A Two-part, Phase 1 Study to Assess the Safety, Tolerability, and Pharmacokinetic Profile of Ascending Single Doses of MMV533, Including a Pilot Food Evaluation in Healthy Participants.
Phase: PHASE1
Conditions: Malaria
Sponsor: Medicines for Malaria Venture

Medicines for Malaria Venture 
 
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Protocol No: MMV_MMV533_19_01 
 
Date: 27 October 2021 
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CLINICAL STUDY PROTOCOL  
A two-part, Phase 1 study to assess the safety, tolerability, and 
pharmacokinetic profile of ascending single doses of 
MMV533, including a pilot food evaluation in healthy 
participants.  
 
Protocol Number: 
MMV-MMV533_19_01 
Investigational Product: 
MMV533 for oral administration 
Principal Investigator: 
Jason Lickliter, Nucleus Network 
Level 5, Burnet Tower, AMREP Precinct, 
89 Commercial Road 
Melbourne, Victoria 3004 
Australia 
Local Sponsor and CRO: 
Southern Star Research Pty Ltd (SSR) 
1 Merriwa St 
Gordon, NSW 2072 
Australia 
Tel: +61 (0)2 9011 6266 
Global Sponsor: 
Medicines for Malaria Venture (MMV) 
ICC-Block G 3rd Floor 
20 route de Pré-Bois 
PO Box 1826 
1215 Geneva 15 
Switzerland 
Trial Medical Monitor: 
Dr Michael Marx, MD 
ICON Clinical Research 
Heinrich-Hertz Str. 26 
63225 Langen 
Germany 
Date and Version: 
Version 7.0 27 October 2021 
Confidentiality Statement 
This document contains the confidential information of Medicines for Malaria Venture.  
It is provided to you as an Investigator or consultant for review by you, your personnel, 
and the applicable Human Research Ethics Committee (HREC).  Your acceptance of this 
document constitutes an agreement that you will not disclose the information contained 
herein to others without the prior written consent of Medicines for Malaria Venture, unless 
it is necessary to obtain informed consent from potential study participants.  No other use 
or reproduction is authorized by Medicines for Malaria Venture, nor does Medicines for 
Malaria Venture assume any responsibility for unauthorized use of this protocol. 

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1 PROTOCOL SUMMARY 
1.1 
PROTOCOL SYNOPSIS 
Protocol Title 
A two-part, Phase 1 study to assess the safety, tolerability, and 
pharmacokinetic profile of ascending single doses of 
MMV533, including a pilot food evaluation in healthy 
participants. 
IND Number 
Not applicable 
Protocol Number 
MMV-MMV533_19_01 
Local Sponsor/CRO 
Southern Star Research Pty Ltd (SSR) 
Global Sponsor 
Medicines for Malaria Venture (MMV) 
Principal Investigator 
Jason Lickliter, Nucleus Network (NN) 
Phase of Development 
Phase 1 
Number of Study Sites 
A Phase 1 clinical trial unit site will be conducting the study.  
Treatment Groups 
Part 1: MMV533 or placebo. 8 participants per cohort for 7-8 
cohorts (56-64 participants total). Single ascending dose 
commencing at 5 mg with maximum 400 mg as determined by 
Safety Review Committee (SRC). 
Part 2: MMV533. 8 participants in one cohort. Single dose to be 
determined by SRC after review of Part 1 data. 
Participant Population 
Healthy adult volunteers. Efforts should be made within each 
dosing cohort to have a reasonable gender balance.  
Investigational 
Medicinal Product 
(IMP) 
MMV533, single dose taken orally (5mg or 50mg tablets) with 
240 mL water under fasting conditions (except as described below 
for Part 2). 
Dose: 
Part 1: commencing with 5 mg with single ascending dose per 
cohort, maximum 400 mg. SRC to determine each dose after 
review of previous cohort. 
Part 2: single dose three-fold less than highest dose considered 
safe by the SRC in Part 1. Participants will consume an FDA-type 
high fat high calorie breakfast before IMP administration in the 
fed arm. 
Placebo 
Part 1 only: Placebo, taken orally as tablets matched to MMV533.  
Duration of Study per 
Participant 
Part 1: Screening 28 days (Day -28 to Day -1), Confinement and 
Treatment period 5 days (Day -1 to Day 5), Follow-up of 23 days 
until End of Study visit (EOS) (Day 28). Total study duration: up 
to 8 weeks from Screening until EOS. 

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Part 2: Screening 28 days (Day -28 to Day -1), Confinement and 
Treatment period (in fasted or fed condition) 10 days (Period 1 
Day -1 to Day 5 and Period 2 Day 21 to Day 26), follow up of 20 
days after last IMP administration until EOS (Day 42). Total study 
duration: up to 10 weeks from Screening until EOS.   
Objectives 
Part 1 and 2 – Single ascending dose (SAD) and food effect: 
To assess in healthy adult participants: 
Primary: 
• 
The tolerability and safety of ascending single oral doses of 
MMV 533 
Secondary: 
• 
To characterize the pharmacokinetic parameters of parent 
drug and major metabolites after single oral doses of 
MMV533 
• 
To obtain preliminary information on the effect of a high-fat 
meal on the pharmacokinetics of MMV533 
Exploratory: 
• 
To explore the excretion of MMV533 in urine 
• 
To perform genotyping of CYP450 and/or Transporter genes 
related to drug absorption, distribution, metabolism and 
excretion of MMV533 in the event of specific circumstances 
including abnormal or unexpected PK or safety results (to be 
decided when all data available after last patient last visit 
[LPLV]) 
Endpoints 
Part 1 and 2: 
Primary endpoints: 
Safety 
• 
Assessment of adverse events (AEs) /treatment-emergent 
adverse events (TEAEs) (treatment phase for Part 1 and 2 
defined as from IMP administration up to and including 
EOS).  
• 
Clinical laboratory evaluations including haematology, 
biochemistry, urinalysis. 
• 
Vital signs (blood pressure and heart rate supine and 
standing, respiratory rate and body temperature),  
• 
12-lead electrocardiogram (ECG): triplicate ECGs with 
central ECG reading from Day 1 pre-dose up to and 
including 96 hours post-IMP administration, and single 
ECGs at all subsequent scheduled timepoints: RR, heart rate 
(HR), PR, QRS, QT, QTcB and QTcF. Overall assessment 
as normal, abnormal not clinically significant, or abnormal 
clinically significant.  
Secondary endpoints: 
Pharmacokinetics of MMV533 
• 
Plasma parameters: at least but not limited to Cmax, tmax, tlag,, 
AUClast, AUCinf, t1/2, CL/F, Vd/F  

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Pharmacokinetics of major metabolites (if applicable) 
• 
Plasma parameters: at least Cmax, tmax, AUClast, AUC 
• 
Comparison of MMV533 PK parameters between fed and 
fasted dosing  
Exploratory endpoints: 
• 
Urine parameters: Ae0-t, fe0-t and CLR0-t. 
• 
Investigation of allelic variants related to drug metabolism 
enzymes and drug transporters (DME/T) potentially 
involved in the absorption, distribution, metabolism and 
excretion (ADME ) of MMV533  
Study Description 
Phase 1, single -centre study in 2 parts. The study designs for each 
part are well established for first-in-human studies and are 
appropriate to assess safety, tolerability and preliminary 
pharmacokinetics. 
Part 1: 
Double-blind, 
randomized, 
placebo-controlled, 
sequential 
ascending single dose study in healthy adult participants, 7 
cohorts, up to 1 additional cohort may be considered if needed 
according 
to 
the 
observed 
safety, 
tolerability, 
and 
pharmacokinetics results. 
Up to 64 participants will be enrolled within a 28 day screening 
period to ensure participants meet all the inclusion criteria and 
none of the exclusion criteria, with 8 participants per cohort for 7 
scheduled cohorts (6 receiving MMV533 and 2 receiving 
placebo), and up to 1 optional cohort (6 participants receiving 
MMV533 and 2 receiving placebo). Efforts should be made within 
each dosing cohort to have a reasonable gender balance. 
Participants will be admitted to the clinical unit on Day -1 for 
confinement, and randomised to be administered a single dose of 
MMV533 or placebo on Day 1. After confinement for at least 96 
hours after IMP administration for safety assessments and 
collection of PK samples, participants will attend subsequent 
outpatient visits for safety assessments and PK sampling. The End  
of Study Visit (EOS) will be conducted on Day 28.  
A sentinel dosing strategy will be implemented at each dose level 
to ensure the best conditions of safety. Each cohort will be divided 
into 2 subgroups. The first group (sentinel cohort) will include 2 
participants that will be dosed on the first day, with 1 participant 
receiving MMV533 and 1 participant receiving placebo. The 
blinded safety and tolerability data (including, but not limited to: 
AEs, vital signs, 12-lead ECG, and available clinical laboratory 
safety tests ) from the sentinel cohort up to and including 96 hours 
post-dose will be reviewed by the Principal Investigator, the study 
Medical Monitor and the Sponsor´s Medical Director. Following 
a satisfactory safety review, dosing of the remaining participants 
in the cohort (Rest of Cohort) may proceed. 
Part 2: 
Open label, 2-period cross-over, randomised, pilot food effect 
study to provide preliminary information on the effect of a high-

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fat meal on the pharmacokinetics of a single-dose oral 
administration of MMV533 to healthy male and female 
participants aged between 18-55 years old. Efforts should be made 
to have a reasonable gender balance. Part 2 may be conducted in 
parallel to or after completion of Part 1 at the discretion of the 
SRC. The dose will be selected by the SRC based on PK and safety 
results obtained in Part 1 and also taking into account the human 
efficacious dose/exposure predicted from preclinical efficacy 
studies in rodent malaria models. The dose will be at least 3-fold 
less than a dose that was determined to be safe in Part 1 in order 
to cover for a possible increased exposure when the drug is given 
in a fed state. Part 2 will consist of a single cohort of 8 participants. 
Participants will be enrolled within a 28 day screening period to 
ensure participants meet all the inclusion criteria and none of the 
exclusion criteria. Participants will be admitted to the clinical unit 
on Day -1 for confinement. Participants will be randomised to 
receive initial MMV533 dosing on Day 1 in either a fasted or fed 
condition in a 1:1 ratio (Period 1). After a wash-out time of 21 
days, the participants will cross over to the opposite fed or fasted 
condition (Period 2). For Period 2, participants will be admitted to 
the clinical unit 1 day prior to the second MMV533 dose on Day 
22. For both periods of the study, participants will be confined 
within the clinical unit for 96 hours after MMV533 administration 
for safety assessments and blood sampling for PK analysis. Visits 
to the clinical unit will then occur on an outpatient basis until the 
End of Study visit on Day 42. The wash-out time of 21 days 
between the two periods will be confirmed based on the 
elimination half-life of MMV533 observed in Part 1 of the study. 
If the elimination half-life of MMV533 is substantially different 
than that predicted from the preclinical data, the wash-out period 
and timing of assessments for Part 2 may be adjusted accordingly 
by ensuring a minimum of 5 half-lives (5x t½) between the two 
periods. This will be decided by the SRC before Part 2 
commences. 
Fasted condition 
Participants will be administered a single dose of MMV533 after 
an overnight fast of at least 10 hours. 
Fed condition 
Participants will consume a high-fat meal after an overnight fast 
of at least 10 hours. The high-fat meal will consist of an FDA-type 
high fat and high calorie breakfast. A single oral dose MMV533 
will be administered 30 minutes after the start of the meal; 
participants will be required to consume the whole meal prior to 
dosing. 
Sample Size 
Part 1 (SAD) 
Up to 64 participants: 7 groups with 8 participants each with one 
additional optional cohort of 8 participants (6 participants 
receiving MMV533 and 2 participants receiving placebo in each 
cohort).  
Part 2 (Pilot food effect) 

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1 cohort of 8 participants all receiving MMV533 
Both Parts: extra eligible participants are permitted to be available 
per cohort as back-up replacements for any withdrawal of planned 
participants prior to IMP administration.  
Efforts should be made within each dosing cohort to have a 
reasonable gender balance. 
Inclusion Criteria 
Potential participants must fulfil all of the following inclusion 
criteria to be eligible to participate in the study: 
1. Males and females (of childbearing and non-childbearing 
potential) , between 18 and 55 years of age, inclusive. Women 
of childbearing potential (WOCBP) must use highly effective 
methods of birth control (see Inclusion #3).  
2. Females of non-childbearing potential:  
a) Natural (spontaneous) post-menopausal defined as being 
amenorrhoeic for at least 12 months without an alternative medical 
cause with a screening follicle stimulating hormone level (FSH) 
>25 IU/L (or at the local laboratory levels for post-menopause) 
b) Premenopausal with irreversible surgical sterilization by 
hysterectomy and/or bilateral oophorectomy or salpingectomy at 
least 6 months before screening (as determined by participant 
medical history)  
3. Women of childbearing potential that have or may have male 
sexual partners during the course of the study must agree to 
the use of a double method of contraception of a highly 
effective method of birth control combined with a barrier 
contraceptive (condom) when appropriate from screening 
visit to until 60 days after the last dose of IMP (covering a full 
menstrual cycle of 30 days starting after 5 half-lives of last 
dose of IMP. This duration is based on the predicted half-life 
of IMP, and may be amended once the actual half-life is 
calculated during this study).  
Note: Highly effective birth control methods include: 
combined 
(oestrogen 
and 
progestogen 
containing) 
oral/intravaginal/transdermal 
hormonal 
contraception 
associated with inhibition of ovulation, progestogen-only 
oral/injectable/implantable 
hormonal 
contraception 
associated with inhibition of ovulation, intrauterine device 
(IUD), intrauterine hormone-releasing system, bilateral tubal 
occlusion, vasectomised partner, or sexual abstinence or same 
sex relationship.  
4. Male participants who have, or may have female sexual 
partners during the course of the study must agree to use a 
double method of contraception including condom plus 
diaphragm, or condom plus stable insertable (implant or 
IUD), 
injectable, 
transdermal 
or 
combination 
oral 
contraceptive by the female partner, from the time of 
informed consent through to 90 days after the last dose of the 
IMP (covering a full spermatogenesis cycle of 60 days 
starting after 5 half-lives of last dose of IMP. This duration is 
based on the predicted half-life of IMP, and may be amended 
once the actual half-life is calculated during this study). 

