be 
set to zero. 
Pharmacokinetic parameters will be determined using STATAﬁ (version 14.0 or higher). 
PD parameters  
Parasite Reduction Ratio (PRR) . The PRR of asexual parasites will be based on the decay of 
parasitaemia after drug treatment determined by malaria 18S qPCR. The PRR for asexual parasites 
will be estimated using the slope of the optimal fit of the log-linear relationship of the parasitaemia 
decay [45]. The optimal fit can be derived using summarised replicate parasitaemia data, which 
have been cleaned by dealing with potential outliers, values below the limit of detection and non-
detectable values (ND). The optimal fit of the log-linear parasitaemia-by-time relationship is 
determined by using left and right censoring to systematically remove the potential lag phase and 
tail phase of the parasitaemia decay. The decay rate, estimated by the slope coefficient from the 
log-linear decay regression of qPCR data, will be calculated for each subject. The overall cohort-
dose specific PRR will be estimated with its 95% CI by calculating the weighted average slope 
estimate and corresponding standard error (SE) using an inverse-variance method. Only subjects 
who have optimal regression models with appropriate fit contribute toward the dose-specific PRR. 
Details are presented in the SAP. 
Parasite clearance half -life (t t/2). The Pt t/2 will be derived from the optimal decay rate. Details 
regarding the calculation will be in the SAP.    
Percentage of subjects with recrudescence of parasitaemia
. The percentage of subjects with 
recrudescence of parasitaemia following treatment with OZ439 and PQP.  This will be determined 
by the number of subjects who experience recrudescence which is defined as ≥5 000 blood stage 
parasites/mL and a 2-fold parasitaemia increase within 48 hours, or re-occurrence of malaria 
symptoms with a malaria clinical score >6). This will be determined by parasite lifecycle qRT-
PCR. 
 
10.3.4 SAFETY ANALYSES 
The overall number and percentage of subjects with at least one AE (and SAE) will be tabulated 
over the entire study period. All AE data will be summarised by pooled treatment group and study 
period, i.e. Day 0 to Day 8 (inoculum), Day 8 after dosing or earlier to Day 42–2 (OZ439 and 
PQP) and Day 42–2 after dosing (Rescue treatment) to (EOS visit). 
Treatment emergent AE’s will also be summarised with frequency counts by MedDRA system 
organ class (SOC; i.e. body system) and preferred term (PT), for each pooled treatment group and 
by Study period.  
Vital signs, routine safety laboratory data and ECG parameters will be presented in data listing 
and will be summarised descriptively by treatment group and by protocol specified time-point. 


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Where applicable, both absolute values and change from baseline (inoculation and IMPs 
administration) will be presented and listings of clinically relevant abnormal laboratory results will 
be generated.  
The safety and tolerability of a single combined dose of OZ439 and PQP will be evaluated by the 
incidence, severity and relationship of observed and self-reported AEs up to trial Day 42–2. 
10.3.5 ADHERENCE AND RETENTION ANALYSES 
Not applicable. 
10.3.6 BASELINE DESCRIPTIVE STATISTICS 
Demographic data will be summarised by descriptive statistics and will include total number of 
observations (n), mean, standard deviation (SD) and range for continuous variables and number 
and percentages with characteristics for dichotomous variables.  
The subject disposition will be summarised. Study completion, study withdrawals, exclusions and 
violations will be summarised and the reasons for withdrawal, exclusions and violations will be 
listed.  
Medical history, current medical conditions, previous and concomitant medications, results of 
laboratory screening tests, drug and alcohol screening tests and any other relevant baseline 
information will be listed by subject and cohort.   
10.3.7 PLANNED INTERIM ANALYSES  
 
10.3.7.1 
SAFETY REVIEW 
A review of the safety and tolerability data from the preceding cohort will be conducted by the 
SDRT prior to inoculation of the next cohort. All safety and tolerability data up to and including 
Day 35–2 will be required for each review.  
 See Section 5.5 for study stopping rules.  
10.3.7.2 
EFFICACY AND PK REVIEW 
A review of the parasitaemia data and PK data analysis from the preceding cohort will be 
conducted by the SDRT prior to inoculation of the next cohort. All data up to and including Day 
42–2 will be required for each review. A review of the PK/PD analysis based on PD data up to 
Day 42–2 and PK data up to Day 35– 2 post-dose from the preceding cohort(s) will be conducted 
by the SDRT prior to inoculation of the next cohort.  
10.3.8 ADDITIONAL SUB-GROUP ANALYSES 


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Not applicable. 
10.3.9 MULTIPLE COMPARISON/MULTIPLICITY 
Not applicable.  
10.3.10 TABULATION OF INDIVIDUAL RESPONSE DATA 
All individual subject data will be listed by measure and time point.  
10.3.11 EXPLORATORY ANALYSES 
No formal statistical analyses are planned for exploratory endpoints. 
10.4 SAMPLE SIZE 
A total of up to 24 healthy subjects will be enrolled in the study (up to 3 cohorts of 8 subjects 
each). Subjects will be malaria naïve healthy male or female adults, aged between 18-55 years old, 
who meet all of the inclusion criteria and none of the exclusion criteria. 
In each cohort, if more than 2 discontinuations due to non-safety related reasons occur; additional 
subjects may be recruited to replace the discontinued subjects on agreement with the study sponsor. 
Historically, 8 participants in a dose has proven to be sufficient to characterise the effect of a drug 
on malaria parasite kinetics following induction of IBSM of healthy subjects. 
10.5 MEASURES TO MINIMIZE BIAS 
 
10.5.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
Randomisation will be performed for subjects in all cohorts. The 8 subjects of all cohorts will be 
randomised to one of the dose groups for each cohort, (see Tables 1 and 2 Section 4.1) after 
inoculation day but prior to Day 8. 
The randomisation schedule will be generated by a statistician using a validated system. A copy 
of the randomisation schedule will be sent to the clinical unit pharmacist and clinical unit project 
manager.  
10.5.2 EVALUATION OF SUCCESS OF BLINDING  
Not applicable.  
10.5.3 BREAKING THE STUDY BLIND/SUBJECT CODE 
Not applicable.  


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11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE  
DATA/DOCUMENTS  
The Investigator will maintain source documents for each subject in the study. Information entered 
into eCRFs will be traceable to these source documents in the subject’s file. The Investigator must 
certify that the data entered into the eCRFs are complete and accurate. After database lock, the 
Investigator will retain copies of the subject data for archiving at the investigational site. 
Upon request, the Investigator(s)/institution(s) will permit direct access to source data/documents 
for trial-related monitoring, audits, Ethics Committee review, and regulatory inspection(s) by the 
Sponsor (or their appropriately qualified delegate) and Regulatory Authorities. Direct access 
includes examination, analysis, verification and reproduction of records and reports that are 
important to the evaluation of the trial. 
12 
QUALITY ASSURANCE AN D QUALITY CONTROL  
Data management, including the development and management of a secure database, will be 
performed in accordance with regulatory requirements. CNS will review the data entered into the 
eCRFs by clinical unit staff for completeness and accuracy. A formal querying process will be 
followed whereby the data management team will request the clinical site staff to clarify any 
apparent erroneous entries or inconsistencies and will request additional information from the 
clinical site as required. 
Medical history/current medical conditions and AEs will be coded using the Medical dictionary 
for regulatory activities (MedDRA) terminology (version 20.1 or higher). Prior and concomitant 
medications are to be coded using the WHO-DDE dictionary (March 2014 or later). 
After all data have been captured and reviewed, all queries have been resolved with the site and 
any protocol non-compliances that were identified during the data management processes have 
been confirmed by the site, the database will be declared to be complete and accurate, it will be 
locked and made available for data analysis. Any changes to the database after that time may only 
be made by the data manager, in consultation with the Sponsor and in accordance with documented 
database unlock and relock procedures. 
Clinical monitoring will be conducted as described in Section 9. 
Audits may be carried out by Sponsor quality assurance representatives, local authorities or 
authorities to whom information on this study has been submitted. All documents pertinent to this 
study must be made available for such inspections after adequate notice of intention to audit. 
13 
ETHICS/PROTECTION OF
 HUMAN  SUBJECTS  
 


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13.1 ETHICAL STANDARD  
The study will be conducted in accordance with the protocol approved by the QIMR Berghofer 
HREC, the principles of the Declaration of Helsinki (Recommendations guiding Medical Doctors 
in Biomedical Research Involving Human Participants, Fortaleza, Brazil 2013), the NHMRC 
National Statement on Ethical Conduct in Human Research (2007, updated May 2015) [46] and 
the Note for Guidance on Good Clinical Practice – Annotated with TGA Comments 
(CPMP/ICH/135/95), as adopted by the Australian Therapeutic Goods Administration (July 2000) 
[47]. 
The Investigator will minimise any discomfort experienced by subjects during the study. The only 
invasive procedures will be the intravenous inoculation of the malaria inoculum and the blood 
collection by cannulation/venepuncture. The maximum amount of blood to be collected from an 
individual in the study would be up to approximately 495 mL (Appendix 2): 
Blood Volume  
Time-frame  
mL (approximately)  
Main study 
Screening to Day 30 
239  
Optional components 
Screening to Day 30 
173 
Total 
Screening to Day 30 
412 
 
 
 
Main study 
Screening to Day 45 (EOS) 
297 
Optional components 
Screening to Day 45 (EOS) 
201 
Total 
Screening to Day 45 (EOS) 
497 
The total volume of blood drawn from each subject will not exceed 450 mL in any given 30-day 
period. This volume includes allowance for unscheduled safety and qPCR assessments that may 
be required at the discretion of the Principal Investigator or the Sponsor to ensure subject safety.  
 
 


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13.2 ETHICAL REVIEW  
The protocol, Participant Information Sheets and informed consent forms will be reviewed by the 
QIMR Berghofer HREC, and no study activities will be initiated prior to approval from the QIMR 
Berghofer HREC. All amendments and addenda to the protocol and consent forms will similarly 
be submitted to the QIMR Berghofer HREC for approval prior to their implementation.  
Changes to the final study protocol can only be made with the prior consent of the Principal 
Investigator, the Sponsor and the QIMR Berghofer HREC. All such changes must be attached to, 
or incorporated into, the final protocol, and communicated to all relevant members of Q-Pharm 
staff and, if appropriate, to study subjects. All deviations from this study protocol will be included 
in the trial master file and included in the CSR. An assessment of the significance of each protocol 
deviation will be given in the CSR. All deviations/amendments will be reported to Sponsor and 
the QIMR Berghofer Project Manager. The different types of amendments are discussed below. 
Non-substantial amendment  
Administrative or logistical minor changes require a non-substantial amendment. Such changes 
include but are not limited to changes in study staff or contact details (e.g., Sponsor instead of 
CRO monitors) or minor changes in the packaging or labelling of study drug. An amendment 
deemed to be non-substantial must have no ethical implications.  
The implementation of a non-substantial amendment may be done without notification to the 
QIMR Berghofer HREC. It does not require their approval or to be signed by the Investigator. The 
QIMR Berghofer HREC will be notified of these non-substantial changes in the next submission 
round, with the annual study report or study close out report, which ever will be submitted first to 
QIMR Berghofer HREC.    
Substantial amendment  
Significant changes require a substantial amendment. Significant changes include but are not 
limited to: new data affecting the safety of subjects, change of the objectives/endpoints of the 
study, eligibility criteria, dose regimen, study assessments/procedures, treatment or study duration, 
with or without the need to modify the Participant Information Sheet and Informed Consent.  
Substantial amendments are to be approved by the QIMR Berghofer HREC. The implementation 
of a substantial amendment can only occur after formal approval by the QIMR Berghofer HREC 
and must be signed by the Investigator. 
Urgent amendment  
An urgent amendment might become necessary to preserve the safety of the subjects included in 
the study. The requirements for approval should in no way prevent any immediate action being 


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taken by the Investigator or the Sponsor in the best interests of the subjects. Therefore, if deemed 
necessary, an Investigator can implement an immediate change to the protocol for safety reasons. 
This means that, exceptionally, the implementation of urgent amendments will occur before 
submission to and approval by the QIMR Berghofer HREC.  
In such cases, the Investigator must notify the Sponsor within 24 hours. A related substantial 
amendment will be written within 10 working days and submitted to the QIMR Berghofer HREC, 
together with a description of the steps that have already been taken in regard to implementation 
of this amendment.  
HREC approval of future research 
In the event that the Principal Investigator or the Sponsor want to perform testing on the samples 
that is not described in the protocol, additional QIMR Berghofer HREC approval will be sought. 
This may be done if a subject has consented to blood storage for use in future research (Section 
13.3.1)  
13.3 INFORMED CONSENT PROCESS  
 
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
PROVIDED TO SUBJECTS 
The Participant Information Sheet and informed Consent Form describes in detail the study agents, 
study procedures, and risks. Subjects will also receive an Informed Consent for Blood Storage and 
an option to grant permission to be contacted about future study involvement. 
Details regarding the optional study components will be provided in a separate Participant 
Information Sheet and subjects agreeing to participate in these components will provide specific 
written consent for this. Subjects will also receive an Informed Consent for Blood Storage and an 
option to grant permission to be contacted about future study involvement. Refusal to participate 
in the optional study components will not jeopardise a subjects’ participation in the main study.   
Subjects will also receive the product insert for artesunate, and the Consumer Medicine 
Information for Riametﬁ and Primacin™ (if required; Appendix 1). Subjects may also receive the 
Consumer Medicine Information for any other registered antimalarial agents in the event that these 
are required. 
 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
During the initial screening visit/recruitment, potential subjects will read the Participant 
Information Sheet. The Investigator or clinical unit staff will explain the study via the Participant 
Information Sheet and the potential subjects will be encouraged to ask questions. Individuals 


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willing to be considered for inclusion in the study will sign and date the informed Consent Form 
in the presence of an Investigator. Subjects will be given a copy of their signed informed Consent 
Form. Once the subject has consented to the study, the trial-specific screening activities may 
commence. See Section 7.3.1 for further details.  
 
13.4 SUBJECT AND DATA CONFIDENTIALITY  
Subjects will be informed that their data will be held on file by Q-Pharm and that these data may 
be viewed by staff of Q-Pharm (including, where necessary, staff of Q-Pharm other than the named 
Investigators).  
Upon request, the Investigator(s)/institution(s) will permit direct access to data and documents for 
trial-related monitoring, audits, Ethics Committee review, and regulatory inspection(s) by the 
Sponsor (or their appropriately qualified delegates) and Regulatory Authorities (see Section 11).  
Subjects will also be informed that a report of the study will be submitted to the Sponsor and may 
also be submitted to government agencies and perhaps for publication, but that they will only be 
identified in such reports by their study identification number, and their gender and age. The 
Investigator undertakes to hold all personal information in confidence. 
Subjects will be informed that samples collected for the purposes described in the protocol will be 
sent to Sponsor’s nominated national or international laboratory for assessment. 
13.4.1 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA 
Samples and data collected during this study will be used to achieve the study objectives.  
Samples and data will be stored according to Q-Pharm and QIMR Berghofer SOPs, and access 
will be limited to authorised personnel. Biological samples will be retained for the time required 
to complete analysis, and may then be discarded. 
 
13.5 FUTURE USE OF STORED SPECIMENS  
As part of the study, safety serum samples will be stored indefinitely at Q-Pharm/QIMR Berghofer 
for retrospective safety assessments that may later be indicated. Subjects consent to this storage 
and the use of the sample for safety assessments, when they sign the informed Consent Form for 
the study.  
For all other samples, consent must be obtained from the subjects to store and use their samples 
for future research. Consent will be obtained via the Informed Consent for Blood Storage that 
subjects receive during recruitment/screening. Subjects can decide if they want their samples to be 


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used for future research or have their samples destroyed at the EOS. A subject’s decision can be 
changed at any time prior to the EOS by notifying the study doctors or nurses in writing. However, 
if a subject has consented to future use and some of their blood has already been used for research 
purposes, the information from that research may still be used.  
Any future research using the stored samples that is beyond the current study will be reviewed by 
the QIMR Berghofer HREC (Section 13.2). All samples will be stored at QIMR Berghofer in 
accordance with the laboratory SOPs. The Investigator will ensure that confidentiality will be 
maintained continuously in all future research that involves use of these samples. The vials 
containing the samples of the consented subjects will be coded and the identifying information 
will not be released to any unauthorised third party. The subjects can also choose (via the Informed 
Consent for Blood Storage Form) for the samples to be re-labelled with only the study number, 
malaria strain and visit. No genetic testing will be performed on the stored samples without 
obtaining consent from the subjects. The stored samples will not be sold or used directly for 
production of any commercial product. There are no benefits to subjects in the collection, storage 
and subsequent research use of their samples. Reports about future research done with subject 
samples will NOT be kept in their health records, but a subject’s samples may be kept with the 
study records or in other secure areas.  
14 
DATA HANDLING AND RE CORD KEEPING  
 
14.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Each subject will have a clinical file (source data) and case report form (CRF, for protocol specific 
data) into which relevant data will be recorded. All recording will be done only in black ink. 
Corrections will only be made by drawing a single line through the incorrect entry, writing the 
correction in the nearest practicable space, and initialling and dating the correction. Correction 
fluids are not allowed. 
A log of names, signatures and initials of all staff authorised to enter data into a subject’s Clinic 
File and CRF will be kept. Upon completion of each study visit, all CRFs will be reviewed 
internally by the clinic for omissions or apparent errors so that these can be corrected without 
delay. Any corrections made after the review and signature of the Principal Investigator will be 
noted in the audit trail and will required reauthorisation (electronic sign off) by the Principal 
Investigator.  
14.2 STUDY RECORDS RETENTION  
All source data, clinical records and laboratory data relating to the study will be retained in the 
archive of the clinical unit (Q-Pharm) for a minimum of 15 years after the completion of the study. 
Data will be available for retrospective review or audit by arrangement with the Chief Executive 


