Phase 1b to Assess Safety, Tolerability, Pharmacokinetic Profile, and Antimalarial Activity of Single Doses of Co-administered OZ439and PQP Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Adult Volunteers
Phase: PHASE1
Conditions: Malaria
Sponsor: Medicines for Malaria Venture

 
 
 
 
 
 
 
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 

 
 
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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 

 
 
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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 

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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 
 
 
 
 
 
 

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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 

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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 
hours and then daily for up to 7 days or until able to take oral drugs. 

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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 
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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 
PQP under fasting conditions and will have ECGs recorded before and after treatment.  

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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-
benefit profile of OZ439 and PQP are judged acceptable for the proposed clinical study. 
 
 

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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 
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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 
during the 5 years preceding screening.  

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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 
development. 

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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 
Notification (CTN) scheme.  

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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 
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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 
mapped against NGS transcriptomic and genomic data 

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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 
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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.  
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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. 
 
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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: 
screening, inoculation day, and day of admission for OZ439 and PQP treatment.  

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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 
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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 
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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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ClinicalTrials.gov ID: NCT02389348, A proof-of-concept study to assess the effect of a 
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ClinicalTrials.gov ID: NCT02543086, A phase 1 interventional sequential single site study 
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mosquitoes. 2015. 
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Duncan, C.J., et al., Impact on malaria parasite multiplication rates in infected volunteers 
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Lawrence, G., et al., Effect of vaccination with 3 recombinant asexual-stage malaria 
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Payne, R.O., et al., Demonstration of the blood-stage Plasmodium falciparum controlled 
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infected with Plasmodium falciparum. Lancet, 2002. 360(9333): p. 610-617. 
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Sanderson, F., et al., Blood-stage challenge for malaria vaccine efficacy trials: a pilot study 
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ClinicalTrials.gov ID: NCT02431650, A proof-of-concept study to assess the effectiveness 
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ClinicalTrials.gov ID: NCT02573857, A phase Ib study to characterise the antimalarial 
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Krause, A., et al., Pharmacokinetic/pharmacodynamic modelling of the antimalarial effect 
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falciparum blood-stage malaria infection in healthy volunteers.  J Antimicrob Chemother, 
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McCarthy, J.S., et al., A Phase II pilot trial to evaluate safety and efficacy of ferroquine 
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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