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Abstinent male participants must agree to start a double 
method if they begin a sexual relationship with a female 
during the trial, and through to 90 days after the last dose of 
the IMP. Male participants with female partners that are 
surgically sterile or post-menopausal (defined as being 
amenorrhoeic for at least 12 months without an alternative 
medical cause), or male participants who have undergone 
sterilisation and have had testing to confirm the success of the 
sterilisation, may also be included and will not be required to 
use above described methods of contraception. Male 
participants must also agree not to donate sperm up to 3 
months after dosing with the IMP.  
5. Total body weight greater than or equal to 50 kg, and body 
mass index (BMI) between 18 and 32 kg/m2 inclusive. 
6. Certified as healthy by a comprehensive clinical assessment 
(detailed 
medical 
history 
and 
complete 
physical 
examination).  
7. Vital signs after 5 minutes resting in supine position: 
• Systolic blood pressure (SBP) - 90–140 mmHg, 
• Diastolic blood pressure (DBP) - 40–90 mmHg, 
• Heart rate (HR) 40–100 bpm. 
DBP 40-49 mmHg and HR 40-49 bpm are outside the study 
normal ranges but are acceptable for eligibility (including 
Screening, Day -1 and Day 1 pre-dose) if considered not 
clinically significant by the Principal Investigator or 
delegate.  
8. Standard 12-lead electrocardiogram (ECG) parameters after 
10 minutes resting in supine position in the following ranges 
for both males and females, irrespective of clinical 
significance of out-of-range values:  
• QRS 50 – 120 msec,  
• QT ≤ 500 msec,  
• QTcF ≤450 msec,  
• QTcB ≤450 msec, and  
• PR interval ≤210 msec.  
The ECG tracing must be normal unless the Principal 
Investigator or delegate considers an ECG tracing 
abnormality to be not clinically significant. 
9. Having given written informed consent prior to undertaking 
any study-related procedure. 
10. Available for the duration of the study and for 2 weeks 
following the End of Study visit.  
11. In the opinion of the Principal Investigator or delegate, the 
individual has a high probability of adherence with and 
completion of the study, and willing and able to withdraw and 
refrain from restricted medications. 

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12. Fluent in English and able to understand and comply with 
written and verbal protocol-related requirements.  
13. Willing to defer blood donations to a blood service for a 
minimum of 6 months after the End of Study visit.   
Exclusion Criteria 
If any of the following exclusion criteria apply, the potential 
participant will not be permitted to participate in the study: 
1. Haematology, biochemistry or urinalysis results that are 
abnormal/outside of laboratory normal reference ranges AND 
are either: 
• 
considered clinically significant by the Principal 
Investigator or delegate; OR  
• 
considered not clinically significant by the Principal 
Investigator or delegate BUT ARE ALSO outside of 
the 
Sponsor-approved 
clinically 
acceptable 
laboratory ranges in Appendix 1.  
NOTE: Participants are not excluded if abnormal/out of 
laboratory normal reference range results are considered not 
clinically significant by the Principal Investigator or delegate 
AND are within the ranges specified in Appendix 1.  
2. Positive serum pregnancy test at screening, positive urine 
pregnancy test upon admission or at other timepoints as 
specified by schedule of assessments.  
3. Male participants with a female partner(s) who is (are) 
pregnant or lactating from the time of the administration of 
study medication.  
4. Any history or presence of clinically relevant cardiovascular, 
broncho-pulmonary, gastrointestinal, hepatic/ gallbladder*/ 
bile duct, renal, metabolic, haematological, neurological, 
musculoskeletal/rheumatologic, 
systemic, 
ocular, 
gynaecologic (if female), or infectious disease, or signs of 
acute illness. *including medical history of asymptomatic 
gallbladder stones.  
5. Any gastrointestinal surgery or any condition or disease that 
could affect drug absorption, distribution or excretion (eg, 
gastrectomy, cholecystectomy, diarrhoea). 
6. Severe recurring headaches (cluster or migrainous headaches) 
requiring prescription medication/s. History of recurrent 
nausea and/or vomiting (for vomiting only: more than twice a 
month).  
7. Participation in any research study involving blood sampling 
(more than 450 mL/unit of blood) or blood donation during 
the 8 weeks prior to IMP administration (Parts 1 and 2).   
8. Any documented evidence of current or past cardiovascular 
disease including cardiac arrhythmias or family history of 
congenital long QT syndrome, Brugada syndrome, or 
unexplained sudden cardiac death. Symptomatic postural 
hypotension at screening (confirmed on two consecutive 

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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 min when 
changing from supine to standing position. 
9. History 
or 
presence 
of 
diagnosed 
(by 
an 
allergist/immunologist) or treated (by a physician) food or 
known drug allergies, or any history of anaphylaxis or other 
severe allergic reactions including face, mouth, or throat 
swelling or any difficulty breathing. Participants with 
seasonal allergies/hay fever or allergy to animals or house 
dust mite that are untreated and asymptomatic at the time of 
dosing can be enrolled in the trial. 
10. History of convulsion (including drug or vaccine-induced 
episodes). A medical history of a single febrile convulsion 
during childhood is not an exclusion criterion.  
11. History of substance use disorder(s) within 5 years of 
screening, including alcohol consumption of more than 40g/4 
units/4 standard drinks per day or any prior intravenous use 
of an illicit substance.  
12. Smoked >1 pack of cigarettes per day for >10 years, or who 
currently (within 14 days prior to IMP administration (Parts 1 
and 2) smokes >5 cigarettes per day.  
13. Any vitamin supplements within 7 days prior to IMP 
administration (Parts 1 and 2). 
14. Any other medication (including herbal such as St John´s 
Wort and over the counter [OTC]) within 5 half-lives prior to 
IMP administration (Parts 1 and 2), except occasional intakes 
(for acute pain) of ibuprofen at doses up to 1.8g/day, 
paracetamol at doses up to 4g/day, acetylsalicylic acid (300 to 
650 mg orally every 4 to 6 hours as needed, maximum dose: 
4g in 24 hours), diclofenac (diclofenac potassium liquid-filled 
capsules: 25mg orally 4 times a day; diclofenac free acid 
capsules: 18 or 35 mg orally 3 times a day; diclofenac 
potassium immediate-release tablets: 50mg orally 3 times a 
day [initial dose of 100mg orally followed by 50mg oral doses 
acceptable if required for better relief]) and contraceptives.  
15. Any individual who, in the judgement of the Principal 
Investigator or delegate, is likely to be noncompliant during 
the study, or unable to cooperate because of a language 
problem or poor mental development.  
16. Any individual in the exclusion period of a previous study 
according to applicable regulations.  
17. Any individual who cannot be contacted in case of 
emergency.  
18. Any individual who is the Investigator, or delegates, research 
assistant, pharmacist, study coordinator, project manager, or 
other staff thereof, directly involved in conducting the study.  
19. Any individual without a good peripheral venous access.   

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20. Participation in any investigational product study within the 
12 weeks preceding IMP administration (Parts 1 and 2) or 5 
times the half-life of the Investigational product, whichever is 
longer.  
21. Positive serology test for hepatitis B (positive HB sAG or 
anti-HBc Ab), hepatitis C (anti-HCV) or human immune 
deficiency virus (HIV) (positive for anti-HIV1 and anti-HIV2 
Ab).  
22. Positive drug test at screening or prior to IMP dosing.  Any 
drug from the list of drugs tested unless there is an acceptable 
explanation to the Principal Investigator or delegate (eg, 
participant has stated in advance that they consumed a 
prescription of over the counter product which contained the 
detected drug) and/or the participant has a negative urine drug 
screen on retest. Any participant tested positive for serum 
paracetamol at screening may still be eligible for study 
participation, at the Principal Investigator’s or delegate’s 
discretion.  
23. Positive alcohol screen at screening or prior to IMP dosing.  
24. Any consumption of citrus fruits (grapefruit, Seville oranges) 
or their juices within 5 days prior to IMP administration.    
25. Use of antidepressant medication in the past 12 months prior 
to IMP administration in Part 1 and 2. 
26. Individuals with history of schizophrenia, bipolar disorder 
psychoses, disorders requiring lithium, attempted or planned 
suicide, or any other severe (disabling) chronic psychiatric 
diagnosis including generalised anxiety and obsessive-
compulsive disorders. 
27. Individuals who have been hospitalised within five years prior 
to enrolment for either a psychiatric illness or due to danger 
to self or others.   
28. History of an episode of mild/moderate depression lasting 
more than 6 months that required pharmacological therapy 
and/or psychotherapy within the last 5 years; or any episode 
of major depression. The Beck Depression Inventory (BDI-
II) will be used as a validated tool for the assessment of 
depression at screening. In addition to the conditions listed 
above, individuals with a score of 20 or more on the BDI-II 
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 individuals will be referred to a general 
practitioner or medical specialist as appropriate. Individuals 
with a BDI-II score of 17 to 19 may be enrolled at the 
discretion of an 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 individual or to the execution of the trial and 
interpretation of the data gathered. 
29. History of malignancy of any organ system (other than 
localized basal cell carcinoma of the skin or in situ cervical 

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cancer considered treated and cured), treated or untreated, 
within 5 years of screening, regardless of whether there is no 
evidence of local recurrence or metastases.  
30. Any COVID-19 vaccine within 14 days of IMP intake, any 
other vaccination within 28 days of IMP intake, and any 
vaccination (including COVID-19 initial or second dose) 
planned up to the final follow-up visit.  
31. Any medical condition that in the opinion of the Principal 
Investigator or delegate would jeopardize the individual’s 
involvement in the study.  
Specific to Part 2 only: 
32. Any individual who, in the opinion of the Principal 
Investigator or delegate, would be unwilling or unable to 
consume the pre-dose test meal during the fed arm.  
33. Individuals with food intolerance or food allergy are 
excluded. Vegetarian individuals must be excluded, unless 
they agree to eat a full diet during the study. 
Data Analysis 
Safety (all study parts): 
Safety analysis (AE, laboratory parameters, vital signs, ECGs) 
will be based on the review of individual values, and descriptive 
statistics. 
The safety analysis will focus on the TEAE period, defined as the 
time from the first IMP administration up to and including EOS.  
AEs will be coded according to the Medical Dictionary for 
Regulatory Activities (MedDRA). Their severity will be graded 
according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE V5.0 27 Nov 2017). 
The number (%) of participants experiencing TEAEs will be 
summarized by dose group. 
Safety analysis of ECGs will include in particular the number of 
participants during the study with:  
• 
QTcF and/or QTcB prolongation of more than 30 ms and 60 
ms; and/or  
• 
QTcF and/or QTcB > 450 msec.  
Part 1 
Concentration-ECG 
analysis: 
Exposure-response 
analysis 
between the change from baseline in centrally-read ECG intervals 
and corresponding drug concentrations will be performed using 
graphical tools and regression methods. Estimate and 90% 
confidence interval (CI) of change from baseline in ECG 
parameters (HR, PR, QRS, QTcB and QTcF) at the observed 
geometric mean of Cmax will be computed from the final model 
chosen. This analysis will be supporting further development of 
MMV533, and results will be presented in a separate companion 
report after completion of the main study clinical study report 
(CSR).  
Pharmacokinetics 

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For both parts, MMV533 PK profiles will be plotted individually 
and summarized by dose group and by food intake. 
For both Parts, MMV533 PK parameters calculated in plasma will 
be summarized by dose group and by food intake using descriptive 
statistics. All the statistical analyses described below will be done 
separately on plasma parameters. 
The tmax values will be represented by histogram plots for each 
dose level. Dose proportionality will be assessed using a power 
model on Cmax, AUClast and AUC.  
For Part 2 only, impact of food effect on Cmax, tmax AUClast and 
AUC and t1/2 will be assessed.  
Exploratory parameters  
Exploratory parameters identified for this study (urine excretion 
of MMV533 and, if analysed, CYP450/Transporter genetic 
polymorphism) will be summarized by treatment group using 
descriptive statistics. 
 