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Officer of the clinical unit. Written agreement from the Sponsor must precede destruction of the 
same. 
14.3 PROTOCOL DEVIATIONS  
Protocol Deviation: a protocol deviation is any departure or change from, and addition to, the study 
design or procedures defined in the protocol that has received approval by the competent 
authorities and favourable opinion from the ethics committees. 
Important Protocol Deviation: an important protocol deviation (sometime referred to as a 
violation) is a protocol deviation that has or has the potential to affect the rights, safety or well-
being of the trial subjects and may impact the integrity (completeness, accuracy and reliability) of 
the data to a degree that the data is not usable. 
NTF: a note to file is a record that documents in detail actions taken, important decisions made or 
explains a sequence of events where no other detailed record exists to enable the conduct of the 
trial to be reconstructed. 
All protocol deviations will be documented in the trial master file and included in the CSR. An 
assessment of the significance of each protocol deviation will be discussed in the CSR.  
All NTFs, protocol deviations and important protocol deviations are to be viewed by the Principal 
Investigator delegate (QIMR Berghofer Project Manager) and signed by the Principal Investigator.  
All NTFs, protocol deviations and important protocol deviations will be assessed and significance 
assigned at the end of each cohort by the SDRT team.  
All, important protocol deviations will be reported by the clinical site to the Sponsor and at the 
Sponsors request to the QIMR Berghofer HREC as early as possible, but within 7 days. A protocol 
violation report form provided by QIMR Berghofer will be used for this purpose. 
All protocol deviations will be reported by the clinical site to the QIMR Berghofer PM as early as 
possible but within 7 days, and to the Sponsor at the end of each cohort. A protocol deviation 
report form provided by QIMR Berghofer will be used for this purpose. 
Protocol deviation logs will be submitted by the clinical site to the Sponsor and QIMR Berghofer 
HREC via inclusion with the annual report.  
14.4 PUBLICATION AND DATA SHARING POLICY 
 
The data management, statistical and medical writing team appointed by the Sponsor will 
collaborate to provide a detailed CSR upon conclusion of the study. This will include appendices 
of all tables and listings generated during the analyses of data. The tables and listings will be 


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provided by CNS. The Sponsor undertakes to ensure that all safety observations made during the 
conduct of the trial are documented in this report. 
Publication and reporting of results and outcomes of this trial will be accurate and honest, 
undertaken with integrity and transparency and in accordance with the relevant clauses outlined in 
the QIMR Berghofer Policy on Criteria for Authorship [48]. QIMR Berghofer and the Principal 
Investigator have a responsibility to ensure that results of scientific interest arising from the clinical 
trials are appropriately published and disseminated. Publication of results will be subjected to fair 
peer-review. Authorship will be given to all persons providing significant input into the 
conception, design, and execution or reporting of the research according to the QIMR Berghofer 
Policy on Criteria of Authorship. No person who is an author, consistent with this definition, will 
be excluded as an author without his/her permission in writing. Authorship will be discussed 
between researchers prior to study commencement (or as soon as possible thereafter) and reviewed 
whenever there are changes in participation. Acknowledgment will be given to collaborating 
institutions and hospitals and other individuals and organisations providing finance or facilities. 
All conflicts arising from disputes about authorship will be reviewed by the QIMR Berghofer 
Director. 
In any press releases, publications or presentations, MMV’s financial contribution to the study and 
its participation in the collaboration shall be expressly acknowledged. QIMR Berghofer agrees 
that MMV will be entitled to access all the de-identified clinical trial data upon completion of the 
trial. Data will not be released publicly until the manuscript is accepted for publication. In the case 
of no publication, information will only be released to the public and media in accordance with 
the QIMR Berghofer Corporate Media Strategy Policy [49]. However, the Investigator undertakes 
not to make any publication or release pertaining to the study and/or results of the study without 
the Sponsor’s prior written consent, being understood that the Sponsor will not unreasonably 
withhold its approval. The Sponsor has the right to publish the results of the study at any time. 
The Investigator shall not use the name(s) of the Sponsor and/or of 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). 
MMV or the local sponsor will ensure that the key design elements of this protocol are posted in 
a publicly accessible database such as Australian New Zealand Clinical Trials Registry (ANZCTR) 
or Clinicaltrials.gov. In addition, upon study completion and finalisation of the study report, the 
results of this trial will be either submitted for publication in an open access journal and/or posted 
in a publicly accessible database of clinical trial results.  
 
 


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15 
STUDY ADMINISTRATION  
 
15.1 STUDY LEADERSHIP 
See Section 1 for key roles. 
15.2 LIABILITY/INDEMNITY/INSURANCE 
The study Sponsor will ensure sufficient insurance is available to enable it to indemnify and hold 
the Investigator(s) and relevant staff as well as any hospital, institution, Ethics Committee or the 
like, harmless from any claims for damages for unexpected injuries, including death, that may be 
caused by the subject’s participation in the study but only to the extent that the claim is not caused 
by the fault or negligence of the subjects or Investigator(s). The Sponsor adheres to the guidelines 
of Medicines Australia for injury resulting from participation in a company sponsored trial, 
including the provision of ‘No-fault clinical trial insurance’. 
 
16 
CONFLICT OF INTEREST
 POLICY  
No conflicts of interest are applicable in this study.  
17  
LITERATURE REFERENCE
S  
1. 
WHO, 2017. 
2. 
Dondorp, A.M., et al., Artemisinin resistance in Plasmodium falciparum malaria.  New 
England Journal of Medicine, 2009. 361(5): p. 455–467. 
3. 
Woodrow, C.J. and N.J. White, The clinical impact of artemisinin resistance in Southeast 
Asia and the potential for future spread.  FEMS Microbiol Rev, 2017. 41(1): p. 34-48. 
4. 
Straimer, J., et al., Drug resistance. K13-propeller mutations confer artemisinin resistance 
in Plasmodium falciparum clinical isolates.  Science, 2015. 347(6220): p. 428-31. 
5. 
Burrows, J.N., et al., New developments in anti-malarial target candidate and product 
profiles. Malar J, 2017. 16(1): p. 26. 
6. 
Phyo, A.P., et al., Antimalarial activity of artefenomel (OZ439), a novel synthetic 
antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium 
vivax malaria: an open -label phase 2 trial.  Lancet Infect Dis, 2016. 16(1): p. 61-69. 
7. 
McCarthy, J.S., et al., Linking Murine and Human Plasmodium falciparum Challenge 
Models in a Translational Path for Antimalarial Drug Development.  Antimicrob Agents 
Chemother, 2016. 60(6): p. 3669-75. 


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8. 
Macintyre, F., et al., A randomised, double-blind clinical phase II trial of the efficacy, 
safety, tolerability and pharmacokinetics of a single dose combination treatment with 
artefenomel and piperaquine in adults and children with uncomplicated Plasmodiu m 
falciparum malaria.  BMC Med, 2017. 15(1): p. 181. 
9. 
ANZCTR Trial ID: ACTRN12611001203943, An experimental study to characterize 
molecular signatures during early Plasmodium falciparum blood stage infection in healthy 
male volunteers. 2011. 
10. 
ANZCTR Trial ID: ACTRN12612000323820, An experimental study to characterize the 
effectiveness of Lariam (Registered Trademark Mefloquine) against early Plasmodium 
falciparum blood stage infection in healthy volunteers 
2012. 
11. 
ANZCTR Trial ID: ACTRN12612000814875, An experimental study to characterize the 
effectiveness of OZ439 against early Plasmodium falciparum blood stage infection in 
healthy volunteers. 2012. 
12. 
ANZCTR Trial ID: ACTRN12613000533796 and A Phase I/Ib study to investigate the 
safety, tolerability and pharmacokinetic profile of DSM265 in healthy subjects and to 
assess the antimalarial activity of DSM265 in healthy subjects with an induced blood stage 
Plasmodium falciparum infection. 2013. 
13. 
ANZCTR Trial ID: ACTRN12613000565741, An experimental study to characterize the 
effectiveness of piperaquine against early Plasmodium falciparum blood stage infection in 
healthy volunteers. 2013. 
14. 
ANZCTR Trial ID: ACTRN12613000698774, An experimental study to characterize the 
effectiveness of griseofulvin against early Plasmodium falciparum blood stage infection in 
healthy volunteers. 2013. 
15. 
ANZCTR Trial ID: ACTRN12613001040752, An experimental study to characterize the 
effectiveness of ferroquine against early Plasmodium falciparum blood stage infection in 
healthy volunteers. 2013. 
16. 
ANZCTR Trial ID: ACTRN12614000781640 and A proof-of-concept study to assess the 
effect of ACT-451840 against early Plasmodium falciparum blood stage infection in 
healthy subjects. 2014. 
17. 
Bijker, E.M., et al., Protection a gainst malaria after immunization by chloroquine 
prophylaxis and sporozoites is mediated by preerythrocytic immunity. Proc Natl Acad Sci 
U S A, 2013. 110(19): p. 7862-7. 
18. 
Cheng, Q., et al., Measurement of Plasmodium falciparum growth rates in vivo: a test of 
malaria vaccines.  Am J Trop Med Hyg, 1997. 57(4): p. 495-500. 
19. 
ClinicalTrials.gov ID: NCT02281344, A proof-of-concept study to assess the effect of 
MMV390048 against early Plasmodium falciparum blood stage infection in healthy 
participants . 2014. 


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20. 
ClinicalTrials.gov ID: NCT02389348, A proof-of-concept study to assess the effect of a 
range of doses of combined therapy with OZ439 and DSM265 against early Plasmodium 
falciparum blood stage infection in healthy participants . 2015. 
21. 
ClinicalTrials.gov ID: NCT02543086, A phase 1 interventional sequential single site study 
to characterize the effectiveness of oral KAE609 in reducing asexual & sexual blood-stage 
P. falciparum following inoculation in healthy volunteers & subsequent infectivity to 
mosquitoes. 2015. 
22. 
Duncan, C.J., et al., Impact on malaria parasite multiplication rates in infected volunteers 
of the protein-in-adjuvant vaccine AMA1-C1/Alhydrogel+CPG 7909. PLoS One, 2011. 
6(7): p. e22271. 
23. 
Lawrence, G., et al., Effect of vaccination with 3 recombinant asexual-stage malaria 
antigens on initial growth rates of Plasmodium falciparum in non -immune volunteers. 
Vaccine, 2000. 18(18): p. 1925-31. 
24. 
McCarthy, J.S., et al., A pilot randomised trial of induced blood-stage Plasmodium 
falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs. 
PLoS One, 2011. 6(8): p. e21914. 
25. 
Payne, R.O., et al., Demonstration of the blood-stage Plasmodium falciparum controlled 
human malaria infection model to assess efficacy of the P. falciparum apical membrane 
antigen 1 Vaccine, FMP2.1/AS01. J Infect Dis, 2016. 
26. 
Pombo, D.J., et al., Immunity to malaria after administration of ultra -low doses of red cells 
infected with Plasmodium falciparum. Lancet, 2002. 360(9333): p. 610-617. 
27. 
Sanderson, F., et al., Blood-stage challenge for malaria vaccine efficacy trials: a pilot study 
with discussion of safety and potential value. Am J Trop Med Hyg, 2008. 78(6): p. 878-83. 
28. 
ClinicalTrials.gov ID: NCT02431637, Blood stage challenge study to assess mosquito 
transmissibility in participants inoculated with Plasmodium falciparum . 2015. 
29. 
ClinicalTrials.gov ID: NCT02431650, A proof-of-concept study to assess the effectiveness 
of OZ439 as a gametocytocidal and transmission blocking agent in experimental P. 
falciparum infection. 2015. 
30. 
ClinicalTrials.gov ID: NCT02573857, A phase Ib study to characterise the antimalarial 
and transmission blocking activity of a single dose of DSM265 or OZ439 in healthy 
subjects with induced blood stage Plasmodium falciparum or Plasmodium vivax infection. 
2015. 
31. 
Krause, A., et al., Pharmacokinetic/pharmacodynamic modelling of the antimalarial effect 
of Actelion-451840 in an induced blood stage malaria study in healthy subjects.  Br J Clin 
Pharmacol, 2016. 


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32. 
McCarthy, J.S., et al., Efficacy of OZ439 (artefenomel) against early Plasmodium 
falciparum blood-stage malaria infection in healthy volunteers.  J Antimicrob Chemother, 
2016. 
33. 
McCarthy, J.S., et al., A Phase II pilot trial to evaluate safety and efficacy of ferroquine 
against early Plasmodium falciparum in an induced blood -stage malaria infection study. 
Malar J, 2016. 15: p. 469. 
34. 
Pasay, C.J., et al., Piperaquine Monotherapy of Drug -Susceptible Plasmodium falciparum 
Infection Results in Rapid Clearance of Parasitemia but Is Followed by the Appearance of 
Gametocytemia. J Infect Dis, 2016. 214(1): p. 105-13. 
35. 
Investigators Brochure, Blood stage Plasmodium falciparum challenge inoculum P. 
falciparum 3D7 (BSPC) v8.0 ed. 2017, QIMR Berghofer Medical Research Institute. 
36. 
Warrell, D.A., Essential malariology. 4 ed ed. 2002, London: Arnold. 
37. 
S, C., et al., Poster presentation: Moderate and severe LFT elevations in controlled human 
P. falciparum malaria infection model: recent experience, li terature review and 
mechanistic hypotheses, in American Society of Tropical Medicine and Hygiene:  65th 
Annual Meeting. 2016. 
38. 
Investigators Brochure: Medicines for Malaria Venture, OZ439 (artefenomel) Version 12.0 
21 December 2017. 2017, Medicines for Malaria Venture. 
39. 
Myint, H.Y., et al., Efficacy and safety of dihydroartemisinin-piperaquine. Trans R Soc 
Trop Med Hyg, 2007. 101(9): p. 858-66. 
40. 
Ratcliff, A., et al., Two fixed-dose artemisinin combinations for drug-resistant falciparum 
and vivax malaria in Papua, Indonesia: an open -label randomised comparison.  Lancet, 
2007. 369(9563): p. 757-65. 
41. 
Karunajeewa, H., et al., Safety evaluation of fixed combination piperaquine plus 
dihydroartemisinin (Artekin) in Cambodian children and adults with mala ria. Br J Clin 
Pharmacol, 2004. 57(1): p. 93-9. 
42. 
Mytton, O.T., et al., Electrocardiographic safety evaluation of dihydroartemisinin 
piperaquine in the treatment of uncomplicated falciparum malaria.  Am J Trop Med Hyg, 
2007. 77(3): p. 447-50. 
43. 
European Medicines Agency, Eurartesim: European Public Assessment Report - Product 
Information. Updated 2016. 
44. 
Australian Therapeutic Goods Administration, Access to unapproved therapeutic goods: 
Clinical trials in Australia . 2004. 
45. 
Marquart, L., et al., Evaluating the pharmacodynamic effect of antimalarial drugs in 
clinical trials by quantitative PCR.  Antimicrob Agents Chemother, 2015. 59(7): p. 4249-
59. 


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46. 
National Health and Medical Research Council, National statement on ethical conduct in 
human research  2007 2007. p. 1 - 95. 
47. 
Australian Therapeutic Goods Administration, Note for Guidance on Good Clinical 
Practice (GCP) (CPMP/ICH/135/95) . 2000. 
48. 
QIMR Berghofer Medical Research Institute, Policy on the criteria for authorship . 2008. 
49. 
QIMR Berghofer Medical Research Institute, Media relations policy. 2010. 
 
 
 


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APPENDIX  
 
Appendix 1: Product information and consumer medicine information
 
 
Riametﬁ 
 Product Information (TGA, updated August 2016) 
 Consumer Medicine Information (TGA, updated December 2015) 
Primacin™  
 Product Information (TGA, updated February 2017) 
 Consumer Medicine Information (TGA, updated February 2017) 
Artesunate  
 WHO Public Assessment Report (2011) 
 
 
 
 
 


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Appendix 2 : Total blood volume  
 
Procedure  
Sample  
Volume per 
sample 
(mL) 
No. samples 
per subject  
Total volume per 
subject  (mL) 
Laboratory 
Safety 
Assessment 
Haematology 
(including 
G6PD) 
2 
7 
14 
4 
2 
8 
Biochemistry 
/biomarker (may 
include 
Serology, CRP, 
)
5 
6 
30 
8.5 
3 
25.5 
Coagulation 
profile 
2.7 
1 
2.7 
Safety serum 
storage 
5 
2 
10 
RBC 
alloantibody 
4 
2 
8 
Bioanalysis 
PK analysis 
4 
21 
84 
Cannulation 
Discard 
2 
19 
38 
Malaria 
Monitoring 
Malaria 18S 
qPCR 
2 
36 
72 
Parasite 
lifecycle stage 
qRT-PCR  
2 
2 
4 
Main study total (mL)  
~297 
Exploratory 
(optional) 
Immune Cell 
Characterisation 
53 
2 
106 
26 
3 
78 
Complement 
Regulatory 
Proteins  
2 
8 
16 
Additional optional exploratory total (mL) 
~203 
Main study and exploratory components
 (mL) 
~497 


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This table is indicative and may vary based on qPCR levels and safety follow-up samples. 
Additional blood samples may be taken for unscheduled safety and qPCR assessments as required 
by the Investigator, provided the total volume taken during the study does not exceed 450 mL 
during any period of 30 consecutive days. 
 