 

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1.2 
SCHEMAS 
1.2.1 Part 1 Schema 
 
1.2.2 Part 2 Schema 
 
 
 
 

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1.3 
SCHEDULE OF ACTIVITIES 
Table 1: PART 1 Schedule of Activities 
Part 1 Phase 
Screening/Eligibility 
Treatment and 
Confinement  
Outpatient Monitoring  
EOS 
Early 
Termination 
Day 
D-28 to D-2 
D-1 
D1 
D2 
D3 
D4 
D5 
D8 
D14 
D21 
D28±24h 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Admission to clinical unit 
 
X 
 
 
 
 
 
 
 
 
 
 
Confinement at clinical unit 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
Discharge from clinical unit 
 
 
 
 
 
 
X 
 
 
 
 
 
Outpatient visit to clinical unit 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Inclusion/exclusion criteria – confirm 
eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
BDI-II 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
< 
- 
- 
- 
- 
- 
 
- 
- 
- 
> 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
Study treatment administration 
 
 
 
 
 
 
 
 
 
 
 
 
MMV533 or placebo (IMP) 
 
 
X 
 
 
 
 
 
 
 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam - full 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
Physical exam – symptom directed 
when clinically indicated 
 
 
X 
X 
X 
X 
X 
 
 
Height (cm) 
X 
 
 
 
 
 
 
 
 
 
 
 
Body weight (kg) 
X 
X 
 
 
 
 
 
 
 
 
 
 
Serology tests 
X 
 
 
 
 
 
 
 
 
 
 
 
Drug screen, alcohol testa 
X 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs (BP, HR & RR: supine and 
standing at Screening and EOS, all 
others supine) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
Tympanic body temperature (ºCelcius) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haematology, biochemistryb, urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Part 1 Phase 
Screening/Eligibility 
Treatment and 
Confinement  
Outpatient Monitoring  
EOS 
Early 
Termination 
Day 
D-28 to D-2 
D-1 
D1 
D2 
D3 
D4 
D5 
D8 
D14 
D21 
D28±24h 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test/ FSHc 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
Adverse event collectiond 
< 
- 
- 
- 
- 
- 
 
- 
- 
- 
> 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
MMV533 plasma samples 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xf 
MMV533 urine samplese 
 
 
X 
X 
X 
 
 
 
 
 
 
 
Pharmacogenetics 
 
 
 
 
 
 
 
 
 
 
 
 
DME/T DNA blood sampleg 
 
 
X 
 
 
 
 
 
 
 
 
 
ABBREVIATIONS: BDI-II = Beck Depression Inventory; BP = blood pressure; DME = drug metabolizing enzymes; ECG = Electrocardiogram; exam = 
examination; EOS = End of study visit; FSH = follicle stimulating hormone; HR = heart rate; IMP= Investigational Medicinal Product; RR = respiratory rate. 
a. Drug test will be performed on urine sample, except serum paracetamol which will be assayed using blood sample(s) taken for clinical laboratory 
testing. Alcohol test will be performed by breathalyser. 
b. Blood sampling for safety biochemistry laboratory tests require fasting (at least 10 hours) when taken in the morning:  must be fasted for Screening, 
and fasting blood samples must be collected only in the morning before breakfast when Total Bile Acids (TBA) are tested. TBA will be tested pre-dose, 
then 24 hours, 48 hours, 72 hours and 96 hours post-IMP administration and on Days 8, 14, 21 and EOS. TBA not required at Screening, Day -1, or at 
6 and 12 hours post-IMP administration. Samples taken 6 and 12 hours post-IMP administration are not required to be fasting if not collected in the 
morning. NOTE: Results of all safety laboratory tests conducted on blood and urine samples collected on Day -1 must be available and reviewed by the 
Principal Investigator or delegate prior to dosing with IMP on Day 1 and must satisfy relevant inclusion/exclusion criteria.  
c. Serum β-human chorionic gonadotropin (hCG) pregnancy test for all female participants and FSH test for post-menopausal female participants at 
Screening. For women of child bearing potential (WOCBP), urine β-hCG pregnancy test will be performed on Day -1 prior to IMP administration and 
serum β-hCG pregnancy test conducted at EOS. If urine tests are positive, blood should be collected for serum β-hCG pregnancy test to confirm.  
d. Medically untoward events occurring between informed consent and IMP administration will be recorded and considered as medical history; will be 
recorded as AEs from time of IMP administration.  
e. Urine samples for PK analysis: all urine will be collected for defined time intervals as detailed in Table 3.  
f. PK sample to be obtained if applicable and in agreement with participant who is withdrawing/having their participation terminated early. 
g. Mandatory sample for future analysis of CYP450/Transporter genetic polymorphism.  
NOTE: This table is an overview only. See Table 3 for more detailed timepoint and procedural information from Day 1 onwards. Assessment results 
available prior to dosing must satisfy relevant inclusion/exclusion criteria for first dosing to proceed.  
 
 

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Table 2: PART 2 Schedule of Activities 
Part 2 Phase 
Screening/ 
Eligibility 
Period 1: Treatment 
and Confinement 
Period 1: Out-
patient Monitoring  
Period 2:  Treatment and 
Confinement 
Period 2: 
Out-
patient 
Monitoring 
EOS 
ET 
Day 
D-28 to 
D-2 
D-1 
D1 
D2 
D3 
D4 
D5 
D8 
D 
14 
D21 
D 
22 
D 
23 
D 
24 
D 
25 
D 
26 
D 
29 
D 
35 
D42 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission to clinical unit 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Confinement at clinical unit 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
Discharge from clinical unit 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Outpatient visit to clinical unit 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
Inclusion/exclusion criteria – 
confirm eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history/BDI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
< 
- 
- 
- 
- 
- 
 
 
 
 
 
- 
 
 
- 
- 
- 
> 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatment administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMV533 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
High fat breakfast when 
applicablea 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam - full 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Physical exam - symptom 
directed when clinically indicated 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Height (cm) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight (kg) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Serology tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug screen, alcohol testb 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Vital signs – BP, HR, RR 
(supine and standing at Screening 
& EOS; all others supine) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 

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Page 17 of 91 
 
Part 2 Phase 
Screening/ 
Eligibility 
Period 1: Treatment 
and Confinement 
Period 1: Out-
patient Monitoring  
Period 2:  Treatment and 
Confinement 
Period 2: 
Out-
patient 
Monitoring 
EOS 
ET 
Day 
D-28 to 
D-2 
D-1 
D1 
D2 
D3 
D4 
D5 
D8 
D 
14 
D21 
D 
22 
D 
23 
D 
24 
D 
25 
D 
26 
D 
29 
D 
35 
D42 
 
Tympanic body temperature 
(ºCelcius) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haematology, biochemistryc, 
urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test/ FSHd 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Adverse event collectione 
< 
- 
- 
- 
- 
- 
 
 
 
 
 
- 
 
 
- 
- 
 
> 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMV533 plasma samples 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xf 
Pharmacogenetics 
 
DME/T DNA blood sample 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ABBREVIATIONS: BDI = Beck Depression Inventory; BP = blood pressure; DME = drug metabolizing enzymes; ECG = electrocardiogram; EOS = end of 
study visit; ET = early termination visit; exam = examination; FSH = follicle stimulating hormone; HR = heart rate; RR = respiratory rate.  
a. High fat breakfast (FDA-type high fat and high calorie breakfast) administered in Period 2 only if participant was fasted in Period 1 
b. Drug test will be performed on urine sample, except serum paracetamol which will be assayed using blood sample(s) taken for clinical laboratory 
testing. Alcohol test will be performed by breathalyzer. 
c. Safety biochemistry laboratory tests require fasting of at least 10 hours when blood samples collected in the morning. Participants must be fasted for 
blood sampling at Screening , and fasting blood samples must be collected only in the morning before breakfast in both Periods when Total Bile Acids 
(TBA) are tested (TBA to be included in testing: pre-dose, then 24 hours, 48 hours, 72 hours and 96 hours post-IMP administration and on Days 8, 14, 
21, 29, 35 and EOS Day 42). NOTE: Results of all safety laboratory tests conducted on blood and urine samples collected on Day -1 and Day 21 (except 
Day 21 TBA results) must be available and reviewed by the Principal Investigator or delegate prior to dosing with IMP on Day 1 and Day 22 respectively. 
Day -1 results must satisfy relevant inclusion/exclusion criteria.  
d. Serum β-human chorionic gonadotropin (hCG) pregnancy test for all female participants and FSH test for post-menopausal female participants at 
Screening. For WOCBP, urine β-hCG pregnancy test will be performed  prior to IMP administration on Days -1 and 21 and serum β-hCG pregnancy 
test conducted at EOS. If urine tests are positive, blood should be collected for serum β-hCG pregnancy test to confirm.  
e. Medically untoward events occurring between informed consent and IMP administration will be recorded and considered as medical history; will be 
recorded as AEs from time of IMP administration. 

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f. PK sample to be obtained if applicable and in agreement with participant who is withdrawing/having their participation terminated early. 
g. Mandatory sample for future analysis of CYP450/Transporter genetic polymorphism (Period 1 only)    
 
NOTE: This table is an overview only. See Table 4 and Table 5 for more detailed timepoint and procedural information from Day 1 onwards. 
Assessment results available prior to dosing on Day 1 must satisfy relevant inclusion/exclusion criteria for first dosing to proceed. 
 
 
 

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Table 3: PART 1 Detailed Schedule of Activities 
Part 1 Phase 
Part 1: Treatment and Confinement 
Part 1: Out-patient 
Monitoring 
EOS 
Part 1 Day 
D1 
D2 
D3 
D4 
D5 
D8 
D14 
D21 
D28 
Time 
(hour/minute)a 
Pre-dose 
0H 
0H 
30 
1H 
1H 
30 
2H 
3H 
4H 
6H 
8H 
10H 
12H 
24H 
48H 
72H 
96H 
168H 312H 480H 648H 
Confinement 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Outpatient visit at 
clinical site 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Concomitant 
medications 
 
- 
- 
- 
- 
- 
- 
  -         - 
- 
- 
- 
- 
- 
- 
 
- 
- 
- 
> 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatment 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMV533/ placebo 
(IMP) b 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safetyc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
Xd 
Xd 
Xd 
Xd 
Xd 
X 
Tympanic body 
temperature (ºC)e 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs BP, HR, 
RR (supine; supine 
/standing at EOS) e 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
Xf 
 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
X 
X 
X 
Hematology, 
biochemistry, 
urinalysisg 
Xh 
 
 
 
 
 
 
 
X 
 
 
X 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Serum β-hCG  
(WOCBP only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse event 
collectioni 
 
- 
- 
- 
- 
- 
- 
  -         - 
- 
- 
- 
- 
- 
- 
 
- 
- 
- 
> 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Medicines for Malaria Venture 
 
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Protocol No: MMV_MMV533_19_01 
 
Date: 27 October 2021 
CONFIDENTIAL  
 
Page 20 of 91 
 
Part 1 Phase 
Part 1: Treatment and Confinement 
Part 1: Out-patient 
Monitoring 
EOS 
Part 1 Day 
D1 
D2 
D3 
D4 
D5 
D8 
D14 
D21 
D28 
Time 
(hour/minute)a 
Pre-dose 
0H 
0H 
30 
1H 
1H 
30 
2H 
3H 
4H 
6H 
8H 
10H 
12H 
24H 
48H 
72H 
96H 
168H 312H 480H 648H 
MMV533 PK  
plasma  samplesj 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MMV533 PK  urine 
samplesk 
U00l 
<  
 
- 
- 
U01 
- 
- 
>< 
U02 
>< 
U03 
>< 
U04>< U05>< U06> 
 
 
 
 
 
Pharmacogenetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DME/T DNA 
samplem 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ABBREVIATIONS: C = Celcius; DME = drug metabolizing enzymes; ECG = electrocardiogram; EOS = end of study visit; hCG = human chorionic gonadotropin; IMP = 
investigational medicinal product; PK = pharmacokinetics; WOCBP = woman of child bearing potential. 
a. Time (hour/minute) is expressed in reference to the administration of IMP (MMV533/placebo; t = 0). Day 1 is defined as the day of IMP administration. 
Efforts should be made to ensure all study volunteers are dosed after a minimum of 10 hours fasting and before 10:00AM.  
b. A single oral dose of MMV533 or placebo (IMP) will be administered on Day 1 (t = 0). See Section 5.1 for details. Part 1 is double-blinded. Assessment 
results available prior to dosing must satisfy relevant inclusion/exclusion criteria.  
c. Refer to Safety Section 7 for detailed safety investigations.  
d. Symptom-directed physical examination: body systems reviewed only if clinically indicated and at discretion of Principal Investigator or delegate. Any 
results available prior to dosing must satisfy relevant inclusion/exclusion criteria. Prior to participant discharge on Day 5, clinical unit staff must clarify 
with the Principal Investigator or delegate if a symptom directed physical examination is required. Full physical examination required at EOS. 
e. Vital signs (tympanic body temperature [ºCelcius], BP [systolic and diastolic, mmHg], HR [beats per minute], respiratory rate [breaths per minute]. 
Tympanic body temperature at the timepoints indicated. BP, HR and RR at the timepoints indicated; measured after participant rested supine for at least 
5 minutes for all scheduled timepoints except EOS, where BP, HR and RR will be measured after 5 minutes in supine resting position and then after 3 
minutes in standing position. Results available prior to dosing must satisfy relevant inclusion/exclusion criteria.Time windows: pre-dose: ≤ 2 hours; 
post-dose during confinement: ± 15 minutes of nominal timepoints up to and including 12 hours post-dose, and then for all scheduled timepoints as per 
PK blood sampling time windows in Section 6.3 Table 8. 
f. Triplicate 10-second ECGs will be conducted after participant supine for at least 10 minutes: pre-dose on Day 1 (three lots of triplicate baseline ECGs 
[ie 9 conducted pre-dose] conducted consecutively within one hour prior to dosing with IMP with triplicates performed at least 10 minutes apart from 
last one to the first one of the next set, prior to any blood sampling) and then at each scheduled timepoint through to Day 5 96H. Results available prior 
to dosing (using the mean of each triplicate ECG for ECG intervals) must satisfy relevant inclusion/exclusion criteria. All triplicate ECGs will be 
centrally read. All other scheduled ECGs are single standard 12-lead safety ECGs. From time of IMP dosing to Day 5 inclusive, ECGs will be conducted 

Medicines for Malaria Venture 
 
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Date: 27 October 2021 
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Page 21 of 91 
 
within 15 minutes prior to the actual time of PK blood sampling. From Day 8 onwards, ECGs will be conducted +/- 2 hours of the actual PK blood 
sampling time, except for EOS Day 28 where the time window is as permitted for PK sampling (+/- 24 hours).  
g. Safety biochemistry laboratory testing require fasting of at least 10 hours for all scheduled timepoints except for samples collected at 6 and 12 hours 
post-IMP administration. Time windows for safety blood sampling are as per PK sampling in Section 6.3 Table 8, except ± 15 minutes permitted for 
the 6 and 12 hour post-dose timepoints. Time windows for urine collection for safety urinalysis are ≤ 2 hours pre-dose, then ± 1 hour post-dose from 
the nominal timepoint during confinement and then as per PK blood sampling in Section 6.3 Table 8. Day -1 results must be available for review prior 
to dosing on Day 1 and must satisfy relevant inclusion/exclusion criteria. If available prior to dosing, Day 1 results must also satisfy relevant 
inclusion/exclusion criteria.  
h. Total bile acids (TBA) included in biochemistry laboratory testing (10 hour fasting required for morning sampling before breakfast). TBA not required 
for safety blood sampling scheduled for 6 and 12 hours post-IMP administration.  
i. 
Medically untoward events occurring between informed consent and IMP administration will be recorded and considered as medical history, and must 
satisfy relevant inclusion/exclusion criteria for dosing to proceed; will be recorded as AEs from t = 0.  
j. 
Blood samples for PK analysis will be collected at the scheduled timepoints with time windows as per Section 6.3 Table 8.  
k. Urine samples for PK analysis will be collected during the following time ranges (hours) post-IMP administration: 0-4 (U01), 4-8 (U02), 8-12 (U03), 
12-24 (U04), 24-48 (U05) and 48-72 (U06). All urine will be collected and pooled during these time ranges, except for samples required for safety 
urinalysis.  
l. 
U00 is a 2-hour pre-dose urine collection. All urine will be collected and pooled from -2h to 0h pre-dose.  
m. Mandatory sample for future analysis of CYP450/Transporter genetic polymorphism as per Section 6.2. 
NOTE:  
• 
To respect exact timing of pharmacokinetic samples, the other assessments/activities will be done ahead of the scheduled time from Day 1 to Day 
5. Time windows for PK sampling are defined in Section 6.3 Table 8.  
• 
When several items take place at the same time, the following order is recommended: urine sampling for PK /urinalysis,  vital signs, ECG, blood 
sampling, drug administration, meal. 
• 
Date/time of all assessments/activities must be recorded in source document.  
• 
Assessment results available prior to dosing on Day 1 must satisfy relevant inclusion/exclusion criteria before dosing can proceed.  
 
  
 

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Table 4: PART 2 Period 1 Detailed Schedule of Activities 
Part 2 Phase 
Part 2 Period 1: Treatment and Confinement  
 Part 2 Period 1: Out-patient 
Monitoring 
Day 
D1 
D2 
D3 
D4 
D5 
D8 
D14 
D21 
Time 
(hour/minute)a 
Predose 
0H 
0H30 
1H 
1H30 
2H 
3H 
4H 
6H 
8H 
10H 
12H 
24H 
48H 
72H 
96H 
168H 
312H 
480H 
Confinement 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Outpatient visit at 
clinical site 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Prior/concomitant 
medications 
 
- 
- 
- 
- 
- 
 
 
 
 
 
 
- 
 
 
- 
- 
> 
Study treatment 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMV533b 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
High fat breakfast 
when applicablec 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safetyd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug screen, alcohol 
teste 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 Physical 
Examinationf 
Xf 
X 
X 
X 
X 
Tympanic body 
temperature (ºC)g 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs BP, HR, 
RR (supine) g 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
Xh 
 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
X 
 
X 
Hematology, 
biochemistry, 
urinalysis 
 
Xi 
 
 
 
 
 
 
 
 
 
 
 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Urine β-hCG 
(WOCBP only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xj 

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Part 2 Phase 
Part 2 Period 1: Treatment and Confinement  
 Part 2 Period 1: Out-patient 
Monitoring 
Day 
D1 
D2 
D3 
D4 
D5 
D8 
D14 
D21 
Time 
(hour/minute)a 
Predose 
0H 
0H30 
1H 
1H30 
2H 
3H 
4H 
6H 
8H 
10H 
12H 
24H 
48H 
72H 
96H 
168H 
312H 
480H 
Adverse event 
collectionk 
 
- 
- 
- 
- 
- 
 
 
 
 
 
 
- 
 
 
- 
- 
> 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMV533 PK 
plasma samplesl 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacogenetics 
 
DME/T DNA 
sample 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ABBREVIATIONS: BP = blood pressure; C = Celcius; DME = drug metabolizing enzymes; ECG = electrocardiogram; hCG = human chorionic gonadotropin; HR = heart 
rate; RR = respiratory rate; PK = pharmacokinetics; WOCBP = woman of child bearing potential. 
a. Time (hour/minute) is expressed in reference to the administration of MMV533 (t = 0). Day 1 is defined as the day of IMP administration. Efforts 
should be made to ensure all study volunteers are dosed after a minimum of 10 hours fasting and before 10:00AM. 
b. A single oral dose of MMV533 (IMP) will be administered on Day 1 (t = 0) either in the fed or fasted condition as described in Section 5.1.1. Part 2 is 
open-label; participants will be randomized to the fed or fasted arm for Period 1. Assessment results available prior to dosing on Day 1 must satisfy 
relevant inclusion/exclusion criteria.  
c. If randomized to the fed arm in Period 1, participants will consume a high fat breakfast (FDA-type high fat and high calorie breakfast) after overnight 
fast of at least 10 hours. Entire breakfast must be consumed within 30 minutes and IMP administered 30 minutes after start of breakfast. See Section 
5.3.1.2 for details. If randomized to the fasted arm in Period 1, participants will remain fasted prior to IMP administration.  
d. Refer to Safety Section 7 for detailed safety investigations. 
e. Drug test will be performed on urine sample except serum paracetamol which will be assayed using blood sample(s) taken for clinical laboratory testing 
Alcohol test will be performed by breathalyzer. 
f. Full physical examination will be conducted on Day 21 (prior to Period 2 IMP administration on Day 22). Symptom directed physical examination may 
be performed at any time during confinement and at outpatient visits if clinically indicated and at the discretion of the Principal Investigator or delegate. 
Any results available prior to dosing on Day 1 must satisfy relevant inclusion/exclusion criteria. Prior to participant discharge on Day 5, clinical unit 
staff must clarify with the Principal Investigator or delegate if a symptom directed physical examination is required.  
g. Vital signs (tympanic body temperature [ºCelcius], BP [systolic and diastolic, mmHg], HR [beats per minute], respiratory rate [breaths per minute]. 
Tympanic body temperature at the timepoints indicated. BP, HR and RR at the timepoints indicated; measured after participant rested supine for at least 
5 minutes for all scheduled timepoints. Results available prior to dosing on Day 1 must satisfy relevant inclusion/exclusion criteria. Time windows: 

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Page 24 of 91 
 
pre-dose: ≤ 2 hours; post-dose during confinement: ± 15 minutes of nominal timepoints up to and including 12 hours post-dose, and then for all 
scheduled timepoints as per PK blood sampling time windows in Section 6.3 Table 8. 
h. Triplicate 10-second ECGs will be conducted pre-dose on Day 1 (three lots of triplicate baseline ECGs [ie 9 conducted pre-dose] conducted 
consecutively within 90 minutes prior to dosing with IMP with triplicates performed at least 10 minutes apart from last one to the first one of the next 
set, prior to any blood sampling) and then at each scheduled timepoint through to Day 5 96H. Results available prior to dosing on Day 1 (using the 
mean of each triplicate ECG for ECG intervals) must satisfy relevant inclusion/exclusion criteria. All triplicate ECGs will be centrally read. All 
subsequent scheduled ECGs are single standard 12-lead safety ECGs. From time of IMP dosing to Day 5 96H inclusive, ECGs will be conducted within 
15 minutes prior to the actual time of PK blood sampling. From Day 8 until Day 21, ECGs will be conducted +/- 2 hours of the PK blood sampling 
time.  
i. 
Safety biochemistry laboratory tests require fasting for at least 10 hours and to be collected in the morning before breakfast. Total bile acids (TBA) to 
be included in safety biochemistry laboratory tests. Time windows for safety blood sampling are as per PK sampling in Section 6.3 Table 8. Time 
windows for urine collection for safety urinalysis are ≤ 2 hours pre-dose, then ± 1 hour post-dose from the nominal timepoint during confinement and 
then as per PK blood sampling in Section 6.3 Table 8. NOTE: Safety laboratory test results from blood and urine samples collected on Days -1 and 21 
(except Day 21 TBA results) must be available and reviewed by the Principal Investigator or delegate prior to dosing with IMP on Days 1 and 22 
respectively. Day -1 results (and Day 1 results if available) must satisfy relevant inclusion/exclusion criteria.  
j. 
If urine tests are positive, blood should be collected for serum β-hCG pregnancy test to confirm.  
k. Medically untoward events occurring prior to time of IMP administration will be recorded and considered as medical history; will be recorded as AEs 
from t = 0. 
l. 
Blood samples for PK analysis will be collected at the scheduled timepoints with time windows as per Section 6.3 Table 8. 
m. Mandatory sample for future analysis of CYP450/Transporter genetic polymorphism (Period 1 only) as per Section 6.2. 
 
NOTE:  
• 
To respect exact timing of pharmacokinetic samples, the other assessments/activities will be done ahead of the scheduled time from Day 1 to Day 
5. Time windows for PK sampling are defined in Section 6.3 Table 8.  
• 
When several items take place at the same time, the following order is recommended: urinalysis, vital signs, ECG, blood sampling, drug 
administration, meal. 
• 
Date/time of all assessments/activities must be recorded in source document.  
• 
Available assessment results prior to dosing on Day 1 must satisfy relevant inclusion/exclusion criteria before dosing can proceed.  

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Table 5: PART 2 Period 2 Detailed Schedule of Activities 
Part 2 Phase 
Part 2 Period 2: Treatment and Confinement 
Part 2 Period 2: Out-
patient Monitoring 
EOS 
Day 
D22 
D23 
D24 
D25 
D26 
D29 
D35 
 
D42 
Time 
(hour/minute)a 
Predose 
0H 
0H30 
1H 
1H30 
2H 
3H 
4H 
6H 
8H 
10H 
12H 
24H 
48H 
72H 
96H 
168H 
312H 
 
480H 
Confinement 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Outpatient visit at 
clinical site 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Prior/concomitant 
medications 
 
- 
- 
- 
- 
- 
 
 
 
 
 
 
- 
 
 
- 
- 
> 
Study treatment 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMV533b 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
High fat breakfast 
when applicablec 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safetyd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exame 
Xe 
X 
X 
X 
X 
Body weight (kg) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Tympanic body 
temperature (ºC) f 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs supine; 
supine/standing at 
EOS only f 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
Xg 
 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
X 
 
X 
Haematology, 
biochemistry, 
urinalysis 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 

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Part 2 Phase 
Part 2 Period 2: Treatment and Confinement 
Part 2 Period 2: Out-
patient Monitoring 
EOS 
Day 
D22 
D23 
D24 
D25 
D26 
D29 
D35 
 
D42 
Time 
(hour/minute)a 
Predose 
0H 
0H30 
1H 
1H30 
2H 
3H 
4H 
6H 
8H 
10H 
12H 
24H 
48H 
72H 
96H 
168H 
312H 
 
480H 
Serum β-hCG 
(WOCBP only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse event 
collectioni 
 
- 
- 
- 
- 
- 
 
 
 
 
 