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Appendix 3: Symptoms and signs of malaria
 
 
Following challenge via the intravenous malaria parasite inoculation and during the post-challenge 
period, the following signs and symptoms of malaria will be monitored: 
 
Signs of malaria  
 Fever (oral temperature of ≥38°C) 
 Chills/shivering/rigors  
 Tachycardia 
 Hypotension 
Symptoms of malaria  
 Headache 
 Myalgia (muscle ache) 
 Arthralgia (joint ache) 
 Fatigue/lethargy 
 Malaise (general discomfort/uneasiness) 
 Sweating/hot spells 
 Anorexia 
 Nausea 
 Vomiting 
 Abdominal discomfort 
 
 
 


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Appendix 4: Beck Depression Inventory  
 
Appendix 5: Version History  
 
Version  
Date 
Author(s)/Reviewer(s)  
Revisions  
1.0-1.1 
29.1.18 
Rebecca Webster 
Minor typographical updates 
1.1-2.0 
19.3.18 
Rebecca Webster  
See table below 
2.0-3.0 
30.4.18 
Rebecca Webster 
See table below 
3.0-4.0 
20.8.18 
Rebecca Webster 
See table below 
 
Summary of Changes to QP17C19 
(Version 1.1 to 2.0) 
 
Protocol Section(s)  Change  
Rationale  
Abbreviations 
 Added 2 additional 
abbreviations 
 Missing from initial 
protocol  
Protocol Summary 
and Objectives and 
Purpose 
 Added optional exploratory 
objectives and endpoints 
 Additional scientific 
exploratory objectives have 
been added to the protocol. 
These are optional studies 
and participants that choose 
to participate will sign a 
separate consent form  
Key Roles 
 An additional independent 
medical monitor has been 
added to the trial key roles 
 Data management, site 
monitoring and regulatory 
function personnel has been 
added to the trial key roles 
 The sponsor requested an 
additional medical monitor 
 A specific person from the 
local sponsor has been 
identified to perform this 
role 
4.1 
 Added additional text 
regarding the exploratory 
study components  
 Additional scientific 
exploratory objectives have 
been added to the protocol. 
These are optional studies 
and participants that choose 
to participate will sign a 
separate consent form 
6.1.1 
 Change of sucrose provider 
from MMV to Q-Pharm  
 Updated to highlight that 
sucrose will be provided by 
the phase 1 site pharmacy 
7.1.1  
 Added additional text to 
further explain; 
 Clarification and 
completeness of protocol  


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– ECG procedural requirements   
– exploratory study blood 
sampling  
– medical diary cards and 
temperature self-recording 
7.2.2 
 Added details about; 
– PK blood collection and 
processing  
– optional exploratory 
components  
– optional exploratory 
components  
 Clarification and 
completeness of protocol 
and updated information 
regarding the additional 
exploratory objectives 
7.3 Study Schedule  
 Added blood collection for 
optional exploratory 
components at each relevant 
time-point 
 Added a subject diary card 
check at all relevant time-
points  
 Updated with information 
related to the additional 
exploratory objectives 
7.3.7 
 Updated schedule of events 
 Clarification of schedule of 
participant activities in line 
with above described text 
13.1 
 Updated study total blood 
volume to include exploratory 
components blood volume  
 Updated with information 
related to the additional 
exploratory objectives 
14.3 
 Added text about reporting of 
protocol deviations and 
violations  
 Clarification of reporting 
obligations  
Appendix 2 
 Updated total blood volume   
 Updated due to additional 
blood volume being 
required for exploratory 
optional components 
 
 


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Summary of Changes to QP17C19 
(Version 2.0 to 3.0)  
Protocol 
Section(s)  
Change  
Rationale  
Protocol 
Summary,  
4.1,  
6.1.5  
7.3.3 
 Added criteria for IMP 
administration (malaria 
clinical score >6) and 
definition of recrudescence as 
a criterion for rescue 
medication administration 
(defined as ≥5 000 blood 
stage parasites/mL and a 2-
fold increase within 48 hours, 
or a malaria clinical score >6) 
 Criteria for IMP and rescue 
medication administration 
based on a 
clinical/biological response 
was deemed necessary 
rather than just a defined 
time-point for these 
activities 
Key Roles 
 An additional co-investigator 
has been added to the trial key 
roles 
 
2.3 IMP 
risks  
 Added vasovagal, orthostatic 
hypotension and atrial 
fibrillation to the risks section   
 Additional risks were 
identified 
5.1 
Inclusion 
criteria  
 Change from 50 to 40 mmHg 
≤ diastolic blood pressure 
 Added male subjects with 
female partners that are 
surgically sterile, or male 
subjects who have undergone 
sterilisation and have had 
testing to confirm the success 
of the sterilisation may also 
be included.   
 
 More appropriate criteria 
5.2 
Exclusion 
criteria  
 Change Participation in any 
investigational product study 
within the 12 weeks preceding 
the study to Participation in 
any investigational product 
study within the 12 weeks 
preceding IMP 
administration. 
 Clarification that 
Symptomatic postural 
hypotension at screening, 
irrespective of the decrease in 
blood pressure, or 
asymptomatic postural 
 More appropriate criteria 


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hypotension defined as a 
decrease in systolic blood 
pressure ≥20 mmHg within 2-
3 minutes when changing 
from supine to standing 
position, could be repeated if 
abnormal 
 Clarification and separation of 
severe allergic reaction, 
anaphylaxis and convulsions. 
7.1.1 
 Stated that the mean of the 
three ECGs would be 
recorded  
 Clarification of protocol  
7.2.1 
 Added MCV to haematology  
 Added coagulation testing 
 Missed in previous protocol 
7.3.2 
 Updated schedule of events 
 CRP will be included in all 
biochemistry except screening 
 Urine for urinalysis will be 
collected at EOS 
 Coagulation added to table of 
events 
 Clarification of schedule of 
participant activities 
7.3.3 
 An additional malaria PCR 
time point added 
 Required to collect blood 
for PRR every 6 hours after 
initial administration of 
IMP  
8.1.3  
 Changed ALT or AST above 
3x ULN to 5x ULN 
 QTcB or QTcF prolongation 
from baseline clarification of 
parameter 
 Clarification of 
haematological AESI 
 Clarification and 
specification of appropriate 
AESI’s for malaria 
challenge studies 
13.1 
Appendix 2 
 Updated blood volume  
 Updated since added 
coagulation profile  
 
 
 
 
 


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Summary of Changes to QP17C19 
(Version 3.0 to 4.0) 
 
Protocol 
Section(s)  
Change  
Rationale  
Protocol 
Summary,  
4.1,  
 
 Added planned dose regimen 
for Cohort 2 post SDRT 
meeting and scientific data 
evaluation 
 Cohort 2 doses selected 
after SDRT review. 
Protocol 
Summary,  
4.1,  
7.3.3 
8.6,  
10.3 
 Updated trial day naming 
convention  
 Study Day numbers were 
updated as per study design 
scheme and study flowchart 
for consistency.  
7.3.3 
 Added ECG assessment to 
time of rescue treatment 
administration  
 Provide additional safety 
data prior to rescue 
treatment  
5.2 
 
 Updated citrus consumption 
till the EOS rather than end of 
Riamet treatment 
 
 Consumption of these 
substances could interfere 
with PK analysis. PK 
samples may still be 
collected post Riamet 
administration  
7.6 
 Updated alcohol grams into 
units and standard drinks 
(Australian) 
 Updated to be consistent 
with the eCRF 
8.4.5  
 Updated pregnancy wording      WOCBP can be included in 
this study as per inclusion 
criteria under the condition 
of usage of highly effective 
method of birth control and 
therefore this section 
needed to be revised 
10.5  
 Changed randomisation to 
occur after inoculation but 
prior to Day 8.  
 
 Logistically this provides 
more time for the clinical 
site to prepare for dosing.   
7.1.1 
 Added ‘on study IBSM 
specific ranges’ for ECGs and 
vital signs 
 Provide additional 
information and alignment 
with eCRF guidelines 
7.3.2 
7.3.3 
 Changed symptom directed 
physical examination to a 
compulsory abbreviated 
 Provide additional safety 
assessment of participants 


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physical examination prior to 
inoculum and drug dosing 
prior to inoculum and drug 
dosing 
7.3.3 
 Added text regarding 
assessments to be performed 
if participants are 
administered antimalarial 
rescue treatment prior to the 
(Day 42) scheduled time-
point. 
 To ensure safety 
assessments which are 
required to be performed at 
the end of rescue treatment 
are captured in the protocol 
if participants are provided 
antimalarial rescue therapy 
prior to the scheduled time-
point. 
7.2.1 
7.3 
 Defined CRP as a biomarker  
 CRP is a biomarker and not 
a biochemistry safety 
assessment 
7.2.2 
7.3.3 
 Added the following wording 
to applicable protocol sections 
“Malaria monitoring will 
continue until a minimum of 
one negative 18S qPCR is 
detected post rescue therapy” 
 Provide clarification on 
number of negative qPCR 
required after rescue 
therapy to consider a subject 
successfully rescued 
7.3.4 
 Changed capturing malarial 
clinical score to be mandatory 
at EOS  
 To provide additional safety 
information 
7.3.7 
 Updated SoE table  
Added abbreviated physical exam 
Added rescue treatment column 
 To be consistent with text in 
the protocol 
 

SAP_001.pdf: 
 
STATISTICAL ANALYSIS 
PLAN 
QP17C19 
 
Page 1 of 53 
 
QP17C19 Statistical Analysis Plan v2.0                                                                        29 Mar 2020 
 
 
Protocol No. 
QP17C19 
Title: 
A single-centre Phase 1b study to assess the safety, tolerability, 
pharmacokinetic profile, and antimalarial activity of single doses 
of co-administered artefenomel (OZ439) and piperaquine 
phosphate (PQP) against early Plasmodium falciparum blood 
stage infection in healthy adult volunteers 
Funding Sponsor: 
Medicines for Malaria Venture 
Local Sponsor 
Contact: 
Jolien Visser 
Project Manager 
 
Clinical Network Services Pty Ltd 
Level 2, 381 MacArthur Ave,   
HAMILTON   QLD   4007,  Australia 
Phone: +61 431 133 129   
Email: Jolien.visser@clinical.net.au 
Funding Sponsor 
Contact: 
Heike Huegel-Koerpert 
Senior Clinical Trial Manager 
20, Route de Pré-Bois 
1215 Geneva 15 
Switzerland  
E-mail: huegelh-consultants@mmv.org  
Phone: +41 789 48 18 58 
Project 
Management: 
Clinical Network Services Pty Ltd 
Level 2, 381 MacArthur Ave,   
HAMILTON   QLD   4007,  Australia 
Phone: +61 431 133 129   
Phone: +61 (0)7 3719 6000 
Data 
Management 
and Analysis: 
Clinical Network Services Pty Ltd 
Level 2, 381 MacArthur Ave,   
HAMILTON   QLD   4007,  Australia 
Phone: +61 431 133 129   
Phone: +61 (0)7 3719 6000 
 
Author: 
Clinical Network Services Pty Ltd/QIMR Berghofer/IntiQuan/MMV 
SAP Version: 
Version 2.0 Dated: 29 Mar 2020  
 
 
Property of Medicines for Malaria Venture – Confidential 
The concepts and information contained herein are confidential and proprietary, and shall not be 
disclosed in whole or in part without the written consent of Medicines for Malaria Venture. 






 
STATISTICAL ANALYSIS 
PLAN 
QP17C19 
 
Page 3 of 53 
 
QP17C19 Statistical Analysis Plan v2.0                                                                        29 Mar 2020 
 
 
 
 
TABLE OF CONTENTS 
Section 1: Introduction ............................................................................................................................... 8 
1.1 
Scope ........................................................................................................................................... 8 
1.2 
Study Background ........................................................................................................................ 8 
Section 2: Study Overview .......................................................................................................................... 9 
2.1 
Study Design and Treatments ..................................................................................................... 9 
2.2 
Study Objectives ........................................................................................................................ 12 
2.3 
Study Endpoints ......................................................................................................................... 12 
2.4 
Sample Size ................................................................................................................................ 13 
2.5 
Study Schedule .......................................................................................................................... 13 
Section 3: Interim Analyses ...................................................................................................................... 16 
3.1 
Safety Data Review .................................................................................................................... 16 
Section 4: Overarching SAP information .................................................................................................. 16 
Section 5: Analysis sets ............................................................................................................................. 16 
Section 6: Safety Statistical methodology ................................................................................................ 17 
6.1 
General Considerations ............................................................................................................. 17 
6.2 
Sources of Data.......................................................................................................................... 18 
6.3 
Data Handling ............................................................................................................................ 18 
6.4 
Disposition and Study Participation .......................................................................................... 19 
6.5 
Demographic and Baseline Data ............................................................................................... 19 
6.6 
Medical history .......................................................................................................................... 19 
6.7 
Study Medication/Compliance .................................................................................................. 20 
6.8 
Safety Data ................................................................................................................................ 20 
6.9 
Analysis Software ...................................................................................................................... 25 
6.10 
Data Checking, Management and Security ............................................................................... 25 
6.11 
Archiving .................................................................................................................................... 26 
Section 7: Statistical methodology for Pharmacokinetic data ................................................................. 27 
7.1 
General Considerations ............................................................................................................. 27 
7.2 
Source of Data ........................................................................................................................... 27 
7.3 
Data Handling ............................................................................................................................ 27 
7.4 
Methods .................................................................................................................................... 28 
7.5 
Software and working directory ................................................................................................ 30 
7.6 
Reporting IN MAIN BODY OF CSR .............................................................................................. 30 
Section 8: Statistical methodology for Pharmacodynamic data............................................................... 30 
8.1 
General Considerations ............................................................................................................. 30 


 
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8.2 
Sources of Data.......................................................................................................................... 31 
8.3 
Data Handling ............................................................................................................................ 31 
8.4 
Data Analysis ............................................................................................................................. 31 
8.5 
Analysis Software ...................................................................................................................... 34 
8.6 
Reporting ................................................................................................................................... 34 
Section 9: PK/PD analysis .......................................................................................................................... 35 
9.1 
Overview .................................................................................................................................... 35 
9.2 
Sources of data .......................................................................................................................... 35 
9.3 
Data handling ............................................................................................................................ 35 
9.4 
Methods .................................................................................................................................... 37 
9.5 
Analysis Software and working directory .................................................................................. 43 
9.6 
Reporting ................................................................................................................................... 43 
Literature References ............................................................................................................................... 44 
Appendix 1: Planned Listings .................................................................................................................... 46 
Appendix 2: Planned Summary Tables ..................................................................................................... 49 
Appendix 3: Planned Summary Figures .................................................................................................... 52 
 


 
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List of Tables within this SAP 
Table 1. OZ439 and PQP Cohort 1 dose groups ............................................................................. 10 
Table 2. OZ439 and PQP Cohort 2 dose groups ............................................................................. 10 
Table 3. OZ439 and PQP Cohort 3 dose groups ............................................................................. 11 
Table 4. Schedule of Events ............................................................................................................ 14 
Table 5. Low, normal, and high ranges for vital signs .................................................................... 24 
Table 6. ECG normal ranges ........................................................................................................... 25 
Table 7. Number of decimal places for PK concentration summary statistics ............................... 28 
Table 8. Definitions and calculation of PK Parameters .................................................................. 29 
 
 
 


 
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Abbreviations and Definitions 
ACPR28 
 Adjusted adequate clinical and parasitological response at day 
28 post-dose  
ACT 
 Artemisinin combination therapy 
AE  
 Adverse Event/Adverse Experience  
AESI 
 Adverse event of special interest 
ATC 
 Anatomical Therapeutic Chemical 
AUC  
 Area under the plasma concentration-time curve  
AUC0-∞ 
  Area under the plasma concentration-time curve from 0 to 
infinity 
BDI 
 Beck Depression Inventory 
BMI 
 Body mass index 
BLQ 
 Below limit of quantification  
Cmax 
 Maximum plasma concentration  
CI 
 Confidence interval 
CNS 
 Clinical Network Services Pty Ltd 
eCRF  
 Electronic Case Report Form  
CRA 
 Clinical Research Associate  
CSR 
 Clinical study report 
ECG 
 Electrocardiograph 
EOS 
 End of Study 
FBC  
 Full Blood Count 
FSH 
 Follicle-stimulating hormone 
G6PD 
 Glucose-6-phosphate dehydrogenase 
GCP  
 Good Clinical Practice  
h 
 Hour 
HREC  
 Human Research Ethics Committee  
ICH  
 International Conference on Harmonisation 
IBSM 
 Induced Blood Stage Malaria 
IIV 
 inter-individual variability 
IP  
 Investigational Product  
IRB  
 Institutional Review Board 
LFT 
 Liver function test 


 
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LLOQ 
 Lower limit of quantification  
MedDRA 
 Medical Dictionary for Regulatory Activities 
MMV 
 Medicines for Malaria Venture 
NCA 
 Non-compartmental analysis 
ND 
 Not detected 
NLME 
 Nonlinear mixed effects (modelling) 
PD 
 Pharmacodynamics(s) 
Pf 
 Plasmodium falciparum 
PI  
 Principal Investigator  
PCR  
 Polymerase Chain Reaction  
PK 
 Pharmacokinetic 
PRR 
 Parasite reduction ratio 
QIMR Berghofer  QIMR Berghofer Medical Research Institute 
QTc 
 QT interval corrected for heart rate 
QTcB 
 QT interval corrected with Bazett's formula 
QTcF 
 QT interval corrected with Friderica's formula 
SAE  
 Serious Adverse Event/Serious Adverse Experience  
SAP 
 Statistical Analysis Plan 
SD 
 Standard deviation 
SDRT 
 Safety and Data Review Team 
SE 
 Standard error 
SOP  
 Standard Operating Procedure 
tmax 
  Time at which Cmax was achieved / time to reach maximum 
plasma concentration 
TEAE 
  Treatment-emergent adverse event 
WHO 
 World Health Organization 
WOCBP 
 Women of Childbearing Potential 
%CV 
 Coefficient of variation 
 
 
 
 


 
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SECTION 1: INTRODUCTION 
1.1 
SCOPE 
This Statistical Analysis Plan (SAP) is an adjunct to the Medicines for Malaria Venture 
(MMV) Protocol Number QP17C19 Version 4.0 (dated 27 August 2018).  
This SAP outlines the QP17C19 study and describes the methods for the analysis of the 
data arising from this clinical trial, namely the safety data, the non-compartmental 
analysis of pharmacokinetic (PK), the calculation of parasite reduction ratio (PRR), 
and the PKPD modelling.  
This document is mainly based on the statistical section of the study protocol; 
therefore, some sections are described briefly, and references are made to the 
related sections in the protocol. The analyses outlined in this document, if different 
from the protocol, will supersede those specified in the protocol. 
The structure and content of this SAP are designed to provide sufficient detail to meet 
the requirements described by the International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH): 
Statistical Principles For Clinical Trials. 
1.2 
STUDY BACKGROUND 
Malaria is the second most prevalent infectious disease in the world and threatens 
half of the world’s population. In accordance by the World Health Organisation 
(WHO), there were an estimated 216 million new cases of malaria worldwide and 
445,000 deaths in 2016 [1]. Most of the malaria mortality has been reported in sub-
Saharan Africa and in children under 5 years of age. 
 
Malaria drug resistance is a major hurdle to achieving malaria eradication. Resistance 
has been developed not only to conventional monotherapies such as chloroquine, 
amodiaquine and sulfadoxine/pyrimethamine but also to the gold standard 
treatment for uncomplicated P. falciparum malaria, artemisinin combination therapy 
(ACT). Resistance to ACTs has been reported across the Greater Mekong Subregion 
in South-East Asia [2, 3] and the inevitable spread of artemisinin resistance to Africa is 
of great concern. Artemisinin resistance has been linked to mutations in the propeller 
domain of the P. falciparum Kelch13 gene [4]. Artemisinin-resistant isolates are not 
completely resistant to artemisinin, but instead have a slow parasite clearance 
phenotype compared to artemisinin-sensitive isolates. This can lead to reduced 
clearance of young ring-stage parasites, and therefore further maturation and 
sequestration of parasites leading to increased morbidity and mortality. As such, a 
continual generation of new compounds and drug combinations are needed to 
avoid a dangerous shortage of potential future treatment options. 
 