 
- 
 
 
- 
- 
> 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMV533 PK plasma 
samplesj 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
ABBREVIATIONS: C = Celcius; ECG = electrocardiogram; EOS = end of study visit; Exam = examination ; hCG = human chorionic gonadotropin; PK = pharmacokinetics; 
WOCBP = woman of child bearing potential. 
a. Time (hour/minute) is expressed in reference to the administration of MMV533 (t = 0). Day 1 is defined as the day of IMP administration. Efforts should 
be made to ensure all study volunteers are dosed after a minimum of 10 hours fasting and before 10:00AM. 
b. A single oral dose of MMV533 (IMP) will be administered on Day 22 (t = 0) as described in Section 5.1.1. Part 2 is open-label. 
c. If randomized to the fasted arm in Period 1, on Day 22 in Period 2 participants will cross over to the fed arm and consume a high fat breakfast (FDA-type 
high fat and high calorie breakfast) after overnight fast of at least 10 hours. Entire breakfast must be consumed within 30 minutes and IMP administered 
30 minutes after start of breakfast. If randomized to the fed arm in Period 1, on Day 22 in Period 2 participants will cross over to the fasted arm and will 
remain fasted prior to IMP administration.  
d. Refer to Safety Section 7  for detailed safety investigations. 
e. Full physical examination will be conducted at EOS on Day 42. Symptom directed physical examination may be performed at any time during confinement 
and at outpatient visits if clinically indicated and at the discretion of the Principal Investigator or delegate. Prior to participant discharge at least 96 hours 
post-IMP administration, clinical unit staff must clarify with the Principal Investigator or delegate if a symptom directed physical examination is required.   
f. Vital signs (tympanic body temperature [ºCelcius], BP [systolic and diastolic, mmHg], HR [beats per minute], respiratory rate [breaths per minute]. 
Tympanic body temperature at the timepoints indicated. BP, HR and RR at the timepoints indicated; measured after participant rested supine for at least 5 
minutes for all scheduled timepoints. Prior to dosing on Day 22, Principal Investigator or delegate must review available results from Days 21 & 22 before 
confirming dosing can proceed.  Time windows: pre-dose: ≤ 2 hours; post-dose during confinement: ± 15 minutes of nominal timepoints up to and including 
12 hours post-dose, and then for all scheduled timepoints as per PK blood sampling time windows in Section 6.3 Table 8 

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g. Triplicate 10-second ECGs will be conducted pre-dose on Day 22 (three lots of triplicate baseline ECGs [ie 9 conducted pre-dose] conducted consecutively 
within 90 minutes prior to dosing with IMP with triplicates performed at least 10 minutes apart from last one to the first one of the next set, prior to any 
blood sampling]) and then at each scheduled timepoint through to Day 26 96H. All triplicate ECGs will be reviewed by the Principal Investigator or 
delegate. Prior to dosing on Day 22, Principal Investigator or delegate must review available results from Days 21 & 22 before confirming dosing can 
proceed (using the mean of each triplicate ECG for ECG intervals). All other scheduled ECGs are single standard 12-lead safety ECGs. From time of IMP 
dosing to Day 26 96H inclusive, ECGs will be conducted within 15 minutes prior to the actual time of PK blood sampling. From Day 29 onwards, ECGs 
will be conducted ± 2 hours of the PK blood sampling time, including EOS. 
h. Safety biochemistry laboratory testing requires fasting for at least 10 hours and to be collected in the morning before breakfast. Total bile acids (TBA) to 
be included in safety biochemistry laboratory tests. Time windows for safety blood sampling are as per PK sampling in Section 6.3 Table 8. Time windows 
for urine collection for safety urinalysis are ≤ 2 hours pre-dose, then ± 1 hour post-dose from the nominal timepoint during confinement and then as per PK 
blood sampling in Section 6.3 Table 8. Prior to dosing on Day 22, Principal Investigator or delegate must review results from Day 21 (except TBA) and 
Day 22 (if available) before confirming dosing can proceed on Day 22 (as per Section 6.1.3).  
i. 
Medically untoward events occurring before time of IMP administration will be recorded and considered as medical history; will be recorded as AEs from 
t = 0.  
j. 
Blood samples for PK analysis will be collected at the scheduled timepoints with time windows as per Section 6.3 Table 8. 
NOTE:  
• 
To respect exact timing of pharmacokinetic samples, the other assessments/activities will be done ahead of the scheduled time from Day 22 to Day 
26. Time windows for PK sampling are defined in Section 6.3 Table 8.  
• 
When several items take place at the same time, the following order is recommended: urinalysis, vital signs, ECG, blood sampling, drug 
administration, meal.  
• 
Date/time of all assessments/activities must be recorded in source document. 
 

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TABLE OF CONTENTS 
1 
PROTOCOL SUMMARY ...................................................................................... 2 
1.1 
PROTOCOL SYNOPSIS .......................................................................................... 2 
1.2 
SCHEMAS .......................................................................................................... 13 
1.2.1 
Part 1 Schema .......................................................................................... 13 
1.2.2 
Part 2 Schema .......................................................................................... 13 
1.3 
SCHEDULE OF ACTIVITIES ................................................................................. 14 
2 
INTRODUCTION AND RATIONALE .............................................................. 36 
2.1 
DISEASE BACKGROUND .................................................................................... 36 
2.2 
INVESTIGATIONAL MEDICINAL PRODUCT - MMV533 ...................................... 36 
2.2.1 
Clinical Studies ........................................................................................ 37 
2.2.2 
Non-Clinical Studies ................................................................................ 37 
2.2.3 
Safety and Risk/Benefit Assessment ......................................................... 37 
2.3 
RATIONALE ....................................................................................................... 39 
2.3.1 
Rationale for the Study ............................................................................ 39 
2.3.2 
Rationale for the Dose ............................................................................. 39 
3 
STUDY OBJECTIVES AND ENDPOINTS ....................................................... 41 
4 
INVESTIGATIONAL PLAN ............................................................................... 43 
4.1 
DESCRIPTION OF OVERALL STUDY DESIGN AND PLAN ..................................... 43 
4.1.1 
Part 1 Single Ascending Dose (SAD) ...................................................... 43 
4.1.2 
Part 2 Effect of Food ............................................................................... 43 
4.1.3 
Adaptive Design Features ........................................................................ 44 
4.2 
DISCUSSION OF STUDY DESIGN INCLUDING CHOICE OF CONTROL GROUPS ...... 48 
4.3 
SELECTION OF STUDY POPULATION .................................................................. 48 
4.3.1 
Inclusion Criteria ..................................................................................... 48 
4.3.2 
Exclusion Criteria .................................................................................... 50 
4.3.3 
Lifestyle Considerations .......................................................................... 53 
4.3.3.1 
Parts 1 and 2 ......................................................................................... 53 
4.3.4 
Screen Failures ........................................................................................ 54 
4.3.5 
Withdrawal of Participants ...................................................................... 54 
4.3.5.1 
Replacement of Withdrawn/discontinued Participants ........................ 54 
4.3.6 
Lost to Follow-Up .................................................................................... 55 
4.3.7 
Study Discontinuation .............................................................................. 55 
4.3.8 
Trial Intervention/Treatment Discontinuation – Toxicity Rules .............. 55 
4.3.8.1 
Toxicity Rules for Part 1 (Single Ascending Dose) ............................ 55 
4.3.8.2 
Toxicity rules for Part 2 (Food Effect) ................................................ 56 
4.3.9 
Emergency Unblinding of Study Participants ......................................... 56 
5 
TRIAL INTERVENTIONS/TREATMENTS ..................................................... 57 
5.1 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ............................................... 57 
5.1.1 
MMV533 .................................................................................................. 57 
5.1.2 
Part 1 Placebo ......................................................................................... 57 
5.2 
SELECTION OF DOSE IN THE STUDY .................................................................. 57 
5.2.1 
MMV533 .................................................................................................. 57 
5.2.1.1 
Part 1 .................................................................................................... 57 
5.2.1.2 
Part 2 .................................................................................................... 58 
5.3 
SELECTION AND TIMING OF DOSE FOR EACH PARTICIPANT ............................... 59 

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5.3.1 
MMV533 .................................................................................................. 59 
5.3.1.1 
Part 1 .................................................................................................... 59 
5.3.1.2 
Part 2 .................................................................................................... 59 
5.4 
DOSE INTERRUPTIONS AND REDUCTIONS .......................................................... 59 
5.5 
SUPPLY, PACKAGING AND LABELLING OF STUDY TREATMENTS ....................... 59 
5.5.1 
MMV533 .................................................................................................. 59 
5.5.2 
Placebo .................................................................................................... 60 
5.6 
STORAGE OF STUDY TREATMENTS ................................................................... 60 
5.7 
ACCOUNTABILITY, RECONCILIATION AND RETURN OF THE STUDY TREATMENTS
 
60 
5.8 
PROHIBITED CONCOMITANT THERAPY ............................................................. 60 
5.9 
TREATMENT COMPLIANCE ................................................................................ 61 
5.10 
MEASURES TO MINIMIZE BIAS .......................................................................... 61 
5.10.1 
Randomisation Procedures ...................................................................... 61 
5.10.2 
Blinding .................................................................................................... 61 
6 
STUDY ASSESSMENTS AND PROCEDURES ................................................ 62 
6.1 
STUDY CONDUCT SCHEDULE ............................................................................ 62 
6.1.1 
Screening ................................................................................................. 62 
6.1.2 
Inclusion/Eligibility/Confinement Visit.................................................... 62 
6.1.3 
General Further Information: ................................................................. 63 
6.2 
PHARMACOGENETICS ........................................................................................ 63 
6.3 
PHARMACOKINETICS ......................................................................................... 64 
6.3.1 
Part 1 ....................................................................................................... 64 
6.3.2 
Part 2 ....................................................................................................... 65 
6.3.2.1 
Period 1 ................................................................................................ 65 
6.3.2.2 
Period 2 ................................................................................................ 65 
7 
SAFETY ASSESSMENTS .................................................................................... 66 
7.1 
PHYSICAL EXAMINATION .................................................................................. 66 
7.1.1 
Part 1 ....................................................................................................... 66 
7.1.2 
Part 2 ....................................................................................................... 66 
7.2 
VITAL SIGNS AND BODY MEASUREMENTS........................................................ 67 
7.2.1 
Body Measurements ................................................................................. 67 
7.2.2 
Vital signs ................................................................................................ 67 
7.3 
12-LEAD ELECTROCARDIOGRAM (ECG) .......................................................... 68 
7.4 
CLINICAL LABORATORY TESTS ........................................................................ 70 
7.4.1 
Safety Blood Tests .................................................................................... 70 
7.4.1.1 
Haematology ........................................................................................ 71 
7.4.1.2 
Biochemistry ........................................................................................ 71 
7.4.2 
Coagulation ............................................................................................. 71 
7.4.3 
Serology ................................................................................................... 72 
7.4.4 
Pregnancy Testing ................................................................................... 72 
7.4.5 
Confirming Menopause............................................................................ 72 
7.4.6 
Urinalysis ................................................................................................. 72 
7.5 
ALCOHOL AND DRUG SCREENING ..................................................................... 72 
7.6 
BECK DEPRESSION INVENTORY ........................................................................ 73 
7.7 
ADVERSE EVENTS (AES) .................................................................................. 73 
7.7.1 
Definitions ................................................................................................ 73 

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7.7.2 
Causal Relationship to Investigational Medicinal Product and Other 
Study Treatments...................................................................................................... 74 
7.7.3 
Severity Grading of Adverse Events ........................................................ 75 
7.7.4 
Documentation of Adverse Events ........................................................... 75 
7.7.5 
Adverse Events of Special Interest (AESI) ............................................... 76 
7.7.5.1 
Hepatic AEs of Special Interest ........................................................... 76 
7.7.5.2 
Cardiac AEs of Special Interest ........................................................... 76 
7.7.5.3 
Haematological AEs of Special Interest .............................................. 77 
7.7.5.4 
Dermatological AEs of Special Interest............................................... 77 
7.7.6 
Treatment of Overdose............................................................................. 77 
7.8 
SERIOUS ADVERSE EVENTS (SAES).................................................................. 77 
7.8.1 
Definitions of Serious Adverse Events (SAEs) ......................................... 77 
7.8.2 
Pregnancy ................................................................................................ 78 
7.8.3 
Reporting for Serious Adverse Events (24 hours) ................................... 79 
7.9 
SAFETY REVIEW COMMITTEE (SRC) ................................................................ 79 
8 
STATISTICAL ANALYSES ................................................................................ 81 
8.1 
GENERAL APPROACH ........................................................................................ 81 
8.2 
SAMPLE SIZE AND JUSTIFICATION ..................................................................... 81 
8.3 
ANALYSIS SETS AND SUB-SETS ......................................................................... 82 
8.3.1 
Analysis Sets ............................................................................................ 82 
8.3.1.1 
Full Analysis Set .................................................................................. 82 
8.3.1.2 
Safety Set ............................................................................................. 82 
8.4 
PARTICIPANT DISPOSITION ............................................................................... 82 
8.5 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ......................................... 82 
8.5.1 
Demographics .......................................................................................... 82 
8.5.2 
Medical History ....................................................................................... 82 
8.5.3 
Prior Medications .................................................................................... 82 
8.5.4 
Eligibility ................................................................................................. 82 
8.6 
PROTOCOL DEVIATIONS .................................................................................... 83 
8.7 
TREATMENT EXPOSURE .................................................................................... 83 
8.8 
SAFETY (PRIMARY ENDPOINT).......................................................................... 83 
8.8.1 
Safety Endpoints ...................................................................................... 83 
8.8.2 
Adverse Events ......................................................................................... 83 
8.8.3 
Concomitant Medications ........................................................................ 84 
8.8.4 
Laboratory Findings ................................................................................ 84 
8.8.5 
Physical Examination .............................................................................. 84 
8.8.6 
Body Measurements ................................................................................. 84 
8.8.7 
Vital Signs ................................................................................................ 84 
8.8.8 
12-lead ECG ............................................................................................ 85 
8.9 
PHARMACOKINETIC ENDPOINTS ....................................................................... 85 
8.9.1 
Pharmacokinetic Parameters .................................................................. 85 
8.9.2 
Concentration-ECG Analysis .................................................................. 85 
8.10 
EXPLORATORY PARAMETERS ........................................................................... 85 
8.11 
INTERIM ANALYSIS ........................................................................................... 85 
9 
STUDY ADMINISTRATION .............................................................................. 86 
9.1 
ETHICAL CONSIDERATIONS ............................................................................... 86 
9.1.1 
Ethical Principles .................................................................................... 86 
9.1.2 
Informed Consent ..................................................................................... 86 

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9.1.3 
Investigator and Human Research Ethics Committee (HREC) 
Responsibilities ........................................................................................................ 86 
9.2 
PROTOCOL ADHERENCE .................................................................................... 86 
9.3 
PROTOCOL AMENDMENTS ................................................................................ 86 
9.4 
DATA HANDLING AND RECORD KEEPING ......................................................... 87 
9.5 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................... 87 
9.6 
PUBLICATION POLICY ....................................................................................... 87 
10 REFERENCES....................................................................................................... 88 
11 APPENDICES ........................................................................................................ 89 
APPENDIX 1: SPONSOR APPROVED CLINICALLY ACCEPTABLE INCLUSION LABORATORY 
RANGES ........................................................................................................................ 89 
APPENDIX 2: SEVERITY GRADING FOR FASTING TBA IN PHASE 1 VOLUNTEERS .......... 91 
 
 
List of Tables  
Table 1: PART 1 Schedule of Activities ......................................................................... 14 
Table 2: PART 2 Schedule of Activities ......................................................................... 16 
Table 3: PART 1 Detailed Schedule of Activities ........................................................... 19 
Table 4: PART 2 Period 1 Detailed Schedule of Activities ............................................ 22 
Table 5: PART 2 Period 2 Detailed Schedule of Activities ............................................ 25 
Table 6: Adaptive Design Features for the Study ............................................................ 45 
Table 7: AUCinf and Safety Ratio calculated for the Starting Dose of 5 mg MMV533 and 
Potential Escalated Doses ................................................................................................ 58 
Table 8: Permitted Time Windows for Pharmacokinetic Blood Sampling ..................... 64 
 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ACT 
Artemisinin-based combination therapy 
ADME 
Absorption, distribution, metabolism, excretion 
AE 
Adverse event 
Ae0-t 
Cumulated amount of drug excreted in urine from time 0 to time t 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
AUC 
Area under the curve 
BDI 
Beck Depression Inventory 
BMI 
Body mass index 
CLR0-t 
Renal clearance of drug estimated from time 0 to time t 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration observed 
CSR 
Clinical study report 
DBP 
Diastolic blood pressure 
DME/T 
Drug metabolism enzymes and drug transporters 
ECG 
Electrocardiogram  
EOS 
End of study visit 
FDA 
Food and Drug Administration (US) 
fe0-t 
Fraction of dose of drug excreted in urine from time 0 to time t 
FSH 
Follicle stimulating hormone 
GGT 
Gamma-glutamyl transferase 
GSB 
Global Safety Board 
HDL 
High density lipoprotein 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
HREC 
Human Research Ethics Committee 
IC50 
Concentration for 50% inhibition 
IMP 
Investigational medicinal product 
INR 
International normalised ratio 
IUD 
Intrauterine device 
LDH 
Lactate dehydrogenase 

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LFT 
Liver function tests 
LOQ 
Limit of quantification 
LPLV 
Last patient last visit 
MMV 
Medicines for Malaria Venture 
MPC 
Minimal parasiticidal concentration 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events  
NOAEL 
No observed adverse effect level 
OTC 
Over the counter  
PBPK 
Physiologically based pharmacokinetics 
PK 
Pharmacokinetics  
SAD 
Single ascending dose 
SBP 
Systolic blood pressure 
SCID 
Severe combined immunodeficiency (mouse model) 
SRC 
Safety Review Committee 
SSR 
Southern Star Research Pty Ltd 
TBA 
Total bile acids 
t1/2z 
Terminal half-life  
TEAE 
Treatment emergent adverse event 
tlag 
Lag time  
tmax 
Time to reach maximum plasma concentration (Cmax) 
ULN 
Upper limit of normal 
Vss/F  
Apparent volume of distribution at the steady state after single 
dose 
Vz/F 
Apparent volume of distribution after single dose 
WHO 
World Health Organisation 
 
 

Medicines for Malaria Venture
Protocol No: MMV*MMV 533 _19 _01
Version 7.0
Date:27 October 2021
PROTOCOL APPROVAL/ SIGNATURES
I herewith approve the following protocol entitled "A two-part, Phase 1 study to assess
the safety, tolerability, and pharmacokinetic prolile of ascending single doses of
MMV533, including a pilot food evaluation in healthy participants.", Y7.0 27
October 2021. Effective Date27 October 2021
SPONSOR SIGNATURE
Signature:
r,{!--r'- ,
ul----
Name:
Dr Stephan Chalon MD PhD
Role:
Medical Director, Medicines for Malaria Venture
Date:
WLwr,rox
Signature:
Name:
Dr Andrea Kuemmerle PhD
Role:
Clinical Scienee Lead- Medicines for Malaria Venture
Date:
____J_J202r
DOCUMENT HISTORY
Document
Hisfory
Amendment 5
V7.0 27 October 2021
Amendment 4
V6.022Iune2021
Amendment 3
V5.0 16 December 2020
Amendment 2
V4.0 18 Seotember 2020
Amendment 1
Y3.0 24 June 2020
Orisinal Protocol
Y2.025March2020
CONFlDENTIAL
Page 34 of91
27
Oct

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PRINCIPAL INVESTIGATOR SIGNATURE 
 
A two-part, Phase 1 study to assess the safety, tolerability, and pharmacokinetic 
profile of ascending single doses of MMV533, including a pilot food evaluation in 
healthy participants. 
MMV_MMV533_19_01 
 
Version: V7.0 27 October 2021 
Issue Date: 27 October 2021 
 
Principal Investigator Agreement 
 
I have read the above-mentioned protocol and am aware of my responsibilities as Principal 
Investigator for this study. As such, I agree to: 
• Personally supervise the conduct of this trial; 
• Conduct the trial in accordance with International Conference on Harmonization 
(ICH) E6 Good Clinical Practice: Consolidated Guidance (GCP), applicable 
regulatory requirements, and the protocol; 
• Comply with the procedures for data recording and reporting as required by the 
regulatory authorities and the Sponsor; 
• Permit monitoring, auditing, and inspection of study records as required by ICH 
GCP; 
• Retain the essential clinical study documents as required by ICH GCP and the 
Sponsor. 
 
Principal Investigator Signature: 
 
Principal Investigator Name: 
Jason Lickliter 
Date: 
____/____/2021 
 
 

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2 INTRODUCTION AND RATIONALE 
MMV533 is in development as a potential single dose cure, fast acting and long-lasting 
treatment for malaria.   
2.1 
DISEASE BACKGROUND 
Malaria continues to be a challenge globally. In 2018, some 228 million cases of malaria 
occurred worldwide, resulting in an estimated 405,000 deaths.1 Although the incidence 
rate of malaria globally is declining, the rate of decline has slowed dramatically, 
remaining at similar levels to that reported in 2014. In 2018, nineteen countries in sub-
Saharan Africa and India accounted for almost 85% of global malaria cases, and 94% of 
all malaria deaths were from the African region.  
Malaria is a cyclical parasitic infection of humans and female Anopheles mosquitoes.2 As 
a brief summary, after a female Anopheles mosquito feeds on the blood of a human 
infected with the malarial parasite it is asymptomatically infected with the parasite. The 
parasites grow and multiply in the gut of the mosquito before migrating to its salivary 
glands, and the infected mosquito then injects some of the infected saliva into the next 
human it feeds on. In the human, the parasites first migrate to the liver before infecting 
red blood cells, where the cycle continues with successive generations of asexual parasites 
invading and destroying red blood cells. These blood stage parasites cause the symptoms 
of malaria. After a period of time, some of the blood stage parasites differentiate into male 
and female forms (gametocytes) which continue the cycle of infection when ingested by 
a female Anopheles mosquito feeding on the infected human. Worldwide, Plasmodium 
falciparum is the predominant malaria parasite, causing the vast majority of cases in 
Africa and many cases in South-East Asia, Eastern Mediterranean region and the Western 
Pacific Region. 1 
The World Health Organisation (WHO) promotes several strategies to help combat 
malaria, including preventing mosquito bites with use of insecticide-treated mosquito nets 
while sleeping and insecticide spraying of indoor walls, use of preventative therapies 
especially for vulnerable groups such as children and pregnant women, and improving 
institutional structures for accessing care to diagnose and treat malaria. 1 For treatment of 
malaria, artemisinin-based combination therapy (ACT) has been widely implemented, 
with an estimated 3 billion courses of ACT procured globally between 2010 and 2018. 
However, parasite resistance to artemisinin and other therapies are becoming more 
common especially in Thailand and other South-East Asian countries, while mosquito 
resistance to insecticide is also widespread.  
Therefore, there remains an urgent need to continue the clinical development of novel, 
effective and well-tolerated anti-malarial drugs, of which MMV533 is a promising 
candidate.   
2.2 
INVESTIGATIONAL MEDICINAL PRODUCT - MMV533 
MMV533 is a first in class, fast acting, orally bioavailable blood stage inhibitor of 
Plasmodium falciparum with a long half-life. Its mechanism of action is unknown. 
MMV533 is being developed for the curative treatment of uncomplicated malaria caused 
by P. falciparum in adults and children, and has been evaluated in a range of 
pharmacological models of malaria.  

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2.2.1 Clinical Studies 
MMV533 has not yet been tested in humans.  Part 1 of this study will be the first time 
MMV533 has been administered to humans.  
2.2.2 Non-Clinical Studies 
MMV533 has previously been evaluated extensively by Sanofi in nonclinical studies as 
compound SAR441121. SAR441121 has been acquired by MMV, and renamed as 
‘MMV533’ (short for MMV688533). Refer to the Investigator’s Brochure for further 
details. 
MMV533 has been shown to act on malarial parasite Ring/Schizont erythrocytic stages, 
and has high potency in vitro with an IC50 of 4-8nM on a panel of sensitive and resistant 
strains of Plasmodium falciparum, 2.5-21nM on a panel of field and mutant strains and 
0.8-18 nM on field isolates.   
MMV533 has been shown to be highly efficacious with a single oral dose against 
Plasmodium falciparum in vivo in severe combined immunodeficiency (SCID) mouse 
model. MMV533 also exhibited an outstanding resistance profile after no mutant selection 
was observed after 6 months of drug pressure.   
As observed in animals, a high bioavailability of MMV533 is expected in human based 
on the good in vitro permeability (~ 30.10-7cm-1 in standard condition). No major food 
effect is anticipated in human with this compound. In vitro investigations in human 
hepatocytes in primary culture showed MMV533 is very slowly metabolized. Based on 
this experiment, predicted in vivo metabolic clearance values of MMV533 correspond to 
0.6, 1.4 and 1.0% of human hepatic blood flow at 0.1, 1 and 10 μM, respectively. 
Complementary investigation with a model allowing longer incubation time (HepatoPac) 
suggest involvement of CYP3A4 and possibly CYP2D6 at low concentration (0.1µM) in 
the metabolic clearance. MMV533 showed in vitro competitive inhibition of  CYP2B6, 
2C8, 2C9, 2C19, 2D6 with apparent Ki values of 12.6, 0.783, 2.39, 8.99 and 4.04 μM, 
respectively and exhibited time-dependent inhibition of CYP3A with KI and kinact values 
of 28 μM and 0.036 min-1, respectively. Moreover, there is a risk of increase in exposure 
of drug sensitive substrates of these CYP isoforms when co-administered with MMV533. 
This compound was not identified as an inducer of CYP1A1/2, CYP2B6, or CYP3A4. 
Based on allometric scaling and physiologically based pharmacokinetic (PBPK) 
modelling, the predicted t1/2z in humans is approximately 100 hours. 
MMV533 was found to be a P-glycoprotein (P-gP) inhibitor on Caco-2 cell line with 
digoxin as PgP substrate (IC50:108 μM). As such, it cannot be ruled out that co-
administration of MMV533 will affect the pharmacokinetics of a sensitive substrate such 
as digoxin. 
2.2.3 Safety and Risk/Benefit Assessment  
Part 1 of this study will be the first time that MMV533 is administered to humans, and as 
such there is no existing clinical safety information.  
Nonclinical safety testing included genetic toxicity and phototoxicity studies, as well as 
pivotal Good Laboratory Practice (GLP) safety pharmacology studies and rat and dog 
repeat dose toxicity studies. All pivotal toxicity and safety pharmacology studies were 
conducted by the oral route, which is the intended human route.  
Potential risks have been identified through review (MMV Global Safety Board) of the 
nonclinical studies conducted to date with MMV533: 