 
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To achieve eradication of malaria, long-lasting, single-dose treatments that 
completely clear malaria parasites from the body and provide a period of protection 
following the treatment are required. These ideal types of medicines are referred to 
as single encounter radical cures (SERCs). The WHO and Medicines for Malaria 
Venture (MMV) have identified the key properties that a SERC must have. These 
properties are defined by Burrows et al. (2017) in the antimalarial target product profile 
(TPP) [5]. A key requirement of a target product is the inclusion of two or more active 
molecules with different mechanisms of action. The aim of including two or more 
active compounds is to achieve an increased barrier to resistance by using drugs with 
different mechanisms of action, forcing the parasite to develop multiple simultaneous 
mutations in order to become resistant. Furthermore, in a combination therapy, one 
of the two active compounds should have a rapid onset of action, killing most of the 
parasite load. Both active compounds should maintain plasma concentrations levels 
above the minimal parasiticidal concentration for approximately the same time and 
ensure complete elimination of all parasites [5].  
 
Artefenomel (OZ439) is a novel trioxolane, and a front-runner candidate for inclusion 
in a new antimalarial combination. It is a synthetic ozonide with potency comparable 
to artemisinin, with a rapid parasite clearance rate of approximately 3.6 h in P. 
falciparum. Additionally, OZ439 has a substantially longer half-life than artemisinin (46–
62 h as opposed to 1–3 h for artemisinin [6]). For these reasons, clinical studies in which 
artefenomel is combined with a companion drug with a different mechanism of 
action are being planned, or are currently in progress.  
 
Piperaquine is a bis 4-aminoquinoline and was used mainly in China from the 1960s to 
the 1980s as an antimalarial monotherapy. In the 1980s, it became clear that parasite 
resistance had developed to piperaquine phosphate (PQP) monotherapy. PQP is 
characterised by slow absorption and a long elimination half-life (4–5 weeks) and is 
now widely used in combination with dihydroartemisinin as a fixed dose ACT. The 
successful pairing of PQP with an artemisinin, together with PQP’s long biological half-
life, means PQP is potentially a good drug partner for OZ439.  
 
SECTION 2: STUDY OVERVIEW 
2.1 
STUDY DESIGN AND TREATMENTS 
This is a single-centre, open-label, adaptive, randomised study using the P. falciparum 
induced blood stage malaria (IBSM) inoculum as a model to characterise the safety, 
tolerability, PK, pharmacodynamic (PD) activity, and PK/PD relationship of combined 
single dose administration of OZ439 and PQP.  


 
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The study was conducted in three cohorts of 8 subjects each using up to 4 different 
single doses of OZ439 and PQP in each cohort. Subjects were malaria naïve healthy 
males or females, aged between 18-55 years old, who met all of the inclusion criteria 
and none of the exclusion criteria. 
The first cohort was composed of 4 groups of 2 subjects each. Subjects were 
randomised into one of 4 dose groups and administered single oral doses of OZ439 
and PQP in combination. The combined dose of OZ439 and PQP was different for 
each of the 4 groups in this cohort as shown in Table 1.   
Table 1. OZ439 and PQP Cohort 1 dose groups 
Drug 
Dose group 
1A 
1B 
1C 
1D 
OZ439 (mg) 
200 
200 
400 
400 
PQP    (mg) 
480 
640 
480 
640 
The OZ439 and PQP dose levels and the number of subjects per dose for Cohorts 2 
and 3 were determined adaptively during the study. 
After review of the PK/PD and safety data from Cohort 1 by the Safety and Data 
Review Team (SDRT) it was determined that cohort 2 would be composed of 2 dose 
groups of 4 subjects each. Subjects were randomised into one of 2 dose groups and 
administered single oral doses of OZ439 and PQP in combination. The combined dose 
of OZ439 and PQP will be different for each dose group in this cohort as shown in Table 
2.   
Table 2. OZ439 and PQP Cohort 2 dose groups 
Drug 
Dose group 
2A 
2B 
OZ439 (mg) 
800 
200 
PQP    (mg) 
960 
320 
 
A similar analysis was done at the end of Cohort 2 by combining data from cohorts 1 
and 2 to decide the doses to be tested in Cohort 3. Two groups of 4 subjects each 
were considered. Subjects were randomised into one of 2 dose groups and 
administered single oral doses of OZ439 and PQP in combination as shown in Table 3.   


 
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Table 3. OZ439 and PQP Cohort 3 dose groups 
Drug 
Dose group 
3A 
3B 
OZ439 (mg) 
400 
800 
PQP   (mg) 
640 
640 
 
Each subject was inoculated on Day 0 with approximately 2,800 viable parasites of 
P. falciparum-infected human erythrocytes administered intravenously. Subjects were 
followed up daily via phone call or text message on Days 1 to 3 post-inoculation to 
solicit any AEs.  
Subjects then came to the clinical unit once daily from Day 4 until presence of asexual 
parasites was established by quantitative polymerase chain reaction (qPCR) 
targeting the 18S rRNA gene (referred to hereafter as malaria 18S qPCR). Once 
malaria 18S qPCR became positive and until OZ439 and PQP administration, subjects 
came to the clinical unit twice-daily, separated by approximately 12 hours, for clinical 
evaluation and blood sampling.  
On day 8, subjects were admitted to the clinical unit for single dose administration of 
OZ439 and PQP on Day 8. Subjects were followed up as inpatients for 72 hours to 
ensure tolerance of the investigational treatments (OZ439 and PQP) and clinical 
response. 
After discharge from the clinical unit, subjects were followed up regularly for safety 
assessments, PK sampling, clinical evaluation, and malaria 18S qPCR blood sampling 
until Day 42±2 (34 days after OZ439 and PQP co-administration). All subjects received 
a standard course of Riamet® (artemether-lumefantrine) on Day 42±2, or earlier in the 
event of failure of clearance or recrudescence of parasitaemia or at Investigators 
discretion based on subject safety. For guidance, the definitions for failure of parasite 
clearance and recrudescence are provided.  
– Failure of parasite clearance: failure to clear parasitaemia by at least 10-fold 
at 72 hours post-IP administration  
– Recrudescence: defined as participants who showed substantial increases in 
parasitaemia after the initial clearance and were treated with a standard 
course of Riamet® to clear parasites.  
 
The clinical judgement was made based on serial samples to ensure participant 
safety. Guidelines for increasing parasitaemia following initial clearance were a 2-fold 
parasitaemia increase from previous sample and parasitaemia exceeding the 


 
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clinically safe threshold (e.g. ≥5 000 blood stage parasites/mL), or re-occurrence of 
malaria symptoms with a malaria clinical score >6. However clinical judgement and 
practicality were overriding criteria for rescue treatment. 
2.2 
STUDY OBJECTIVES 
Primary objectives: 
a) To characterise the PK/PD relationship between OZ439 and PQP plasma 
concentrations and blood stage asexual parasitaemia in healthy subjects 
following P. falciparum IBSM infection.  
b) To evaluate the safety and tolerability of OZ439 and PQP when co-
administered as single doses in healthy subjects following P. falciparum IBSM 
infection. 
Secondary objectives: 
a) To describe the PK of OZ439 and PQP when co-administered as single doses in 
healthy subjects under fasted conditions. 
b) To characterise the PD effect of co-administered single doses of OZ439 and 
PQP on clearance of P. falciparum asexual blood stage parasites from the 
blood of healthy subjects in the IBSM model. 
2.3 
STUDY ENDPOINTS  
Primary endpoints: 
• 
The PK/PD relationship between OZ439 and PQP plasma concentrations and 
blood stage asexual parasitaemia will be determined by PK/PD modelling of: 
o OZ439 plasma concentration over time 
o PQP plasma concentration over time 
o Parasitaemia profile over time, following treatment administration 
The following parameters will be estimated from the PK/PD model: 
o Effect of OZ439 on Emax and EC50 of PQP 
o Effect of PQP on Emax and EC50 of OZ439  
The following PD endpoints will be predicted from the PK/PD model: 
• 
Time to recrudescence defined as the time at which parasite levels re-
occur after being BLQ or the time for which parasitaemia levels are 
minimum, or, if not defined, the last observed time point without 
recrudescence. 
• 
ACPR28 defined as the fraction of patients for which no parasitaemia is 
observed at Day 28 after drug administration,  
• 
The incidence, severity and relationship to OZ439 and PQP of observed 
and self-reported AEs after the co-administration of single doses of OZ439 and 
PQP to healthy subjects inoculated with IBSM.  
 


 
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Secondary endpoints: 
• 
Estimation of OZ439 and PQP PK parameters after co-administration of single 
doses using non-compartmental methods: AUC0-168h, AUClast, AUC0-inf, Cmax, tmax, 
t1/2, tlag, C168h, CL/F, Vz/F and λinf. 
• 
The effect of co-administered single oral doses of OZ439 and PQP on clearance 
of P. falciparum blood stage parasites from the blood of inoculated subjects 
as measured by qPCR up to trial Day 42±2 after co-administration of OZ439 and 
PQP. Parasite clearance will be assessed by the following parameters: 
o Parasite clearance half-life (PCt½).  
o Parasite reduction ratio (PRR). 
o Percentage of subjects with recrudescence of parasitaemia, defined as 
≥5 000 blood stage parasites/mL and a 2-fold increase within 48 hours, 
or re-occurrence of malaria symptoms with a malaria clinical score >6). 
Exploratory objectives for the study, including presentation of endpoints, analysis 
methods and results, will be addressed separately, outside of the main clinical study 
report (CSR). 
2.4 
SAMPLE SIZE 
A total of 24 healthy subjects were enrolled in the study (3 cohorts of 8 subjects each). 
Subjects were malaria-naïve healthy males or females, aged between 18-55 years 
old, who met all of the inclusion criteria and none of the exclusion criteria. Sample size 
was not determined based on formal power calculation. 
In each cohort, if more than 2 discontinuations due to non-safety related reasons had 
occurred; additional subjects could have been recruited to replace the discontinued 
subjects on agreement with the study sponsor. 
Historically, 8 subjects per cohort have been manageable from a resourcing and 
logistics perspective. The selection of more than one dose level for each treatment 
should enable the effect of the drugs to be characterised and should provide 
dose/concentration-response information about malaria parasite kinetics following 
IBSM in healthy subjects. 
2.5 
STUDY SCHEDULE 
The complete schedule of events with all procedures is presented in Table 4.


 
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Table 4. Schedule of Events 
Procedure 
Screening 
 
 
 
D-28 to D-1 
Eligibility visita  
 
 
 
D-3 to D-1 
Malaria 
inoculation 
day  
 
D0   
Post-inoculation 
phone call or text 
message 
 
D1 to D3 
Malaria 
monitoringb  
 
 
D4 to D7 
OZ439 
and 
PQP 
treatment and clinical 
unit confinement  
 
D8 to D11 
Out-patient 
monitoring  
 
D12 to D42±2 (35 days 
after OZ439/PQP) 
EOS visit 
 
 
 
D45±2 
Informed consent & BDI 
X 
 
 
 
 
 
 
 
Medical history, eligibility 
& prior medications 
X 
 
X 
 
 
 
 
 
Drug & alcohol screen 
X 
 
X 
 
 
X 
 
 
Full physical examination 
X 
 
 
 
 
 
 
X 
Symptom-directed 
physical examinationc 
 
 
X 
 
X 
X 
X 
 
Vital sign assessment 
X 
 
X 
 
X 
X 
X 
X 
ECG 
X 
 
X 
 
 
Xj 
 
X 
Urinalysis 
X 
X 
 
 
 
Xk 
X 
X 
Haematology & 
biochemistry 
X 
X 
 
 
 
X 
X 
X 
CRP testingf 
 
X 
 
 
 
X 
X 
X 
G6PD testing 
X 
 
 
 
 
 
 
 
RBC alloantibody 
X 
 
 
 
 
 
 
X 
Serology 
X 
 
 
 
 
 
 
X 
Pregnancy testd 
X 
 
X 
 
 
X 
 
X 
Safety serum storage 
 
 
X 
 
 
 
 
X 
AEs & concomitant 
medications 
 
 
X 
X 
X 
X 
X 
X 
Malaria clinical score 
 
 
X 
 
X 
X 
Xl 
X 
Malaria 18S qPCR blood 
sampling 
 
 
X 
 
X 
X 
X 
X 
Parasite lifecycle stage 
qRT-PCR blood samplinge 
 
 
 
 
 
 
X 
X 
OZ439 and PQP  
concentration blood sampling 
 
 
 
 
 
X 
X 
 
Drug treatment 
 


 
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Procedure 
Screening 
 
 
 
D-28 to D-1 
Eligibility visita  
 
 
 
D-3 to D-1 
Malaria 
inoculation 
day  
 
D0   
Post-inoculation 
phone call or text 
message 
 
D1 to D3 
Malaria 
monitoringb  
 
 
D4 to D7 
OZ439 
and 
PQP 
treatment and clinical 
unit confinement  
 
D8 to D11 
Out-patient 
monitoring  
 
D12 to D42±2 (35 days 
after OZ439/PQP) 
EOS visit 
 
 
 
D45±2 
Malaria inoculum 
 
 
Xg 
 
 
 
 
 
OZ439 and PQP treatment 
 
 
 
 
 
X 
 
 
Riamet® treatmenth 
 
 
 
 
 
 
X 
 
Primacin™ treatmenti  
 
 
 
 
 
 
X 
 
PQP: piperaquine phosphate; EOS: End of Study, BDI: Beck Depression Inventory; ECG: electrocardiograph, CRP: C-reactive protein; G6PD: glucose-6-phosphate 
dehydrogenase, RBC: red blood cell, PK: pharmacokinetic, PD: pharmacodynamic, qPCR: quantitative polymerase chain reaction, qRT-PCR: reverse transcription qPCR.  
a An additional safety visit will occur between Day -3 and Day -1 to collect samples for haematology, biochemistry and urinalysis, unless screening laboratory assessments 
were conducted within this period.  
b Daily visits until qPCR positive, and then twice daily visits until OZ439 and PQP treatment. 
c Symptom-directed physical examinations will be performed only if clinically indicated at the discretion of the Investigator (see Appendix 3 of protocol for a list of 
symptoms and signs of malaria). 
d Serum β-hCG pregnancy test (all female subjects) and follicle stimulating hormone test (FSH) (post-menopausal females) at screening. Urine β-hCG pregnancy test for 
WOCBP at other indicated time points (Day 0 pre-malaria inoculation, Day 8 pre-OZ439 and PQP administration, EOS).  
e If required, at the Investigator’s discretion.  
f May be performed at the Investigator’s discretion.  
g Cannulate subjects with an indwelling intravenous cannula for the malaria inoculum, and record which arm is utilised. Cannulate subjects with an indwelling intravenous 
cannula for the malaria inoculum, and record which arm is utilised. Administer the malaria inoculum of ~2 800 viable P. falciparum 3D7 infected human RBCs intravenously 
in the morning (approximately 9:00 AM). Observe for a minimum of 60 minutes after inoculation to evaluate for immediate adverse reactions. Educate subjects on signs and 
symptoms of malaria (Appendix 3 of protocol). Emphasise to subjects the importance of returning on the nominated day (approximately Day 8), or as advised by the clinical 
unit staff, for IP antimalarial treatment. Provide subjects with diary cards and thermometers to record any temperature readings during the study in the event of symptoms 
of fever. Subjects will also record symptoms and concomitant medications on the diary cards during the study. 
h Riamet® treatment will occur on Day 42±2, or earlier if there is failure of clearance or recrudescence of parasitaemia, or at the Investigator’s discretion. 
i Primacin™ treatment if required (Section 6.1.5 of protocol). 
j ECG to be performed in triplicate at 4, 6, 8, 12, 24 and 72 h post-OZ439 and PQP dosing, or at the Investigator’s discretion 
k At the time of admission to clinical unit only. 
l Only if vital signs are abnormal, or at the Investigator’s discretion. 


 
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SECTION 3: INTERIM ANALYSES 
There are no formal interim analyses planned for this study. 
3.1 
SAFETY DATA REVIEW 
A review by the SDRT of data from each cohort will be conducted prior to dosing the 
subsequent cohort. Safety and tolerability data up to Day 42±2 and PK/PD analysis 
outcomes (based on PD data up to Day 42±2 and PK data up to Day 35±2), from all 
subjects from Cohort 1 who received treatment with OZ439 and PQP will be required 
for the review. The SDRT will determine the OZ439 and PQP dose levels and the number 
of subjects per dose for Cohort 2 from that review. A similar analysis will be done at 
the end of cohort 2 combining cohorts 1 and 2 data to decide the dose(s) to be 
tested in cohort 3. This will be decided by the funding sponsor and the Principal 
Investigator following review of the data by the SDRT and scientific evaluation. 
The doses used in all cohorts will not exceed the maximum acceptable doses 
predefined for this study (800 mg for OZ439 and 1440 mg for PQP) as determined in 
previous safety, pilot efficacy and phase 2 studies. 
Currently, no formal interim analysis is planned. Additional interim analyses may be 
conducted to support decision making concerning the current clinical study, the 
sponsor’s clinical development projects in general or in case of any safety concerns. 
In this case, the analyses as described in the sections below are conducted for the 
relevant endpoints. 
SECTION 4: OVERARCHING SAP INFORMATION 
This SAP document presents all pre-planned analyses, as approved prior to final 
database lock. Any major deviations from the final approved SAP or additional 
unplanned post-hoc analyses will be documented (with justification) in the CSR. 
SECTION 5: ANALYSIS SETS 
Data from all enrolled subjects will be listed. Listings will present data ordered by 
cohort, dose group, subject, and timepoint (as relevant). 
In this study, dose group (e.g., 1A, 2B) is defined as the combination of OZ439 and PQP 
single dose levels. For subjects for which the actual treatment received does not 
match the randomised treatment the treatment actually received will be used for the 
analysis. Unless specified otherwise, summary outputs will be presented by dose group 
and timepoint (as relevant). 
The inoculation set will include all subjects inoculated with the P. falciparum challenge 
agent. 


 
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The safety analysis set will include all subjects that received any study treatment.  
The PK analysis set will include all subjects with at least one available valid (i.e. not 
flagged for exclusion) PK concentration measurement, who received any study 
treatment and experienced no protocol deviations with relevant impact on PK data. 
The PD analysis set will include all subjects with any available PD data, who received 
any study treatment and experienced no protocol deviations with relevant impact on 
PD data. 
The PK/PD analysis set will include all subjects from the PK set and all subjects from the 
PD set. 
Protocol deviations will be reviewed and exclusion of subjects from the analysis sets 
will be decided during final data review prior to database lock. 
SECTION 6: SAFETY STATISTICAL METHODOLOGY 
6.1 
GENERAL CONSIDERATIONS  
The statistical analysis and reporting of safety data will be the responsibility of the study 
biostatistician at CNS. Data will be reported for the inoculation set and/or for the 
safety set as relevant. 
For categorical/discrete variables, the population size (N for sample size and n for 
available data) and the percentage (of available data) for each class of the variable 
will be presented. Continuous variables will be summarised using descriptive statistics, 
including n, mean, standard deviation (SD), median, minimum, and maximum values.  
Numeric safety variables (i.e. clinical laboratory values, vital signs, and key ECG 
parameters) will be reported to the same precision as the source data. Derived 
variables will be reported using the same precision to the value(s) from which they 
were derived. For the reporting of descriptive statistics, the minimum and maximum 
values will be presented to the same precision as the source data; mean and median 
will be reported to 1 decimal place greater than the source data and SD will be 
reported to 2 decimal places greater than the source data. The coefficient of 
variation (%CV) will always be reported as a percentage (i.e. ×100) to 1 decimal 
place. 
Extra measurements (such as unscheduled or repeat assessments) will not generally 
be included in summary tables, but will be included in subject listings. 
For safety data, unless specifically mentioned otherwise, baseline is defined as: 
• 
the last scheduled observation prior to the administration of the inoculum 
[Inoculation Baseline], 
• 
the last scheduled observation prior to the first administration of IP(s) [Treatment 
Baseline].  


 
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If a scheduled baseline reading is missing, then the last non-missing measurement (e.g. 
screen value or unscheduled) will be used. 
6.2 
SOURCES OF DATA 
Analysis datasets will be generated from data extracted from the Clinical Study 
Database.  
6.3 
DATA HANDLING 
Subject Identification Codes 
For each cohort, all eligible subjects will be randomised to one of the dose groups on 
the morning of Day 8. 
Randomisation and subject identification codes will be listed. Subject identification 
codes will be reported in all other listings.  
Subjects who are inoculated but do not receive the IP will be included in all safety 
listing using their subject identification codes. 
Assessment Time-Point Identifiers 
In the data listings and summary tables presented as part of the CSR, scheduled 
assessments for Safety data will be identified by the study day name/number and/or 
protocol scheduled time points (Screening, Day -3 to -1, Day 0, Malaria Monitoring 
Visit, OZ439 and PQP treatment, and clinical unit confinement, Outpatient Monitoring, 
Rescue treatment with Riamet® and EOS visit and/or 4, 6, 8, 12, 24 and 72 hours post-
OZ439 and PQP dosing), where relevant.  
Derived Data 
Derived data variables for inclusion in data listings will be calculated as follows: 
• 
Age (in integer years) = (Screening Date – Date of Birth + 1) / 365.25)  
• 
Body Mass Index (BMI) = Weight (kg) / (Height 2 (m)) 
• 
AE time since Inoculum (in hours, to one decimal place) = (Onset Date + 
Onset Time) – (Inoculum Date + Inoculum Time). 
• 
AE time since study treatment administration (in hours, to one decimal 
place) = (Onset Date + Onset Time) – (Study Treatment Administration Date 
+ Study Treatment Administration Time). 
• 
Duration of AE (in hours, to one decimal place) = (Resolution Date + 
Resolution Time) - (Onset Date + Onset Time). 
AE time since Inoculum/study treatment administration and duration of AE will be 
converted to days (to one decimal place) in the follow-up period. 
Handling of Missing Data 
Missing values will not be imputed and will be reported in the listings as either “missing” 
or as the justification for the value being missing e.g. “ND” (not detected), where 
appropriate. 


 
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For the current study the duration of historical medical conditions and prior and 
concomitant medication administration will not be calculated or summarised and as 
such missing start and end times/dates will not be imputed.  
Descriptive statistics will be calculated from actual data only, with the number of 
actual data points used for the calculation of the summary statistics reported. Missing 
data will not be imputed. 
For censored safety lab data (i.e. haematology, clinical biochemistry and urinalysis 
results that are outside the limit of quantification) the actual values reported by the 
lab (e.g. “<2” for bilirubin) will be presented in the data listings. For the calculation of 
summary statistics, safety lab data values below the lower limit of quantification 
(LLOQ) will be set to ½ the LLOQ. For the calculation of summary statistics, safety lab 
data values above the upper limit of quantification (ULOQ) will be set to the ULOQ. 
6.4 
DISPOSITION AND STUDY PARTICIPATION 
A disposition listing will present date and time of informed consent, date of study 
completion or early withdrawal, and the reason for early discontinuation. 
The number of subjects that completed, number of subjects that discontinued and 
the main reasons for early withdrawal will be summarised by dose group. Dose group 
assignment and IP administration will be presented for individual subjects in a data 
listing. 
All available information concerning major protocol deviations, violations on eligibility 
criteria, exclusion from analysis sets and subjects not treated will be listed. The number 
of subjects in each analysis set will be tabulated. 
6.5 
DEMOGRAPHIC AND BASELINE DATA 
Individual subject demographics at screening (age, sex, race, height, weight and 
BMI), serology and special tests, red cell alloantibody, urine drug screen results, 
alcohol breath test results, G6PD status, pregnancy and FSH test results, and the Beck 
Depression Inventory will be presented in data listings. 
Subject age, height, weight, and BMI will be summarised by treatment using 
descriptive statistics. Sex and race will be summarised using frequency counts and 
percentages. 
6.6 
MEDICAL HISTORY 
Medical history findings are coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) into system organ classes and preferred terms. For each finding, 
a start and stop date or ongoing flag is collected. 
Medical history will be tabulated as below: 
• 
The number and percentage of subjects with and without findings 


 
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• 
The number and percentage of subjects with findings by system organ class 
and preferred term 
All medical history data will be listed. 
6.7 
STUDY MEDICATION/COMPLIANCE 
Individual records of drug name, dose levels, date and time of challenge agent 
administration, IP administration and rescue medication administration will be 
presented in data listings.  
6.8 
SAFETY DATA 
Adverse events 
Adverse events (AEs) and AESIs will be coded using the most current Medical 
Dictionary for Regulatory Activities (MedDRA®) available at CNS (21.0). Listings of AEs, 
as well as the severity, relationship, duration, outcome, actions taken, and whether 
the AE was treatment-emergent and/or an SAE will be presented for each subject. 
Treatment-emergent adverse events (TEAEs) will be defined as any AE with an onset 
after administration of study drug, or any AE that has worsened after administration of 
study drug.  
An AESI (serious or non-serious) is one of scientific and medical concern specific to the 
Sponsor’s product or programme, for which ongoing monitoring and rapid 
communication by the Investigator to the Sponsor could be appropriate. Any 
abnormalities listed below should be reported as AESI: 
 
Hepatic: 
• 
any ALT or AST above 5xULN 
• 
an elevation in bilirubin 2xULN 
• 
any AST or ALT above 2xULN and (TBL > 1.5x ULN or INR > 1.4) 
• 
any AST or ALT above 2xULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash and/or eosinophilia 
(eosinophil percent or count above the ULN) 
 
 


 
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Cardiac: 
• 
QTcB or QTcF at any time >480 msec, 
• 
bundle branch block (except right bundle branch block that was present prior 
to IP administration) 
any arrhythmia, except:  
• 
sinus bradycardia that is 
– clinically asymptomatic, and 
– not associated with any other relevant ECG abnormalities 
• 
sinus tachycardia that is 
– clinically asymptomatic, and 
– associated with a body temperature >38.0 °C, and 
– not associated with any other relevant ECG abnormalities 
respiratory sinus arrhythmia, 
wandering atrial pacemaker, 
isolated, single premature atrial/ventricular complex (i.e. no bigeminy, trigeminy, 
couplets, triplets or salvos) that does not occur more than once in a particular ECG 
tracing. 
Haematological: 
HB drop >2.0 g/dL from baseline prior to inoculation 
Absolute neutrophil count <500/μl. 
Platelet count <75,000 /mm3 
Dermatological: 
Clinical signs of possible cutaneous adverse reactions such as: 
• 
dermatitis, 
• 
rash, 
• 
erythematous rash, 
• 
macular rash, 
• 
papular rash, 
• 
maculopapular rash, 
• 
pruritic rash, 
• 
pustular rash, 
• 
vesicular rash. 
Data for AEs for each subject will be presented in data listings. A listing of deaths, other 
serious and significant AEs, as well as AESIs, will also be presented.  
All AEs and AESIs will be summarised in tables. An overview table will show the number 
and percentage of subjects with at least one event and the number of events for the 
following: 
• 
TEAEs 
• 
Serious TEAEs 
• 
Fatal TEAEs 


 
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• 
Treatment-related TEAEs 
• 
TEAEs related to IBSM inoculum  
• 
TEAEs related to procedure 
• 
TEAEs related to rescue drug 
• 
Serious treatment-related TEAEs 
• 
TEAEs for which the study was discontinued 
• 
TEAEs for which the study drug was discontinued 
• 
TEAEs of special interest 
Summary tables by MedDRA system organ class and preferred term will show the 
number and percentage of subjects with at least one event. The table of TEAEs will 
additionally show the number of events. Separate tables will be prepared for the 
following: 
• 
TEAEs by phase (treatment/rescue) and overall 
• 
TEAEs related to IBSM inoculum 
• 
TEAEs related to treatment 
• 
TEAEs related to rescue drug  
Additionally, a summary table by MedDRA preferred term will show the number and 
percentage of subjects with at least one event, by descending order of frequency 
(number of subjects with events in the total group). This table will be shown by phase 
(treatment/rescue) and overall. Treatment phase is defined as Day 8 after dosing or 
earlier to Day 42±2 (OZ439 and PQP) and rescue phase from Day 42±2 after dosing 
(Rescue treatment) to (EOS visit).  
Prior and concomitant medications 
Prior and concomitant medications relative to inoculum and IP will be listed for each 
subject and coded using the WHO drug dictionary (latest version available to CNS) 
with the listing to include the verbatim term and WHO drug dictionary drug class and 
preferred term (anatomical therapeutic chemical (ATC) Level 2 and standardised 
medication name), where appropriate. Prior medications relative to inoculum will be 
defined as those medications started before the administration of Inoculum (Day 0) 
and prior medications relative to IP will be defined as those medications started 
before the administration of IP (Day 8).  
Concomitant medications relative to inoculum will be defined as those medications 
started on or after the administration of inoculum (Day 0) up to the EOS visit or 
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relative to IP will be defined as those medications started on or after the administration 
of IP (Day 8) up to the EOS visit or premature study withdrawal, whichever is earliest. 
Medications with a start date/time prior to administration of inoculum and an end 
date/time after administration of the inoculum will be assigned to both prior 
medication and concomitant medication categories relative to inoculum. 
Medications with a start date/time prior to the administration of IP and an end 
date/time after administration of IP will be assigned to both prior medication and 
concomitant medication categories relative to IP. 
Laboratory parameters 
All individual laboratory results (haematology, biochemistry, and urinalysis) and 
change from baseline values will be presented in data listings. Values outside the 
laboratory reference range will be flagged (low-L, high-H). Classification will be done 
in standardised units, using non imputed values and limits. In addition, abnormal 
haematology, biochemistry and urinalysis laboratory parameters considered clinically 
significant will be presented in a listing with all parameters listed in a single column. All 
laboratory data will be listed. In addition, a listing will be provided showing only 
parameters for which abnormal values were reported.  
Additionally, for liver enzymes, the following elevation categories will be defined: 
• 
ALT: >3 x Upper Limit of Normal (ULN); >5 x ULN; >8 x ULN 
• 
AST: >3 x Upper Limit of Normal (ULN); >5 x ULN; >8 x ULN 
• 
ALT or AST >3 x ULN; 
• 
Total bilirubin >2 x ULN; 
• 
ALT or AST >3 x ULN and total bilirubin >2 x ULN at the same time point, together 
with a conjugated bilirubin fraction (direct bilirubin / total bilirubin) > 35% 
(Potential Hy’s law cases). 
The statistical analysis will present results in standardised units. 
Continuous laboratory parameters will be summarised by means of descriptive 
statistics at each analysis visit. Actual values and changes from baseline will be 
tabulated separately. Categorical and semi-quantitative parameters will be listed 
only. 
Laboratory abnormalities will be presented as cross-tabulations of the abnormality at 
each post-baseline analysis visit versus the baseline abnormality. Numbers of subjects 
with treatment-emergent abnormalities will also be shown. 
Additionally, a frequency table showing the liver enzyme elevation categories for the 
highest post-dose values will be prepared. 


 
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Vital signs 
The following vital signs parameters are collected: supine heart rate, supine systolic 
(SBP) and diastolic blood pressure (DBP) and body temperature. 
Low, normal, and high ranges for vital signs are defined in Table 5 below. 
Table 5. Low, normal, and high ranges for vital signs   
 
Heart rate 
(bpm) 
SBP 
(mmHg) 
DBP 
(mmHg) 
Temperature 
(°C) 
Low 
<40 
<90 
<45 
<35.0 
Normal 40-100 
90-150 
45-90 
35.0-37.5 
High 
>100 
>150 
>90 
>37.5 
 
Vital signs parameters will be summarised by means of descriptive statistics at each 
analysis visit. Actual values and changes from baseline will be tabulated separately.  
Abnormalities will be presented as cross-tabulations of the abnormality at each post-
baseline analysis visit versus the baseline abnormality. Numbers of subjects with 
treatment-emergent abnormalities will also be shown. 
All vital signs data will be listed. In addition, a listing will be provided showing only 
abnormal values and their baseline.  
Electrocardiograms 
All individual ECG parameter results (heart rate, PR interval, RR interval, QRS duration, 
QT interval, QTcB interval, QTcF interval) and the clinical assessment of the ECG will 
be presented in a data listing. ECG parameter values and changes from baseline will 
be summarised, using descriptive statistics, by treatment and visit. Where triplicate 
ECG evaluations were performed, the mean value for each subject (for the protocol 
specified time-point) will be used for the calculation of summary statistics. In addition, 
individual abnormal ECG results will be presented in a separate data listing. 
The clinical assessment of the ECG (RR, PR, QRS, QT and QTcF intervals) will be 
presented in subject data listings.  
Clinical assessment of the ECG (Normal, Abnormal NCS, Abnormal CS, Not Evaluable 
and Not Done) will also be summarized, by treatment, using frequency tabulations 
(number and percentage of subjects under each category). The normal ECG ranges 
once on study are in Table 6. 
 
 


 
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Table 6. ECG normal ranges 
Parameter 
Range 
PR interval 
<= to 210 msec 
QRS 
>50 to < = to120 msec 
QT interval 
>200 to < 500 msec 
QTcB/QTcF 
Males: ≤ 450 msec 
QTcB/QTcF 
Females: ≤ 470s msec 
 
Malaria clinical score  
For each subject, malaria clinical score will be listed as individual score for each of 
the 14 symptoms. The total of all the scores obtained on the 14 symptoms will also be 
presented, per timepoint. The number (and percentage) of subjects scoring each 
symptom (0=absent; 1=mild; 2=moderate; 3=severe) will be tabulated per treatment 
and per protocol defined timepoint. In addition, the total malaria clinical score will be 
treated as a continuous outcome and summarised per treatment and over timepoint, 
as well as a change from baseline, using descriptive statistics. 
Physical examinations 
Abnormal physical examination assessment findings will be listed. 
6.9 
ANALYSIS SOFTWARE 
Data manipulation and generation of listings and tables for all safety data and 
disposition and participation data will be performed using SAS Enterprise Guide 
Software version 7.12.  
6.10 DATA CHECKING, MANAGEMENT AND SECURITY 
Quality control review of listings and tables will be undertaken to ensure data 
contained in these documents correctly represent data recorded in the study 
databases. Where review by the Sponsor identifies erroneous values or the 
requirement for modification, the appropriate SAS program will be updated, and the 
document recreated. Updated documents will undergo a repeat of the quality 
control process. Where modification to electronic data files is required (e.g., SAS 
program, analysis data file), the old file will be retained. 
 


 
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All electronic data storage systems containing study data or analysis information will 
be password protected at all times, with access restricted to authorised CNS staff. 
Multisite backup of all electronic data and files will be performed daily. 
6.11 ARCHIVING 
All statistical analysis documents and records are to be retained for a minimum of 
fifteen years after trial completion. Written agreement from the Sponsor must precede 
destruction of the same. 
 
 


 
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SECTION 7: STATISTICAL METHODOLOGY FOR PHARMACOKINETIC DATA 
7.1 
GENERAL CONSIDERATIONS 
Listings of pharmacokinetic data will be generated by CNS. Summary statistics, non-
compartmental analysis (NCA), and graphical representation of PK data and their 
statistics will be performed by IntiQuan.  
NCA of PK data will be performed to determine the AUC0-168h, AUClast, AUC0-inf, Cmax, 
tmax, t1/2, tlag, CL/F, Vz/F and λinf for OZ439 and PQP for the subjects in QP17C19. 
7.2 
SOURCE OF DATA  
Plasma concentration of OZ439 and PQP, treatment and blood sampling information 
will be recorded and merged to produce source PK concentration data for analysis. 
7.3 
DATA HANDLING 
Data Imputation for Pharmacokinetic Concentration Data Reporting 
No imputations will be done for missing concentration values or missing time 
information, i.e., records with missing concentrations or times will be discarded. 
Concentrations that are below the lower limit of quantification (LLOQ) are defined 
as being below limit of quantification (BLQ) and will be reported as "BLQ" in data 
listings. For calculation of geometric means, geometric standard deviation (SD) and 
geometric coefficient of variation (CV%) concentration values reported as BLQ will 
be set to ½ × LLOQ and for all other summary statistics concentration values 
reported as BLQ will be set to zero. 
Data used for Pharmacokinetic Estimation 
In general, only concentration values above the LLOQ are used, hence, BLQ values 
are discarded with the following exceptions: 
 
• 
Individual BLQ concentration values between the first dosing time and the first 
time point above LLOQ (i.e. during lag-time) are set to 0 and included in the PK 
evaluation. 
• 
Pharmacokinetically plausible concentration value(s) below LLOQ at time points 
between two measurable concentration values are replaced by the LLOQ/2 
value, flagged and included in the PK evaluation. 
 
Actual time from dose administration will be used for parameter estimation except 
for the pre-(first) dose data point which will be set to the nominal time of 0 hour. 
Data with missing time information will be discarded. 
 