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• MMV533 in vitro induced an inhibition of human ether-a-go-go-related gene 
(hERG) current at 3 μM (average of 22% inhibition, statistically significant) and 
IC50 value was estimated to be greater than 3 μM. In the Purkinje fiber assay, there 
was no evidence of torsadogenic potential up to 6.4 μM, while some minimal effects 
attributable to calcium and sodium channels were noted from 4.9 μM. In the 
subsequent anesthetized guinea-pig effect (continuous intravenous (IV) infusion at 
rising doses of 10, 20 and 30 mg/kg), none of the in vitro effects translated into 
impairment of the cardiovascular function. This was confirmed in the GLP safety 
pharmacology study in conscious, unrestrained, and telemetered beagle dogs. ECG 
monitoring (QTc interval including two correction methods used in this study, i.e. 
QTcF and QTcB) will be performed during single dose escalation in healthy 
participants and detailed reports will be available for the Safety Review Team to 
evaluate whether dose-escalation can proceed. 
• In the 2-week GLP studies, the dog was the most sensitive species with a no-
observed-adverse-effect-level (NOAEL) of 1mg/kg/day above which changes in 
safety laboratory tests (notably alanine transaminase (ALT)/aspartate transaminase 
(AST) and bile acids elevations) were detected (3mg/kg/day). These changes 
appeared after multiple dose administration and are considered reversible based on 
monitoring in the reversibility group. At 3mg/kg/day, two male dogs also showed 
minimal bile duct hyperplasia after multiple dose administration which appeared to 
be reversible based on the analysis of the reversibility group. These findings could 
possibly suggest an effect of MMV533 or a metabolite on acid bile homeostasis 
during multiple dose administration. The two dogs with minimal bile duct 
hyperplasia are not different with respect to exposure or liver enzymes parameters 
than the other dogs in the same group. Standard liver function parameters AST, ALT, 
alkaline phosphatases, gamma-glutamyl transferase (GGT), total bilirubin, indirect 
bilirubin and conjugated bilirubin) will be monitored throughout of the study while 
Total Bile Acids (TBA) measured in a fasting state will be part of the extended safety 
monitoring in Part 1 (single dose escalation) and Part 2 (Food effect). Additionally, 
as serum bile acids are not part of the NCI-CTCAE criteria, a specific toxicity rule 
is proposed for this First-In-Human study (Part 1). The proposed threshold for 
clinically relevant elevation in fasted total bile acids in serum is based on published 
human data.3,4  
• From these preclinical safety data generated in rodents and dogs with toxicological 
doses of MMV533 and after a two week administration, it can be concluded that the 
main safety risk for human volunteers receiving a single dose of MMV533 could 
possibly consist of an acute or delayed elevation in fasting TBA reflecting a direct 
drug effect on bile acid secretion and interpreted as a marker for subsequent drug-
induced bile duct injury. As the findings in dogs are considered reversible, no major 
persistent or long-lasting effect would be expected within the proposed dose range 
(5 to 400 mg). Additionally clinically relevant increase in fasted TBA will be used 
as a toxicity criteria in Part 1. 
Refer to the Investigator’s Brochure for more detailed information about the known and 
expected benefits and risks of MMV533. The risks to the study participants will be 
managed by frequent safety monitoring, including close monitoring during periods of 
confinement at the clinical unit when MMV533 as the investigational medicinal product 
(IMP) will be administered.  Safety monitoring will include clinical laboratory safety tests 
(chemistry, haematology, serology, urinalysis), physical examination, vital signs and 
frequent ECG analysis. In Part 1, the blinded safety data (including TBA results if 

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available) of sentinel groups of 2 participants up to and including 96 hours post-dose will 
be assessed by the Principal Investigator, Sponsor Medical Director and study Medical 
Monitor prior to commencing the study participation of the rest of the cohort.   
There are no known direct benefits to the study participants, as they are healthy 
volunteers. However, the study has been designed to minimise the risk to participants by 
appropriate selection of eligibility criteria, and rigorous schedule of clinical monitoring, 
in-house observation and IMP administration and treatment duration.  
2.3 
RATIONALE 
2.3.1 Rationale for the Study 
This is a first-in-human study of MMV533 divided into 2 parts. MMV533 is being 
developed for the curative treatment of uncomplicated malaria caused by P. falciparum 
in adults and children as a single dose regimen in a fixed-dose combination with another 
non-artemisinin antimalarial drug.  However this study will be performed in healthy adult 
volunteers with no history of malaria to exclude bias related to previous malarial infection, 
underlying disease or pathological conditions on the safety and PK parameters. The study 
designs for each part are well established for first-in-human studies, and are appropriate 
to assess safety, tolerability and preliminary PK.5  
Part 1 will be the first safety, tolerability and PK evaluation of single ascending doses 
(SAD) of MMV533 administered orally to healthy adults under fasting conditions. This 
part of the study will be double-blind, placebo-controlled and randomised, and is an 
established SAD design to obtain preliminary safety and tolerability data without bias.  
Part 2 will evaluate the effect of food on the PK of MMV533 after being administered 
orally to healthy adults. This part of the study will be open-label, cross-over and 
randomised for either the fed or fasted arm, and is an appropriate design to obtain 
information on the effect of food on oral dosing of MMV533. This evaluation is 
considered a pilot food effect evaluation and will be conducted with a dose expected to 
be close to the therapeutic dose. A single dose of MMV533 will be used for Part 2, based 
on results obtained for Part 1.  
2.3.2 Rationale for the Dose 
A human dose that could maintain blood concentrations above Minimal Parasiticidal 
Concentration (MPC) for 100 hours (corresponding to 2 parasite erythrocyte cycles) was 
identified as a target minimal efficacious dose for the treatment of acute uncomplicated 
Plasmodium falciparum malaria. Using allometry methods and physiologically based 
pharmacokinetics (PBPK) modelling for predicting human PK profile and a typical 
human body weight of 70 kg, the predicted efficacious human dose of MMV533 is 
estimated to be between 50 and 70 mg.  
For the Part 1 single ascending dose study, the proposed starting dose is 5 mg, which in 
humans is predicted to generate mean Cmax and AUC values of 4.3 ng/ml and 949  ng∙h/ml, 
respectively. These estimates provide a predicted safety margin of 120- and 139-fold-fold 
when compared to the NOAEL Cmax (517 ng/ml) and cumulative AUC0-360 (125 µg∙h/ml) 
in the most sensitive species (dog) at 1 mg/kg/day.   
After completion of Cohorts 1 to 3 in Part 1, the Safety Review Committee (SRC) will 
review all available safety data up to and including Day 14 and PK data up to and 
including Day 8 before the next cohort may progress to the next dose level. For Part 1 

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cohorts from Cohort 4 onwards, safety and PK data up to and including Day 21 will be 
reviewed by the SRC.  
The highest single dose will be capped at 400 mg, as the safety ratio is 1.7 for AUC and 
Cmax and this dose is approximately 5.5 to 8 times above the predicted active dose based 
on MPC determined from SCID models. See also Section 5.2.1.1. 
For Part 2, the dose will be at least 3-fold less than a dose determined to be safe by the 
SRC in Part 1 as described in Section 5.2.1.2.  
 
 

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3 STUDY OBJECTIVES AND ENDPOINTS 
All parts to be assessed in healthy, adult participants. 
Part 1 and 2 – Single ascending dose (SAD) and Food Effect 
Objectives 
Endpoints 
Primary: 
 
• The 
tolerability 
and 
safety 
of 
ascending single oral doses of 
MMV533 
• Assessment of adverse events (AEs) 
/treatment-emergent adverse events 
(TEAEs) (treatment phase for Part 1 
and 
2 
defined 
as 
from 
IMP 
administration up to and including 
EOS).  
• Clinical 
laboratory 
evaluations 
including hematology, biochemistry, 
and urinalysis. 
• Vital signs (blood pressure and heart 
rate supine and standing, respiratory 
rate and body temperature),  
• 12-lead triplicate ECG: triplicate 
ECGs with central ECG reading from 
Day 1 pre-dose up to and including 
96 hours post-IMP administration, 
and single ECGs at all subsequent 
timepoints: RR, heart rate (HR), PR, 
QRS, QT, QTcB and QTcF. Overall 
assessment as normal, abnormal not 
clinically significant, or abnormal 
clinically significant.  
Secondary: 
 
• To characterize the pharmacokinetic 
(PK) parameters of parent drug and 
major metabolites after single oral 
doses of MMV533 
Pharmacokinetic of MMV533:  
• Plasma parameters: at least but not 
limited to Cmax, tmax, tlag, AUClast, 
AUCinf, t1/2, CL/F, Vd/F  
Pharmacokinetics of major metabolites (if 
applicable): 
• Plasma parameters: at least Cmax, tmax, 
AUClast, AUC 
 
• To obtain preliminary information on 
the effect of a high-fat meal on the PK 
of MMV533 
• Comparison 
of 
MMV533 
PK 
parameters 
(as 
outlined 
above) 
between fed and fasting doses 

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Part 1 and 2 – Single ascending dose (SAD) and Food Effect 
Objectives 
Endpoints 
Exploratory: 
 
• To explore the excretion of MMV533 
in urine 
• Exploratory Urine parameters: Ae0-t, 
fe0-t and CLR0-t. 
• To perform genotyping of CYP450 
and/or Transporter genes related to 
drug 
absorption, 
distribution, 
metabolism and excretion in the 
event of specific circumstances 
including abnormal or unexpected 
PK or safety results (to be decided 
when all data available after last 
patient last visit [LPLV]).  
• Investigation 
of 
allelic 
variants 
related to drug metabolism enzymes 
and drug transporters (DME/T) 
potentially 
involved 
in 
the 
absorption, distribution, metabolism 
and excretion (ADME) of MMV533.  
 
 

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4 INVESTIGATIONAL PLAN 
4.1 
DESCRIPTION OF OVERALL STUDY DESIGN AND PLAN 
The study is Phase 1 and will be conducted in two parts. Part 1 is first-in-human and will 
provide information on safety, tolerability and dosing.  Part 2 will provide information on 
the effect of food on the PK of the IMP.   
4.1.1 Part 1 Single Ascending Dose (SAD) 
Part 1 is a double-blind, randomised, placebo-controlled, sequential ascending single dose 
study in healthy adult volunteers.  Up to 64 participants will be enrolled, with 7 cohorts 
of 8 participants planned and 1 additional optional cohort of 8 participants if needed 
according to the observed safety, tolerability and PK results.  In each cohort, 6 participants 
will be randomised to receive MMV533, and 2 to receive placebo. Efforts should be made 
within each dosing cohort to have a reasonable gender balance.  
At each dose level, a sentinel dosing strategy will be implemented to best ensure safety.  
This strategy will involve dividing each cohort into 2 subgroups, with the first group 
(‘sentinel cohort’) composed of 2 participants dosed on the first day. One participant in 
the sentinel cohort will be administered MMV533, with the other participant administered 
placebo.  The Principal Investigator, Medical Monitor, and the Sponsor’s Medical 
Director will review blinded safety and tolerability data (including, but not limited to, 
AEs, vital signs, ECG and clinical laboratory safety tests) up to and including 96 hours 
post-dose. TBA results will be reviewed if available. Only after a satisfactory safety 
review will the remaining participants in the cohort proceed with dosing.  The 96 hour 
window may be modified by the SRC if the observed IMP half-life is longer than 
predicted.  
Study assessments and procedures are as indicated in Table 1 and Table 3 and as described 
in Sections 6 and 7. Briefly, potential participants will be screened between Day -28 to 
Day -1, with written informed consent obtained prior to any study procedures and 
eligibility to be assessed according to the inclusion and exclusion criteria.  Eligibility will 
be confirmed when participants are admitted to the clinical unit on Day -1 for 
confinement. Safety laboratory tests will be conducted on Day -1 with results to be 
reviewed prior to planned dosing with IMP on Day 1 (there is no Day 0). Safety 
assessment results available prior to dosing must satisfy relevant inclusion/exclusion 
criteria before dosing.  Participants will be dosed with a single oral dose of IMP on Day 
1 as described in Section 5.1, with blood sampling for PK analysis and safety assessments 
at times indicated in Table 3. Participants will be discharged a minimum of 96 hours post-
IMP administration, and will attend outpatient visits to the clinical unit for safety 
monitoring and blood sampling for PK analysis on at least Days 8, 14 and 21, and for the 
end of study visit (EOS) on Day 28 (648 ± 24 hours post-IMP administration).   
4.1.2 Part 2 Effect of Food 
Part 2 is an open label, 2-period cross-over, randomised, pilot food effect study, designed 
to provide preliminary information on the effect of a high-fat meal on the PK of a single 
dose of IMP to healthy adult volunteers. There will be a single cohort of 8 participants. 
Part 2 may be conducted in parallel to or after completion of Part 1, at the discretion of 
the SRC. Efforts should be made to have a reasonable gender balance.  
The dose to be used in Part 2 will be selected by the SRC based on the PK and safety 
results obtained in Part 1, and also taking into account the human efficacious 