 
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7.4 
METHODS 
Data Listings 
Individual data listings containing the drug concentrations of OZ439 and PQP will be 
represented with same number of decimal places or significant digits as the source 
data. 
Calculation of descriptive statistics 
The CV% is calculated as 
𝐶𝑉% = 100 ⋅
𝑆𝐷
𝑚𝑒𝑎𝑛 
The geometric SD is calculated as 
𝑆𝐷𝑔𝑒𝑜𝑚𝑒𝑡𝑟𝑖𝑐= 𝑒𝑆𝐷(ln(𝑑𝑎𝑡𝑎𝑣𝑎𝑙𝑢𝑒𝑠)) 
The geometric CV% is calculated as 
𝐶𝑉%𝑔𝑒𝑜𝑚𝑒𝑡𝑟𝑖𝑐= 100 ⋅√𝑒𝑆𝐷(ln(𝑑𝑎𝑡𝑎𝑣𝑎𝑙𝑢𝑒𝑠))2 −1 
Summary Tables 
The concentration time courses will be represented in tables stratified by dose group. 
Descriptive statistics will be reported for each scheduled time-point with the precision 
as given in Table 7. 
 
Table 7. Number of decimal places for PK concentration summary statistics 
Descriptive statistic 
Number of decimal places 
Number of subjects 
none 
Geometric mean 
i + 1 
Median 
i + 1 
Minimum 
i 
Maximum 
i 
Arithmetic mean 
i + 1 
SD 
i + 1 
CV% 
1 
i = number of decimal places in source 
 
Figures 
The concentration-time courses will be represented graphically based on following 
plots. 
1. 
Individual profiles (one panel per subject) with concentrations of OZ439 and PQP 
on linear scale 
2. 
Individual profiles (one panel per subject) with concentrations of OZ439 and PQP 
on log10 scale 
3. 
Spaghetti plots of individual profiles stratified by dose group with concentrations 
on linear scale, separately for OZ439 and PQP. 
4. 
Spaghetti plots of individual profiles stratified by dose group with concentrations 
on log10 scale, separately for OZ439 and PQP. 
5. 
Summary plots of arithmetic means per scheduled timepoint presenting all dose 
groups in one panel, separately for OZ439 and PQP. Subjects are summarized per 


 
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dose group. Plots on both linear and on log10 scale for the concentrations will be 
produced. Error bars representing +/- 1 arithmetic SD will be included. 
6. 
Summary plots of geometric means per scheduled timepoint presenting all dose 
groups in one panel, separately for OZ439 and PQP. Plots on both linear and on 
log10 scale for the concentrations will be produced. Error bars representing +/- 1 
geometric SD will be included. If the (geometric mean – geometric SD) value is 
zero or negative, then only the value for (geometric mean + geometric SD) will 
be displayed as error bars on the plot. 
Pharmacokinetic Parameter Estimation (NCA) 
Definition and calculation of Pharmacokinetic Parameters 
Table 8 provides a list of definitions for PK parameters that will be calculated in this 
study. 
Table 8. Definitions and calculation of PK Parameters 
Parameter 
Description 
AUClast 
Area under the plasma concentration-time curve, calculated using linear-up 
logarithmic down trapezoidal summation from time zero to the last 
measurable concentration. 
AUC0-inf 
Area under the plasma concentration-time curve from time zero to infinity, 
AUC0-inf is calculated as the sum of AUClast plus the last measurable plasma 
concentration divided by elimination rate constant [𝜆inf]. 
Cmax 
Maximum observed drug concentration in observed individual concentration 
time profile. 
tmax 
Time to maximum observed drug concentration within a dose interval. If the 
maximum value occurs at more than one time point, tmax is defined as the first 
time point with this value. 
t1/2 
Apparent elimination half-life, calculated as ln[2]/𝜆inf. 
tlag 
Elapsed time from dosing at which drug concentration was first quantifiable. 
CL/F 
Apparent 
total 
body 
clearance 
after 
extravascular 
administration, 
calculated as Dose/AUC0-inf. 
Vz/F 
Apparent total volume of distribution at the terminal phase after 
extravascular administration, calculated as Dose/[𝜆inf × AUC0-inf]. 
𝜆inf 
Apparent terminal elimination rate constant, calculated by linear regression 
of the terminal linear portion of the log concentration vs. time curve. 
The terminal slope is calculated using the Best slope algorithm that 
sequentially fits (log(y) ~ x) from the last point of x to the previous points with 
at least 3 points. It chooses a slope with the highest adjusted R-square. If the 
difference is less then 1e-4, it picks a longer slope. x here represents the times 
of PK samples and y their observed concentrations. 
 
 
 


 
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Tabular and graphical presentation of NCA results 
 
Values for 𝜆inf, t1/2, CL/F and Vz/F, AUC0-inf for a subject will only be reported if the 
following criteria for the log-linear phase for the concentration-time data are met: 
• 
A minimum of 3 measurable concentration-timepoints during the log-linear 
portion of the terminal elimination phase, excluding Cmax. 
• 
r^2 > 0.80 for the regression of the log-concentration time data during the 
terminal elimination phase. 
• 
Negative slope for log regression fit. 
• 
Extrapolated portion of AUC0-inf < 20% of total AUC0-inf. 
 
Individual PK parameters will be reported as a table grouped by dose level with 
stratification for dose of the second treatment and overall. Individual and dose- 
normalized PK parameters (Cmax and AUCs) will be visualized by dose level for PQP 
and OZ493, separately.  
 
7.5 
SOFTWARE AND WORKING DIRECTORY 
All data processing, summary statistics, and NCA will be performed in R 3.5.1 using the 
IQRtools package 1.0.0 [IQR18]. 
7.6 
REPORTING IN MAIN BODY OF CSR 
The NCA results and key figures of the PK profiles will be reported in the main 
text of the CSR.  
 
SECTION 8: STATISTICAL METHODOLOGY FOR PHARMACODYNAMIC DATA 
8.1 
GENERAL CONSIDERATIONS 
Data listings and summary tables will be generated by CNS for the following, 
• 
Parasitaemia data  
• 
PD endpoints: 
o Parasite reduction ratio at 48 h (PRR48) and parasite clearance half-life 
(PCt1/2) 
o Percentage of subjects with recrudescence of parasitaemia  
Unless specifically mentioned otherwise, baseline is defined as the last observation 
prior to first treatment administration. If a baseline reading is missing, then an earlier 
measurement will be used. 


 
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8.2 
SOURCES OF DATA 
All parasitaemia data will be generated by the Queensland Paediatric Infectious 
Diseases (QPID) laboratory and transferred electronically to QIMR Berghofer, who will 
process the data and provide to CNS for the parastiaemia listing. 
All PD data will be generated from processed parasitaemia data. Please refer to CTM 
QIMR SOP 87 for details regarding the processing of the parasitaemia data.  
The contents of the Clinical Study Database and the processes that will be used for 
reconciliation and locking are described in more detail in the QP17C19 Data 
Management Plan.  
8.3 
DATA HANDLING 
Handling of Replicates 
The data will be recorded as triplicate parasitaemia values for each subject at each 
timepoint. These data will be summarised by calculating the arithmetic mean of the 
replicate log10 parasitaemia to obtain the geometric mean per subject and timepoint.  
Handling of Missing Data 
For any replicates that were ND, the value was substituted with 1 prior to calculating 
the geometric mean. For calculation of the PRR48 and parasite clearance half-life, if 
all replicates within a timepoint for a participant were ND, the first timepoint with all 
ND was included in model fitting, and all other timepoints were set to missing. All 
regression analyses were performed using the mean log10 parasitaemia. If no samples 
were all ND for a subject within 5 days post treatment, the last timepoint included was 
either 5 days post treatment or three timepoints after the minimum observed mean 
log10 parasitemia. 
8.4 
DATA ANALYSIS 
Parasitaemia data will be listed for all enrolled subjects and summarised for the PD 
population. Parasitaemia and PD parameters will be presented for all subjects 
included in the PD population.  
Parasitaemia profiles 
Individual parasitaemia values (parasites/mL), nominal timepoints and actual 
sampling times post-inoculation will be presented in a data listing. ND and BLQ values 
will be flagged. 
The data will be presented as average of triplicate parasitaemia values for each 
subject at each timepoint. These data are summarised by calculating the arithmetic 
mean of the replicate log10 parasitaemia to obtain the geometric mean.  


 
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Parasitaemia data will be summarised on the log10 scale by dose group with 
descriptive statistics at each scheduled timepoint.  
The following descriptive statistics will be calculated: N, mean, SD, CV%, median, 
minimum, and maximum.  
Individual parasitaemia data as well as the mean (by dose group) across time will be 
presented graphically on a log10 scale. Actual sampling times post inoculation will be 
used for the graphical presentation of data and scheduled timepoints for means. 
PD Parameters Determination  
PRR48 and parasite clearance half-life (PCt1/2 ) 
Processed parasitaemia data (refer to CTM QIMR SOP 87) is used to determine PD 
parameters.  
The data used for all model selection and fitting calculations is comprised of the 
geometric mean of parasitaemia per timepoint per subject up to the first time all 
replicates are ND. All subsequent timepoints are set to ‘missing’, regardless of whether 
parasitaemia values increased afterwards due to potential recrudescence of malaria 
infection. 
The PD responses will be estimated by calculating the optimal parasite clearance rate 
(slope coefficient from the log-linear decay regression of qPCR data) for each 
individual, as detailed in CTM QIMRB SOP 41, and Marquart et al. [7]. 
A regression modelling method, to incorporate both left and right censoring to 
remove potential lag and tail phases of the parasitaemia decay curve in a systematic 
way, will be used to determine the optimal number of data-points required to 
calculate the slope (𝛽1) of the log-linear parasitemia decay. A minimum number of 4 
timepoints will be required for regression modelling. If fewer than 4 timepoints are used 
or if the adequacy of the fit to the data is not sufficient (based on the overall model 
R² p value ≥0.001), the slope and derived parameters will be reported as missing.  
The individual PRR48 standardised to 48 hours will be derived from the regression 
modelling versus time in hours as  
𝑃𝑅𝑅48 = 10−48×𝛽1                   (1) 
The parasite clearance half-life is the transformation of the slope coefficient (per time, 
equivalent to PRR48) into a time period. The relationship between PRR48 and parasite 
clearance half-life is a simple transformation of the PRR48, as shown in Equation (2):  
𝑡½ = 𝑙𝑜𝑔10(2) × (
48 ℎ𝑜𝑢𝑟𝑠
𝑙𝑜𝑔10(𝑃𝑅𝑅48)) =
log10(2)
−𝛽1        (2) 
where the PRR48 is the parasitaemia ratio estimated over a 48 h interval that is 
subsequently transformed into a per hour clearance rate.  


 
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Individual regression plots of parasitaemia over time after treatment will be produced. 
Data listings of PRR48 and PCt1/2 will show the first, last time point and the number of 
time points used in the regression model.  
Weighted mean of regression coefficient (95% CI) of PD endpoints (log10-(Parasitemia) 
and PCt1/2 by dose group) will be plotted by dose group. 
Estimating dose group specific PRR (PRR48, D) 
Of the 𝑠 subjects with appropriate overall fit (p<0.001), the average PRR48 and 
corresponding 95% CI for each dose group is estimated by using the inverse variance 
method [9] to calculate the weighted average linear regression slope (𝛽1
̅̅̅)  and 
corresponding SE. The weighted average slope for 𝑠 subjects in the dose with 
appropriate overall fit is given by Equation (3): 
𝛽1
̅̅̅ =
∑
(𝑤𝑖×𝛽1,𝑖)
𝑠
𝑖=1
∑
𝑤𝑖
𝑛
𝑖=1 
, 𝑖= 1, …,     (3) 
where the weight is the inverse of the squared SE, 𝑤𝑖=
1
𝑆𝐸(𝛽1,𝑖)
2 . The SE of 𝛽1
̅̅̅ is estimated 
as, 𝑆𝐸(𝛽1
̅̅̅) = √
1
∑
𝑤𝑖
𝑠
𝑖=1 
 .  
Therefore, the dose group specific PRR (PRR48, D) and corresponding 95% CI is 
estimated as shown in Equation (4) and (5), respectively: 
𝑃𝑅𝑅48,𝐷= 10−48×𝛽1
̅̅̅̅                         (4) 
95% 𝐶𝐼:  10−48×(𝛽1
̅̅̅̅ ±1.96×𝑆𝐸(𝛽1
̅̅̅̅))       (5) 
 
Comparison of dose group specific PRR48s 
To determine whether there are differences between dose group specific PRR48s, an 
omnibus test for between dose group differences is used [10]. The test is used to assess 
whether there are differences in the weighted mean slope of the 𝐽 doses, using the 
test statistic shown in Equation (6) at the 5% significance level, 
𝑄𝐵= ∑
𝑤𝑗. (𝛽̅𝑗. −𝛽̅. . )
2
𝐽
𝑗=1
~𝜒𝐽−1
2
                 𝑗= 1, … , 𝐽       (6) 
 
The weight for the 𝑗𝑡ℎ dose is denoted by 𝑤𝑗. = ∑
𝑤𝑖𝑗
𝑠𝑗
𝑖=1
 for subject 𝑖 with appropriate 
overall fit in dose 𝑗. The 𝛽̅𝑗. is the weighted average slope for dose 𝑗 as defined in 
Equation (7), and 𝛽̅.. is the weighted grand mean given by: 
 


 
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𝛽̅. . =
∑
𝑤𝑗.𝛽̅𝑗.  
𝐽
𝑗=1
∑
𝑤𝑗.
𝐽
𝑗=1
         (7) 
Interim analyses of comparisons between dose-group specific PRR48s will first be 
performed for all dose groups within each cohort. Final analyses will include the 
comparison between the dose groups 1D vs. 3A, each receiving the same dose 
combination (OZ439 400 mg, PQP 640 mg). Final analyses will be performed based on 
the factorial design of the study, for the following dose groups to assess differences in 
increasing PQP dose with constant 200 mg dose of OZ439 (1A vs. 1B vs. 2B), 400 mg 
dose of OZ439 (1C vs. 1D/3A) and 800 mg dose of OZ439 (2A vs. 3B). Similarly, 
comparisons will be made to assess differences between dose groups with increasing 
OZ439 dose with constant 480 mg dose of PQP (1A vs. 1C) and 640 mg dose of PQP 
(1B vs. 1D/3A vs. 3B). Type 1 error corrections will not be performed as analyses was 
implicit by the study design. 
Post-hoc pair-wise comparisons can be calculated using the test statistic 𝑍𝐺=
𝐺
√𝑣𝐺 , 
where 𝐺 is the contrast (𝐺= 𝑐1𝛽̅1. + ⋯+ 𝑐𝐽𝛽̅𝐽) and 𝑣𝐺 is the variance of the contrast 
(𝑣𝐺=
𝑐12
𝑤1. + … +
𝑐𝐽
2
𝑤𝐽.). The p-value of the 𝐿 pair-wise comparisons will be calculated using 
the Scheffe method, by comparing 𝑍𝐺
2 to a chi-squared distribution with 𝐿−1 degrees 
of freedom. 
Recrudescence  
Recrudescence will be defined as subjects who show substantial increases in 
parasitaemia after the initial clearance and are treated with a standard course of 
Riamet® prior to the compulsory scheduled timepoint for Riamet® treatment.  
PD Parameters Analysis  
All PD parameters will be listed. Summary statistics will be produced by dose group. 
For continuous data, the number of observations, mean, SD, median, minimum and 
maximum values will be reported. The number and percentage of subjects will be 
reported for incidence data.  
8.5 
ANALYSIS SOFTWARE 
R version 3.5.0, RStudio version 1.1.447, and SAS Enterprise Guide Software version 7.12 
or more recently updated versions will be used for all data processing and analyses. 
8.6 
REPORTING 
The PD and parasitaemia results will be reported in the main text of the CSR, and will 
also be presented in listings, tables, and figures.  
 


 
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SECTION 9: PK/PD ANALYSIS 
9.1 
OVERVIEW 
A population PKPD model will be derived from the concentrations and parasitaemia 
observed in the challenge volunteers. It is achieved by sequentially developing a 
population PK model to describe the observed individual PK profiles and a population 
PD model for quantifying the relationship of plasma concentrations and the parasite 
clearance. The model building is supported by PK/PD data from studies QP12C10 and 
QP13C05 for OZ439 and PQP mono treatment in healthy volunteers. 
The final model will be employed to simulate patients of the OZ439 mono study 12_006 
and the OZ439/PQP combo study 13_003. Predictions of the ACPR28 will be used to 
evaluate the predictive power of the human challenge model by comparing the 
simulations with the observed ACPR28 in clinical trials 12_006 and 13_003. 
9.2 
SOURCES OF DATA 
9.3 
DATA HANDLING 
Data from studies QP12C10, QP13C05 and QP17C19 will be pooled. The data set will 
contain information on the individual OZ439/PQP doses, OZ439 PK concentrations, 
PQP PK concentrations, the triplicated parasitemia levels and typical covariates such 
as age, height, weight, sex and race. 
Data assembly 
First a master dataset will be assembled formatted according to the MMV dataset 
standard (cf., "MS_IQdataset_V1.docx"). Plasma concentrations will be in µg/mL, total 
parasite levels in counts/mL, and doses in mg. Parasite data after the first 
administration of rescue medication is flagged by setting the IGNORE column to 
"Observations after rescue medication". The time in hours is relative to the OZ439/PQP 
administration time. Total counts of parasites for which counts of gametocytes 
exceeded 10% of total counts are flagged to be ignored (by setting the column 
IGNORE to "gametocytes") If the lab providing the parasitemia data marks records as 
(mainly) gametocytes the values are set to half of the LLOQ. 
 
A general analysis dataset is derived from the master dataset. The general analysis 
dataset will contain the following observations: OZ439 plasma concentrations, PQP 
plasma concentrations, and total counts of parasites. Values of replicate 
measurement and their geometric means are contained for the parasite counts. In 
addition, dosing records for P. falciparum inoculation, OZ439/PQP administration, and 
rescue medication administration will be defined. It is advised to define additional 
columns DOSELEVEL1 and DOSELEVEL2 to indicate the dose amounts of OZ439 and 
PQP a subject received as covariate columns. 


 
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Nonlinear mixed effects (NLME) datasets for the PK and PD modelling will be derived 
from the general dataset. 
PK modelling data set 
Observations below the lower limit of quantification (LLOQ) will be censored by setting 
the CENS column for these observation records to 1 and setting the corresponding 
dependent variable (DV) column to the LLOQ (→ M3 method). Observation records 
with missing values and records with missing times will be ignored. Records flagged to 
be ignored will be removed from the dataset. Observations not analysed in the PK 
modelling (i.e., all parasite count records) will be removed. 
As a result, the PK modelling dataset only contains OZ439/PQP dosing records and 
OZ439/PQP plasma concentration records. 
PD modelling data set 
Observations below the LLOQ will be censored by setting the CENS column for these 
observation records to 1 and the corresponding DV value to the LLOQ, i.e., 10 p/mL 
(→ M3 method). Total counts of parasites for which counts of gametocytes exceeded 
10% of total counts are flagged to be ignored (by setting the column IGNORE to 
"gametocytes"). If the lab providing the parasitaemia data marks records as (mainly) 
gametocytes the values are set to half of the LLOQ. Observation records with missing 
values and records with missing times will be ignored. Records flagged to be ignored 
will be removed from the dataset. Observations not analysed in the PD modelling 
analysis (i.e., concentration records) will be removed. 
 
As a result, the PD modelling dataset only contains only OZ439/PQP dosing records 
and total parasite counts (i.e., cleaned replicate means). The total parasite counts 
will be log-transformed for the PD modelling and estimated individual PK model 
parameters will be added to the dataset as regressors. For a correct estimation of the 
model baseline parasitaemia value that is defined as the value at the first observation 
for each subject, the first observation time needs to be similar across the subject to 
ensure that the baseline values are at similar values. Hence, the first modelled 
observation time is a timepoint at which the observed parasitaemia value is available 
for all subjects. All previous timepoints will be removed. 
 
 


 
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9.4 
METHODS 
Model building 
General PKPD model building approach 
Population models of the PK and PD will be developed in step-wise manner. 
1. 
An NLME model for the PK (OZ439, PQP and combinations) will be developed to 
obtain individual PK parameter estimates based on which the individual PK 
profiles are described well. 
2. 
The PKPD population model for OZ439 mono treatment will be built sequentially. 
That is, a PK model will be developed first. Second, using the individual PK 
parameter estimates as regression parameters and estimating the PD part of the 
model only. Estimation of typical and individual PD parameters will first be 
performed with IQRtools SysFit to investigate model identifiability and second with 
Monolix to additionally estimate inter-individual variability (IIV). 
3. 
The PKPD population model for PQP mono treatment will be built using the 
individual PK parameter estimates as regression parameters and estimating the 
PD part of the model only. Estimation of typical and individual PD parameters will 
first be performed with IQRtools SysFit to investigate model identifiability and 
second with Monolix to additionally estimate IIV. 
4. 
The parasitaemia base line levels and parasite growth rate (PD parameters) in 
the absence of the drug will be estimated from the total parasite counts of the 
OZ439/PQP combo study QP17C19 before treatment. Estimation of typical and 
individual PD parameters will be performed with IQRtools SysFit. 
5. 
The PKPD model for the OZ439/PQP combo study will be built using the 
– 
individual PK parameter estimates as regression parameters, 
– 
individual growth rate and base line parasitaemia values as regression 
parameters, 
– 
typical Emax, EC50 and Hill parameter values of OZ439 and PQP as fixed 
parameters from the mono PD models (Monolix), 
– 
IIV values for and Emax, EC50 of OZ439 and PQP as fixed parameters from 
the mono PD models (Monolix). 
– 
Individual PD parameters and drug-drug interaction parameters will first be 
estimated using IQRtools SysFit to investigate identifiability of multiple drug-
drug interaction models. Second, considering the identifiability analysis, 
Monolix will be used to estimate individual parameters for selected 
models. 
For both PK (NLME with Monolix) and PD (IQRtools SysFit), IIV is implemented for 
normally distributed parameters using the following equation with 𝛩0 as population 
average parameter, 𝛩𝑖 as individual parameter, and 𝜂𝑖 as random effect that is 
distributed normally around zero (𝜂𝑖∼𝑁(0, 𝜔2)): 


 
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𝛩𝑖= 𝛩0 + 𝜂𝑖. 
The following equation is used for log-normally distributed parameters: 
ln(𝛩𝑖) = ln(𝛩0) + 𝜂𝑖. 
Continuous covariates on log-normally distributed parameters will be implemented 
as follows: 
𝛩𝑖= 𝛩0 ⋅(
𝐶𝑂𝑉𝑖
𝐶𝑂𝑉𝑚𝑒𝑑𝑖𝑎𝑛
)
𝛽
⋅𝜂𝑖. 
𝛩𝑖 represents the individual parameter, 𝛩0 the population mean value, 𝐶𝑂𝑉𝑖 the 
individual covariate value, 𝐶𝑂𝑉𝑚𝑒𝑑𝑖𝑎𝑛, the population median covariate value, 𝛽 the 
covariate coefficient, and 𝜂𝑖 the individual random effect. 
 
 


 
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Categorical covariates on log-normally distributed parameters will be implemented 
as follows. 
𝛩𝑖= 𝛩0 ⋅∑(𝑒𝛽𝑗⋅𝐶𝑂𝑉𝑖𝑗)
𝑗
⋅𝜂𝑖 
The individual covariate values 𝐶𝑂𝑉𝑖𝑗 are 1 if subject i belongs to the jth category of 
the covariate and 0 otherwise. 𝛽𝑗 is the covariate value for the jth category. For one 
category, i.e. the reference, 𝛽𝑗 is 0. 
For the NLME PK modelling, the log-likelihood and the Fisher information matrix will be 
approximated by linearization. The number of iterations in the burn-in and the 
accumulation phase will be 500 and 200 respectively, but might be adjusted if 
required based on inspection of parameter estimate and objective function traces 
along estimation iterations. Individual parameters will be determined as conditional 
modes. 
For PD modelling, the IQRtools SysFit implementation using a non-linear fixed-effects 
modelling approach is employed. Typical and individual parameters are both treated 
as fixed effects. The parameterization of individual parameters and covariates is fully 
consistent with the NLME parameterization above. The variances 𝜔2 of NLME random 
effects are accounted for by quadratic priors, 𝑙𝑝𝑟𝑖𝑜𝑟(𝜂) =
1
2
𝜂2
𝜔2 , added to the log-
likelihood function, where the values for 𝜔2  are fixed and the 𝜂 parameters are 
estimated. 
The profile-likelihood method [RAU09, KAS16] is used to compute confidence intervals 
of the parameters estimated with the SysFit approach. 
Model evaluation 
Assessment of model adequacy and decisions about increasing model complexity 
will be driven by the data and guided by goodness-of-fit criteria, including 
1. visual inspection of diagnostic scatter plots (observed vs. predicted 
concentration, residual/weighted residual vs. predicted concentration or time 
and histograms of individual random effects, for example), 
2. successful convergence of the minimization routine with at least 2 significant 
digits in parameter estimates, 
3. plausibility of parameter estimates, 
4. precision of parameter estimates, 
5. correlation between model parameter estimation errors<0.95, and 
6. the Bayesian information criterion, given the minimum objective function value 
and number of estimated parameters. 
For the nonlinear fixed effects models, additional diagnostic plots will be produced: 
7. objective function values across multiple fits from randomised initial guesses, 
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8. profile likelihood plots 
All parameter estimates will be reported with a measure of estimation uncertainty, 
such as the standard error of the estimates. The individual PK fits will be used to 
evaluate the adequacy to use the individual PK parameter estimates as regression 
parameters for PD modelling. 
The adequacy of simulation with the final models will be evaluated by visual 
predictive checks. Visual predictive checks for each dose level will be performed by 
simulation of the study 200 times taking parameter estimation uncertainty into 
account. 95%-confidence intervals for the 5th percentile, the median, and the 95th 
percentile will be derived and compared to the corresponding values based on the 
data. 
To compare simulations of the final model with patient data, both, the data and the 
simulation will be transformed into a life table format indicating for each individual the 
time of recrudescence, i.e., the time at which parasite levels re-occur after being BLQ 
or the time for which parasitaemia levels are minimum, or, if not defined, the last 
observed time point without recrudescence. The Kaplan-Meier estimator [KAP58, 
THE15, TER00] will be used to compare model and data.  
PK modelling 
The PK of OZ439/PQP will be modelled using compartmental models describing the 
absorption after oral administration, distribution between central and peripheral 
compartments, and the elimination from the central compartment. The visual data 
analysis will guide the selection of models that will be tested (e.g., with respect to 
number of compartments, linear or saturable elimination, absorption kinetics and error 
model). 
The allometric function will be used to include the impact of weight (𝑊𝐺𝑇) on the 
clearance rate (𝐶𝐿) and central compartment volume (𝑉𝑐): 
𝐶𝐿𝑖
=
𝐶𝐿⋅(
𝑊𝐺𝑇𝑖
𝑊𝐺𝑇𝑚𝑒𝑑𝑖𝑎𝑛
)
0.75
𝑉𝑐𝑖
=
𝑉𝑐⋅(
𝑊𝐺𝑇𝑖
𝑊𝐺𝑇𝑚𝑒𝑑𝑖𝑎𝑛
)
1.00
.
 
The same relation as for 𝐶𝐿 will be used for the inter-compartmental clearance rate 
𝑄1 and, if a third compartment is required, 𝑄2. The same relation as for 𝑉𝑐 will be used 
for the peripheral volume 𝑉𝑝1 and, if a third compartment is required, 𝑉𝑝2. The 
previous analysis of the OZ439 mono study QP12C10 (human challenge) has revealed 
that the dose amount might be a significant covariate for the clearance rate. The PK 
model is supposed to be used in simulations of patients, including children. Therefore, 
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amount could lead to significantly different drug exposure, depending on the 
clearance that relates to weight. To correctly account for exposure, a new covariate  
𝐴𝑈𝐶= 𝐷𝑜𝑠𝑒𝑎𝑚𝑜𝑢𝑛𝑡
𝑊𝑒𝑖𝑔ℎ𝑡0.75  
is derived from the base covariates and will be included when testing covariates. 
More covariates will be included if appropriate. It will be tested whether including 
interaction terms for the impact of one compound on the clearance of the other 
leads to a better description of the data. 
PD modelling 
As a general concept, the changes in living parasite 𝑃 are modeled as the effect of 
a net exponential growth rate 𝐺𝑅 and a killing or clearance rate 𝐾𝑖𝑙𝑙 due to 
OZ439/PQP with an initial parasitemia level 𝑃𝑏𝑎𝑠𝑒 at time 𝑡0 (time of first observation). 
The equations are expressed on the log-scale such as 
𝑑𝑃𝐿
𝑑𝑡
=
𝐺𝑅−𝐾𝑖𝑙𝑙
𝑃𝐿(𝑡0)
=
𝑃𝐿𝑏𝑎𝑠𝑒,
 
where 𝑃𝐿= ln(𝑃) is the log-transformed parasite counts.  The killing rate 𝐾𝑖𝑙𝑙= 𝐾𝑖𝑙𝑙1 +
𝐾𝑖𝑙𝑙2 is composed of contribution from OZ439 (index 1) and PQP (index 2). The killing 
rate of each drug is described by an Emax model. The Emax model assumes a direct 
effect of concentrations on parasite killing/clearance, such as: 
𝐾𝑖𝑙𝑙1
=
𝐸𝑀𝐴𝑋1 ⋅
𝐶𝑐1
𝐻𝑖𝑙𝑙1
𝐶𝑐1
𝐻𝑖𝑙𝑙1 + 𝐸𝐶501
𝐻𝑖𝑙𝑙1
𝐾𝑖𝑙𝑙2
=
𝐸𝑀𝐴𝑋2 ⋅
𝐶𝑐2
𝐻𝑖𝑙𝑙2
𝐶𝑐2
𝐻𝑖𝑙𝑙2 + 𝐸𝐶502
𝐻𝑖𝑙𝑙2
 
Here, 𝐶𝑐 is the concentration in the central compartment, 𝐸𝑀𝐴𝑋 is the maximum 
effect of the drug, 𝐸𝐶50 is the concentration that results in 50% of the maximum effect 
and 𝐻𝑖𝑙𝑙 is the Hill coefficient. 
Two alternative models to combine the killing effect of each drug are considered. 
First, a so-called empirical Bliss independence approach is applied. The kill is modelled 
as sum of the single effects and an interaction term that is the scaled product of the 
single effect and an interaction coefficient γ. 
𝐾𝑖𝑙𝑙= 𝐾𝑖𝑙𝑙1 + 𝐾𝑖𝑙𝑙2 + 𝛾∙
𝐶𝑐1
𝐻𝑖𝑙𝑙1
𝐶𝑐1
𝐻𝑖𝑙𝑙1 + 𝐸𝐶501
𝐻𝑖𝑙𝑙1
𝐶𝑐2
𝐻𝑖𝑙𝑙2
𝐶𝑐2
𝐻𝑖𝑙𝑙2 + 𝐸𝐶502
𝐻𝑖𝑙𝑙2 min(𝐾𝑖𝑙𝑙1, 𝐾𝑖𝑙𝑙2) 
 
Second, an additive effect of both drugs on the killing rate is assured, 𝐾𝑖𝑙𝑙= 𝐾𝑖𝑙𝑙1 +
𝐾𝑖𝑙𝑙2. However, the Emax and EC50 values employed in the killing contributions can be 
affected by the other drug. In the analysis, two drug-drug interaction models will be 
used to describe the effect one drug exerts on the EC50 and Emax of the other drug: a 
mutual and a non-mutual model.  


 
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The non-mutual model states that 
𝐸𝐶501
∗
=
𝐸𝐶501 (1 + (𝑒−𝛼21 −1)
𝐶𝑐2
𝐻𝑖𝑙𝑙2
𝐸𝐶502
𝐻𝑖𝑙𝑙2 + 𝐶𝑐2
𝐻𝑖𝑙𝑙2)
𝐸𝐶502
∗
=
𝐸𝐶502 (1 + (𝑒−𝛼12 −1)
𝐶𝑐1
𝐻𝑖𝑙𝑙1
𝐸𝐶501
𝐻𝑖𝑙𝑙1 + 𝐶𝑐1
𝐻𝑖𝑙𝑙1)
𝐸𝑀𝐴𝑋1
∗
=
𝐸𝑀𝐴𝑋1 (1 + (𝑒𝛽21 −1)
𝐶𝑐2
𝐻𝑖𝑙𝑙2
𝐸𝐶502
𝐻𝑖𝑙𝑙2 + 𝐶𝑐2
𝐻𝑖𝑙𝑙2)
𝐸𝑀𝐴𝑋2
∗
=
𝐸𝑀𝐴𝑋2 (1 + (𝑒𝛽12 −1)
𝐶𝑐1
𝐻𝑖𝑙𝑙1
𝐸𝐶501
𝐻𝑖𝑙𝑙1 + 𝐶𝑐1
𝐻𝑖𝑙𝑙1) .
 
Hence, the modified EC50 or Emax for one drug is the original value scaled by a factor 
that is modulated by the other drug concentration. In short, 𝛼≥0 decreases the EC50 
and 𝛽≥0 increases the Emax. 
The mutual model assumes that 𝛼12 = 𝛼= 𝛼21 and 𝛽12 = 𝛽= 𝛽21. Thereby, the number 
of interaction parameters is reduced from 4 to 2 in the mutual model. 
IIV will be assumed on all parameters except the Hill coefficient and the interaction 
parameters. Parameters are assumed to be log-normally distributed besides the log-
transformed parasite baseline value for which the normal distribution was assumed. 
The standard deviation of the IIV will be fixed to 0.2 for the SysFit approach. When 
parameters are estimated with Monolix, standard deviations of the IIV will be 
estimated. 
Using the SysFit approach for PD modelling, parameter estimation will be started from 
24 initial guesses. Identifiability of the best fit will be analysed using the profile likelihood 
method. In case, several local optima with similar objective value are found, those 
local optima will be investigated and it will be checked using modelling, if additional 
cohorts could help to reduce the number of local optima. 
Using Monolix, optimization will be initialized with the estimated values obtained with 
SysFit. If optimization with Monolix poorly converges for some of the parameters as 
being assessed by the Monolix convergence traces, these values will be fixed to the 
value obtained with SysFit. 
Simulations to predict ACPR28 in patients 
Simulations of patients will build on the patient characteristics found in the 12_006 and 
13_003 studies. Simulations will be performed as if patient PK and PD information was 
completely missing. Only covariates such as weight, actual dose, expected exposure 
and parasitaemia levels at 𝑡= 0 (shortly before treatment) will be used. 
 


 
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For each dose group, n = 200 patients will be randomly drawn with replacement. 
Individual parameters will be sampled from the IIV estimated by Monolix, taking 
covariates of the randomly chosen patients into account. 
 
Individuals in each dose group will be simulated at densely sampled time points 
between 0 and 1600 hours. Initial values for the parasitaemia simulation will be fixed 
to the parasitaemia level of the selected patient. 
The simulated time-course will be translated to a life table containing the information 
about the time to recrudescence. The Kaplan-Meier estimator will be used to derive 
the recrudescence rate at every time point and the probability of recrudescence  as 
(1-recrudescence rate)x100%. 
9.5 
ANALYSIS SOFTWARE AND WORKING DIRECTORY 
All data processing, analysis, model setup and modelling result analysis including 
goodness-of-fit plots will be performed in R 3.5.1 using the IQRtools package 1.0.0 
[IQR18]. 
NLME modelling will be performed with Monolix 2018R2 [MLX18] using Stochastic 
Approximation Expectation Maximization (SAEM) for parameter estimation. For PD 
modelling where typically the variance of random-effects cannot be estimated from 
the data, the IQRtools SysFit approach [KAS16] will be used to estimate typical and 
individual PD parameters. 
A library of functions related to the analysis of PKPD studies of antimalarials may be 
used (available at https://github.com/IntiQuan/iqrmalaria). 
9.6 
REPORTING 
The analysis results will be reported in the main body of the CSR and technical details 
will be reported as an appendix (referred to here as the ‘technical appendix’). The 
technical appendix will include the clinical data used in the analysis, data assembly, 
modelling methods, all results, discussions, and conclusions. 
Key results will include description and interpretation of the final model, parameter 
estimates, and diagnostic plots of goodness-of-fit and simulations and will be included 
in the main text. Limitations of the model prediction will be discussed in the Discussion 
section of the technical appendix and mentioned in the main text of the CSR. 
 
 


 
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LITERATURE REFERENCES  
1. WHO, 2017. 
2. Dondorp, A.M., et al., Artemisinin resistance in Plasmodium falciparum 
malaria. New England Journal of Medicine, 2009. 361(5): p. 455–467. 
3. Woodrow, C.J. and N.J. White, The clinical impact of artemisinin resistance in 
Southeast Asia and the potential for future spread. FEMS Microbiol Rev, 2017. 
41(1): p. 34-48. 
4. Straimer, J., et al., Drug resistance. K13-propeller mutations confer artemisinin 
resistance in Plasmodium falciparum clinical isolates. Science, 2015. 
347(6220): p. 428-31. 
5. Burrows, J.N., et al., New developments in anti-malarial target candidate and 
product profiles. Malar J, 2017. 16(1): p. 26. 
6. Phyo, A.P., et al., Antimalarial activity of artefenomel (OZ439), a novel 
synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum 
and Plasmodium vivax malaria: an open-label phase 2 trial. Lancet Infect Dis, 
2016. 16(1): p. 61-69. 
7. Marquart L, Baker M, O’Rourke P, McCarthy JS, 2015, Evaluating the 
pharmacodynamic effect of antimalarial drugs in clinical trials by quantitative 
PCR, Antimicrobial Agents and Chemotherapy 59(7): 4249-59. 
8. Beal SL. 2001. Ways to fit a PK model with some data below the quantification 
limit. Journal of Pharmacokinetics and Pharmacodynamics 28:481-504. 
9. Hartung J, Knapp G, Sinha B. 2008. Methods of combining effect sizes, 
Statistical meta-analysis with applications. John Wiley & Sons, Inc., Hoboken, 
NJ, USA. 
10. Konstantopoulos S, Hedges LV. 2009. Analysing effect sizes: Fixed-effects 
models, p 279-294. In Cooper H, Hedges LV, Valentine JC (ed), The Handbook 
of Research Synthesis and Meta-Analysis, Second ed. Russell Sage 
Foundation, New York. 
11. Rockett RJ, Tozer SJ, Peatey C, Bialasiewicz S, Whiley DM, Nissen MD, 
Trenholme K, McCarthy JS, Sloots TP. 2011. A real-time, quantitative PCR 
method using hydrolysis probes for the monitoring of Plasmodium falciparum 
load in experimentally infected human volunteers. Malaria Journal 10:48 
12. R Core Team. R: A language and environment for statistical computing. 
Vienna, Austria: R Foundation for Statistical Computing; 2013. 
13.  Kaizer RJ, Jansen RS, Rosing H, Thijsen B, Beijnen JH, Schellens JHM, Huitema 
ADR. 2015. Incorporation of concentration data below the limit of 
quantification in population pharmacokinetic analyses. Pharmacology 
Research & Perspectives 3(2):1-15. 
14. PhUSE CSS Development of Standard Scripts for Analysis and Programming 
Working Group. 2014, March 25. Analyses and displays associated to non-
compartmental pharmacokinetics – with a focus on clinical trials. Retrieved 
from: 
http://www.phusewiki.org/wiki/images/e/ed/PhUSE_CSS_WhitePaper_PK_final
_25March2014 
15. [FOR04] Foracchia M, Hooker AC, Vicini P, Ruggeri A (2004). "POPED, a 
software for optimal experiment design in population kinetics." Computer 
Methods and Programs in Biomedicine, 74. 


 
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16. [IQR18] https://www.intiquan.com/iqr-tools/ 
17. [KAP58] Kaplan, E. L.; Meier, P. (1958). "Nonparametric estimation from 
incomplete observations". J. Amer. Statist. Assoc. 53 (282): 457–481. 
doi:10.2307/2281868. JSTOR 2281868. 
18. [KAS16] Kaschek D, Mader W, Fehling-Kaschek M, Rosenblatt M, Timmer J. 
"Dynamic modelling, parameter estimation and uncertainty analysis in R." 
bioRxiv. 2016 Jan 1:085001. 
19. [MAC17] Macintyre F, Adoke Y, Tiono AB, Duong TT, Mombo-Ngoma G, 
Bouyou-Akotet M, Tinto H, Bassat Q, Issifou S, Adamy M, Demarest H. "A 
randomised, double-blind clinical phase II trial of the efficacy, safety, 
tolerability and pharmacokinetics of a single dose combination treatment 
with artefenomel and piperaquine in adults and children with uncomplicated 
Plasmodium falciparum malaria." BMC medicine. 2017 Dec;15(1):181. 
20. [MLX18] http://lixoft.com/ 
21. [NYB12] Nyberg J, Ueckert S, Stroemberg EA, Hennig S, Karlsson MO, Hooker 
AC (2012). "PopED: An extended, parallelized, nonlinear mixed effects models 
optimal design tool." Computer Methods and Programs in Biomedicine, 108. 
22. [RAU09] Raue A, Kreutz C, Maiwald T, Bachmann J, Schilling M, Klingmüller U, 
Timmer J. "Structural and practical identifiability analysis of partially observed 
dynamical models by exploiting the profile likelihood." Bioinformatics. 2009 Jun 
8;25(15):1923-9. 
23. [THE15] Therneau T (2015). A Package for Survival Analysis in S. version 2.38, 
https://CRAN.R-project.org/package=survival. 
24. [TER00] Terry M. Therneau, Patricia M. Grambsch (2000). Modelling Survival 
Data: Extending the Cox Model. Springer, New York. ISBN 0-387-98784-3. 
 
 


 
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APPENDIX 1: PLANNED LISTINGS 
The following listings are planned to be generated for the QP17C19 study (note: 
Numbering is indicative only and may be updated based on CSR requirements): 
 
Listing Number 
Listing Title 
Population 
16.2.1 Subject Disposition 
 
Listing16.2.1.1 
Study Enrolment and 
Completion/Discontinuation  
All Enrolled 
 
Listing16.2.1.2 
Visit Dates 
All Enrolled 
 
Listing 16.2.1.3 
Dose Group Assignment 
All Enrolled 
16.2.2 Protocol Deviations 
 
Listing16.2.2.1 
Protocol Deviations 
All Enrolled 
 
16.2.3 Subject Excluded from Analyses 
 
 
Listing16.2.3.1 
Analysis Population Assignment 
All Enrolled 
 
Listing16.2.3.2 
Subjects Excluded from Any Analysis Set(s) 
All Enrolled 
16.2.4 Demographic and Other Baseline Data 
 
Listing16.2.4.1 
Demography 
All Enrolled 
Listing16.2.4.2 
Inclusion and Exclusion Criteria 
All subjects 
 
Listing16.2.4.3 
Medical History 
All Enrolled 
 
Listing16.2.4.4 
Pregnancy Test 
All Enrolled 
 
Listing16.2.4.5 
Follicle Stimulating Hormone (FSH) Test 
All Enrolled 
 
Listing16.2.4.6 
RBC Alloantibody 
All Enrolled 
 
Listing16.2.4.7 
Serology and Special Tests 
All Enrolled 
 
Listing16.2.4.8 
Urine Drug Screen and Alcohol Breath Test 
All Enrolled 
 
Listing 16.2.4.9 
Glucose-6-Phosphate Dehydrogenase 
(G6PD) 
All Enrolled 
 
Listing 16.2.4.10 
Beck Depression Inventory (BDI) 
All Enrolled 
 
Listing 16.2.4.11 
Body Weight, Height and Body Mass Index 
(BMI) 
All Enrolled 
 
Listing 16.2.4.12.1 
Prior Medications 
All Enrolled 


 
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Listing Number 
Listing Title 
Population 
 
Listing 16.2.4.12.2 
Concomitant Medications 
All Enrolled 
 
16.2.5 Compliance and Drug Concentration Data 
 
Listing16.2.5.1 
Malaria Inoculum Administration 
All Enrolled 
 
Listing16.2.5.2 
IMP Administration 
All Enrolled 
 
Listing16.2.5.3 
Rescue Medication Administration 
All Enrolled 
 
Listing16.2.5.4 
Blood Collection for PK Assessments, and 
measured OZ439 and PQP plasma 
concentrations 
 
All Enrolled 
 
Listing16.2.5.5 
Pharmacokinetic (PK) Parameters 
PK 
 
16.2.6 Individual Parasitaemia and Pharmacodynamic Data  
 
Listing16.2.6.1 
qPCR 18S Daily 
All Enrolled 
 
Listing16.2.6.2 
qRT-PCR pfs25 Daily 
All Enrolled 
 
Listing16.2.6.3 
qRT-PCR pfs25 Retrospective 
All Enrolled 
 
Listing16.2.6.4 
Pharmacodynamic (PD) endpoints 
(log10PRR48, PCt1/2, subject recrudescence) 
PD 
 
16.2.7 Adverse Event Data 
 
Listing16.2.7.1 
All Adverse Events  
All Enrolled 
 
Listing16.2.7.2 
Serious Adverse Events  
All Enrolled 
 
Listing16.2.7.3 
Adverse Events of Special Interest (AESIs) 
All Enrolled 
 
Listing16.2.7.4 
Deaths 
All Enrolled 
 
16.2.8 Laboratory Data 
 
Listing16.2.8.1.1 
Individual Haematology Results  
All Enrolled 
 
Listing16.2.8.1.2 
Individual Abnormal Haematology Results  
All Enrolled 
 
Listing16.2.8.2.1 
Individual Biochemistry Results 
All Enrolled 
 
Listing16.2.8.2.2 
Individual Abnormal Biochemistry Results  
All Enrolled 
 
Listing16.2.8.3.1 
Individual Urinalysis Results (Dipstick) 
All Enrolled 
 
Listing16.2.8.3.2 
Individual Abnormal Urinalysis Results 
(Dipstick) 
All Enrolled 


 
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Listing Number 
Listing Title 
Population 
 
Listing16.2.8.4.1 
Individual Urine Microscopy Results  
All Enrolled 
 
Listing16.2.8.4.2 
Individual Abnormal Urine Microscopy 
Results  
All Enrolled 
 
16.4 Other Safety Data 
 
Listing16.4.1 
Vital Signs  
All Enrolled 
 
Listing16.4.2 
Individual Abnormal Vital Signs 
All Enrolled 
 
Listing16.4.3 
ECG Parameters and Changes from Baseline 
All Enrolled 
 
Listing16.4.4 
Abnormal ECG Findings 
All Enrolled 
 
Listing16.4.5  
Physical Examination 
All Enrolled 
 
Listing16.4.6 
Malaria Clinical Score 
All Enrolled 
 
Listing16.4.7 
Additional Comments 
All Enrolled 
 
 
 
 


 
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APPENDIX 2: PLANNED SUMMARY TABLES 
The following tables are planned to be generated for the QP17C19 study (note: 
Numbering is indicative only and may be updated based on CSR requirements): 
 
Table Number 
Table Title 
Population 
14.1 Demographic Data 
 
Table14.1.1 
Study Participation and Disposition 
All Enrolled 
Table14.1.2 
Demographics and Baseline 
Characteristics 
 All enrolled  
 
Table14.1.3 
IMP Administration 
All Enrolled 
 
Table14.1.4 
Analysis Population 
All Enrolled 
14.2 Pharmacokinetic, Parasitaemia, and Pharmacodynamic Data 
 
 
Table14.2.1 
Summary of OZ439 and PQP 
concentrations in plasma by timepoint 
and by dose group 
PK 
 
Table14.2.2 
Summary of PK endpoints by dose 
group 
PK 
 
Table14.2.3 
Summary of qPCR 18S Daily 
measurements by timepoint and by 
dose group 
PD 
 
Table14.2.4 
Summary of PD endpoints by dose 
group 
PD 
 
Table 14.2.5 
Treatment comparison across dose 
groups based on QB test for between-
treatment differences of weighted 
slope 
PD 
 
Table14.2.6 
Final PK parameter estimates 
PK 
 
Table14.2.7 
Final PD parameter estimates 
PKPD 
14.3 Safety Data 
 
Table14.3.1.1a 
Overall Summary of Inoculum-
Emergent Adverse Events  
Inoculum 
 
Table14.3.1.1b 
Overall Summary of Treatment-
Emergent Adverse Events  
Safety 
 
Table14.3.1.2a 
Inoculum-Emergent Adverse Events by 
MedDRA System Organ Class and 
Preferred Term  
Inoculum 


 
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Table Number 
Table Title 
Population 
 
Table14.3.1.2b 
Treatment-Emergent Adverse Events 
by MedDRA System Organ Class and 
Preferred Term 
Safety 
Table14.3.1.3a 
Inoculum-Related Inoculum-Emergent 
Adverse Events  by MedDRA System 
Organ Class and Preferred Term 
Inoculum 
 
Table14.3.1.3b 
IMP-Related Treatment-Emergent 
Adverse Events by MedDRA System 
Organ Class and Preferred Term 
Safety 
 
Table14.3.1.4a 
Inoculum-Emergent Adverse Events by 
MedDRA System Organ Class, 
Preferred Term and Maximum Severity  
Inoculum 
 
Table14.3.1.4b 
Treatment-Emergent Adverse Events 
by MedDRA System Organ Class, 
Preferred Term and Maximum Severity 
Safety 
 
Table14.3.1.5a 
Overall Summary of Inoculum-
Emergent AESIs 
Inoculum 
 
Table14.3.1.5b 
Overall Summary of Treatment-
Emergent AESIs  
Safety 
 
Table14.3.1.6a 
Inoculum-Emergent Adverse Events by 
MedDRA Preferred Term 
Inoculum 
 
Table14.3.1.6b 
Treatment-Emergent Adverse Events 
by MedDRA Preferred Term 
Safety 
 
Table14.3.2a 
Malaria Clinical Score and Change 
from Baseline 
Inoculum 
 
Table14.3.2b 
Malaria Clinical Score and Change 
from Baseline 
Safety 
 
14.3.4 Clinical Laboratory Data 
 
 
Table14.3.4.1a 
Haematology Results and Change 
from Baseline (Inoculum)  
Inoculum 
 
Table14.3.4.1b 
Haematology Results and Change 
from Baseline (IMP)  
Safety 
 
Table14.3.4.2a 
Biochemistry Results and Change from 
Baseline (Inoculum)  
Inoculum 
 
Table14.3.4.2b 
Biochemistry Results and Change from 
Baseline (IMP)  
Safety 
 
Table14.3.4.3a 
Cross-Tabulation of Haematology 
Abnormalities Versus Baseline 
(Inoculum) 
Inoculum 


 
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Table Number 
Table Title 
Population 
 
Table14.3.4.3b 
Cross-Tabulation of Haematology 
Abnormalities Versus Baseline (IMP) 
Safety 
 
Table14.3.4.4a 
Cross-Tabulation of Biochemistry 
Abnormalities Versus Baseline 
(Inoculum) 
Inoculum 
 
Table14.3.4.4b 
Cross-Tabulation of Biochemistry 
Abnormalities Versus Baseline (IMP) 
Safety 
 
14.3.5 Vital Signs 
 
 
Table14.3.5.1a 
Vital Signs Results and Change from 
Baseline (Inoculum)  
Inoculum 
Table14.3.5.1b 
Vital Signs Results and Change from 
Baseline (IMP)  
Safety 
 
Table14.3.5.2a 
Abnormal Vital Signs Results (Inoculum) 
Inoculum 
 
Table14.3.5.2b 
Abnormal Vital Signs Results (IMP) 
Safety 
 
14.3.6 ECG Findings 
 
 
Table14.3.6.1a 
ECG parameters and Change from 
Baseline (Inoculum)  
Inoculum 
 
Table14.3.6.1b 
ECG parameters and Change from 
Baseline (IMP)  
Safety 
 
Table14.3.6.2a 
Abnormal ECG Results (Inoculum) 
Inoculum 
 
Table14.3.6.2b 
Abnormal ECG Results (IMP) 
Safety 
 
Table14.3.6.3a 
ECG Clinical Assessment (Inoculum) 
Inoculum 
 
Table14.3.6.3b 
ECG Clinical Assessment (IMP) 
Safety 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX 3: PLANNED SUMMARY FIGURES 
The following figures are planned to be generated for the QP17C19 study (note: 
Numbering is indicative only and may be updated based on CSR requirements): 
 
Figure Number 
Figure Title 
Population 
14.2 PK and PK Data 
 
Figure 14.2.1.1 
Arithmetic mean (SD) concentration 
time-profiles by dose group 
PK 
Figure 14.2.1.2 
Geometric mean (SD) concentration 
time-profiles by dose group 
PK 
Figure 14.2.1.3.1 
Overlaying individual concentration-
time profiles (Linear) 
PK 
Figure 14.2.1.3.2 
Overlaying individual concentration-
time profiles (Semi-log) 
PK 
Figure 14.2.1.4.1 
Individual concentration-time profiles 
(Linear) 
PK 
Figure 14.2.1.4.2 
Individual concentration-time profiles 
(Semi-log) 
PK 
Figure 14.2.1.5.1 
Individual PQP AUC/Cmax by dose 
group 
PK 
Figure 14.2.1.5.2 
Individual Dose-Normalized PQP 
AUC/Cmax by Dose Group 
PK 
Figure 14.2.1.6.1 
Individual OZ493 AUC/Cmax by dose 
group 
PK 
Figure 14.2.1.6.2 
Individual Dose-Normalized OZ493 
AUC/Cmax by dose group 
PK 
Figure 14.2.2.1 
Geometric Mean (SD) log10-
parasitaemia time profiles 
PD 
Figure 14.2.2.2 
Individual log10-parasitemia time 
profiles 
PD 
Figure 14.2.2.3 
Individual log10-parasitemia regression 
fit  
PD 
Figure 14.2.2.4 
Weighted mean of regression 
coefficient (95% CI) PD endpoints by 
dose group 
PD 
Figure 14.2.3.1 
Scatter plot of observations versus 
predictions of log10(parasitemia) 
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Figure Number 
Figure Title 
Population 
Figure 14.2.3.2 
Distribution of weighted residuals 
[log10(parasitemia)] 
PKPD 
Figure 14.2.3.3 
Scatter plot of weighted residuals over 
time [log10(parasitemia)] 
PKPD 
Figure 14.2.3.4 
Scatter plot of weighted residuals over 
predicted value [log10(parasitemia)] 
PKPD 
Figure 14.2.3.5 
Time courses of individual predictions 
and observations of log10(parasitemia) 
stratified by dose group 
PKPD 
Figure 14.2.3.6 
Kaplan-Meier plots of time to 
recrudescence for simulated Phase 2 
trials 
NA 
Figure 14.2.3.7 
Kaplan-Meier plots of Probability of 
recrudescence for simulated Phase 2 
trials 
NA