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dose/exposure predicted from preclinical efficacy studies in rodent malaria models (see 
Investigator’s Brochure for further details).  As there may be increased exposure to the 
IMP when given to participants after food, the dose for Part 2 will be at least 3-fold less 
than the highest dose determined to be safe in Part 1.  
Study assessments and procedures are as indicated in Table 2, Table 4 and Table 5 and as 
described in Sections 6 and 7. Briefly, potential participants will be screened between Day 
-28 to Day -1, with written informed consent obtained prior to any study procedures and 
eligibility to be assessed according to the inclusion and exclusion criteria. Eligibility will 
be confirmed when participants are admitted to the clinical unit on Day -1 for 
confinement. Safety laboratory tests will be conducted on Day -1 with results to be 
reviewed prior to planned dosing with IMP on Day 1 (there is no Day 0). On Day 1, safety 
assessment results available prior to dosing must satisfy relevant inclusion/exclusion 
criteria before dosing. On Day 1, participants will be randomised to receive a single oral 
dose of IMP on Day 1 in either a fasted or fed condition in a 1:1 ratio.  The fasted condition 
is defined as an overnight fast of at least 10 hours. The fed condition is defined as the 
participant consuming a high-fat meal after an overnight fast of at least 10 hours, with the 
meal consisting of an FDA-type high fat and high calorie breakfast.6 The participants will 
be required to consume the whole meal prior within 30 minutes, and the IMP will be 
administered as per Section 5.1 30 minutes after the participant has started eating.   
After administration of the IMP for both fed and fasted arms, blood samples will be taken 
for PK and safety analysis at times indicated on Table 4 and as described in Sections 6 
and 7. Participants will be discharged from the clinical unit a minimum of 96 hours post-
IMP administration, and will attend outpatient visits to the clinical unit for safety 
monitoring and blood sampling for PK analysis on at least Days 8 and 14. 
After a wash-out time of 21 days, participants will be admitted to the clinical unit on Day 
21 for Period 2 confinement. Clinical laboratory safety tests will be conducted on Day 21, 
with results to be reviewed prior to the second dosing with the IMP on Day 22. Other 
safety assessment results from Days 21 & 22 available prior to dosing will also be 
reviewed by the Principal Investigator or delegate before confirming dosing can proceed 
on Day 22. On Day 22, participants will cross over to the opposite arm (either fed or 
fasted) and will be administered the IMP as per Period 1 and as described in Section 5.1.  
Blood samples for PK and safety analysis will be taken at times indicated in Table 5 and 
as described in Sections 6 and 7. Participants  will be discharged a minimum of 96 hours 
post-IMP administration and will attend outpatient visits to the clinical unit for safety 
monitoring and blood sampling for PK analysis on at least Days 29, 35 and 42. The EOS 
will be conducted on Day 42.   
NOTE: Prior to Part 2 commencing, the wash out period of 21 days will be assessed by 
the SRC based on the elimination half-life of IMP observed in Part 1. If the elimination 
half-life of the IMP is substantially different from that predicted from preclinical data, the 
wash-out period and subsequent timing of assessments for Part 2 may be adjusted 
accordingly.   
4.1.3 Adaptive Design Features 
This study incorporates the use of an adaptive design. Study specific adaptive features 
and their limits are described in Table 6. 

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Table 6: Adaptive Design Features for the Study 
Adaptive Study 
Design Areas  
Features 
Limits 
Dose 
1. All anticipated dosing levels in 
Part 1 & 2 beyond the initial 
dose/cohort1 of Part 1 can be 
adjusted in accordance with PK, 
safety 
and 
tolerability 
data 
collected up to the decision-
making time-point. 
 
I. The PK derived mean exposure for a 
dosing regimen will not exceed the 
defined PK exposure limit (based 
AUC0-last). Please refer to Section 
2.3.2.  
PART 1 - SAD: 
II. The starting dose for Part A of the 
study cannot be changed (5 mg).  
III. If the pharmacokinetic analysis with 
the starting dose demonstrates lower 
exposure compared with the initial 
predictions, the highest revised dose 
for Part A of the study will not 
exceed 400 mg and an amendment 
will be submitted if doses > 400mg 
are anticipated.  
IV. If the pharmacokinetic analysis with 
the starting dose demonstrates lower 
exposure compared with the initial 
predictions, 
the 
revised 
dose 
increments between the dose levels 1 
to 4 in Part 1 will be no more than 
3-fold.  
V. The dose increments between the next 
dose levels (from dose level 4 
onwards) in Part 1 will be no more 
than 2-fold. 
PART 2 – Food Effect: 
VI. The 
planned 
dosing 
regimen 
anticipated mean exposures will not 
exceed mean exposures (based on 
AUC0-last) previously explored in Part 
1 
with 
acceptable 
safety 
and 
tolerability, i.e. exposure levels at 
which no study specific criteria 
stopping dose progression and/or 
escalation were met. 
VII. A potential positive food effect of no 
less than 3-fold will be assumed when 
setting the dose for Part 2. 
Timing 
2. Part 2 can overlap with Part 1 
I. 
Minimum data requirements for 
initiating each dose level in Parts 1 
and 2 apply as outlined in Rules for 
escalation/progression. 

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Adaptive Study 
Design Areas  
Features 
Limits 
Flexible Cohort 
Sizes 
3. Withdrawn participants can be 
replaced at the discretion of the 
sponsor and PI. 
4. 
Replacement participants may be 
enrolled in an ongoing cohort or 
dosed together as a group or 
dosed separately.  
5. The number of participants in Part 
2 can be extended to gather 
further information on this dose 
level/impact of food. 
I. The maximum extension of Part 2 is 
100% of the original cohort size at the 
selected dosing regimen. 
 
Samples 
and 
Assessments 
 
7. The in-house confinement period 
may be shortened if: 
a. 
The 
evolving 
PK 
data 
demonstrates a shorter half-
life than anticipated. 
b. The Safety Review Team 
(SRT) 
considers 
it 
appropriate 
from 
a 
safety/tolerability point for 
an upcoming dose cohort. 
 
8. The in-house confinement period 
or follow-up period may be 
prolonged if: 
a. It is considered clinically 
necessary by the PI for 
individuals on a case-by-case 
basis. 
b. The Safety Review Team 
(SRT) considers it necessary 
from 
a 
safety/tolerability 
point for an upcoming dose 
cohort. 
c. The follow-up period for a 
dose cohort may be prolonged 
if evolving PK data require a 
longer follow-up period. 
I. A minimum in-house confinement 
period of 72 hours post dose. 
II.  If the in-house confinement period is 
shortened, the minimum in-house 
period for study cohorts will be based 
on evolving safety, tolerability, and 
PK data.  
 
 
 
I. A 
maximum 
extended 
in-house 
confinement period or follow-up 
period 
triggered 
by 
safety 
observations for a given participant 
cannot be defined, as the extension 
will be as long as necessary to ensure 
the 
safety 
of 
the 
individual 
participant(s).  
II. The maximum extended in-house 
confinement period or follow-up 
period for study cohorts will be 
based on evolving safety, tolerability, 
and PK data and will not usually 
exceed 5 half-lives of the IMP 
following the last dose.  
 
 
9. Additional safety blood and/or 
urine samples/variables may be 
taken or analyzed if: 
a. 
It is considered clinically 
necessary by the PI and 
Medical 
Monitor 
for 
I. For individuals, a maximum number 
of safety blood samples will be 
determined on a case-by-case basis 
and 
cannot 
be 
pre-defined 
as 
investigations will be performed as 

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Adaptive Study 
Design Areas  
Features 
Limits 
individuals on a case-by-case 
basis. 
b. The 
SRT 
considers 
it 
necessary 
from 
a 
safety/tolerability point for 
an upcoming dose cohort. 
necessary to ensure the safety of the 
individual participants.  
II. In any case, the study specific 
maximum blood volume will not be 
exceeded.  
 
10. Timing of blood and urine PK 
and/or exploratory assessments 
may be adjusted in accordance 
with evolving data and dosing 
schedule. 
11. Additional or less blood and urine 
PK 
and/or 
exploratory 
assessments may be taken in 
accordance with evolving data 
and dosing schedule. 
I. Minimum: sufficient PK samples to 
establish full protocol specific serum 
PK profile.  
II. Study specific maximum blood 
volume will not be exceeded. 
 
12. Timing of safety assessments 
including but not limited to 
laboratory safety samples, vital 
signs and ECGs may be adjusted 
in accordance with evolving data 
and dosing schedule. 
13. Additional 
safety 
assessments 
including but not limited to 
laboratory safety samples, vital 
signs and ECGs may be taken in 
accordance with evolving data 
and dosing regimens. 
I. Alterations in timing of the safety 
assessments need to be a reflection of 
the established PK, safety and 
tolerability profile up to the decision-
making time-point. 
II. Alterations need to be made in the 
spirit of the current Clinical Study 
Protocol (i.e. focus on the capture of 
essential and useful data) and not 
affect the risk profile of the study. 
 
14. Specialist referrals (e.g. to a 
cardiologist or neurologist) may 
be made (and may include all 
relevant 
assessments 
and 
investigations) if it is considered 
clinically necessary by the PI or 
Sponsor or SRC for individuals on 
a case-by-case basis. 
I. A maximum for individuals will be 
determined on a case-by-case basis 
and 
cannot 
be 
pre-defined 
as 
investigations will be performed as 
necessary to ensure the safety of the 
individual participants. 
 
15. Except for those subjects that have 
been 
randomized, 
screening 
assessments 
performed 
on 
volunteers screened for another 
study can be used for this study to 
avoid unnecessary tests.  
 
I. The assessments must meet protocol 
criteria (e.g. the method to be used). 
II. The assessments must be performed 
within the protocol defined screening 
window. 
 
 
16. ECG analysis for the purpose of 
exploratory 
QT/QTcF/QTcB 
analysis 
/ 
intensive 
cardiac 
assessments may be performed on 
I. 
For the purpose of exploratory 
QT/QTcF/QTcB analysis ECG 
sampling 
must 
match 
PK 
sampling time.  

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Adaptive Study 
Design Areas  
Features 
Limits 
selected or all dose levels in Part 
1. Under these circumstances : 
- If PK sampling times are 
changed then the ECG sampling 
times 
will 
be 
changed 
accordingly, for the purpose of 
exploratory 
QT/QTcF/QTcB 
analysis/ 
intensive 
cardiac 
assessments.  
 
 
17. For Part 2, the washout period 
may be increased for both periods 
if IMP half-life calculated from 
Part 1 PK data is longer than 
expected.  
I. 
The washout period will be of at 
least 5 half-lives as recommended 
by regulatory guidances. 
 
4.2 
DISCUSSION OF STUDY DESIGN INCLUDING CHOICE OF CONTROL 
GROUPS 
The study design for Parts 1 and 2 are well established for first-in-human studies and are 
appropriate to assess safety, tolerability and preliminary PK of the IMP.   
Part 1 is the only part to use a placebo-controlled arm in a double-blind, randomised study. 
This is appropriate for first-in-human study to provide information on the safety and 
tolerability of the IMP compared to placebo. Part 1 will also use a sentinel group strategy, 
whereby 2 participants from each cohort form a subgroup that undergoes dosing prior to 
the rest of the cohort. Dosing of the rest of the cohort with the IMP will only proceed once 
preliminary blinded safety (including TBA results if available) from the sentinel subgroup 
up to and including 96 hours post-dose are assessed by the Principal Investigator, study 
Medical Monitor and the Sponsor’s Medical Director.  
Parts 2 is open label, to assess the effect of food on the PK of IMP. Control groups are not 
required or appropriate for this part which will be considered a pilot food effect 
investigation. 
4.3 
SELECTION OF STUDY POPULATION 
The intended patient population for MMV533 is people infected with Plasmodium 
falciparum, but this first-in-human study will be performed in healthy adult volunteers. 
Efforts should be made within each dosing cohort to have a reasonable gender balance.  
4.3.1 Inclusion Criteria 
Potential participants must fulfil all of the following inclusion criteria to be eligible to 
participate in the study: 
1. Males and females (of childbearing and non-childbearing potential) , between 18 and 
55 years of age, inclusive. Women of childbearing potential (WOCBP) must use 
highly effective methods of birth control (see Inclusion #3).  
2. Females of non-childbearing potential:  

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a. Natural (spontaneous) post-menopausal defined as being amenorrhoeic for at 
least 12 months without an alternative medical cause with a screening follicle 
stimulating hormone level (FSH) >25 IU/L (or at the local laboratory levels for 
post-menopause) 
b. premenopausal with irreversible surgical sterilization by hysterectomy and/or 
bilateral oophorectomy or salpingectomy at least 6 months before screening (as 
determined by participant medical history)  
3. Women of childbearing potential that have or may have male sexual partners during 
the course of the study must agree to the use of a double method of contraception of 
a highly effective method of birth control combined with a barrier contraceptive 
(condom) when appropriate from screening visit to until 60 days after the last dose 
of IMP (covering a full menstrual cycle of 30 days starting after 5 half-lives of last 
dose of IMP. This duration is based on the predicted half-life of IMP, and may be 
amended once the actual half-life is calculated during this study).  
Note: Highly effective birth control methods include: combined (estrogen and 
progestogen containing) oral/intravaginal/transdermal hormonal contraception 
associated with inhibition of ovulation, progestogen-only oral/injectable/implantable 
hormonal contraception associated with inhibition of ovulation, intrauterine device 
(IUD), 
intrauterine 
hormone-releasing 
system, 
bilateral 
tubal 
occlusion, 
vasectomised partner, sexual abstinence or same sex relationship.  
4. Male participants who have, or may have female sexual partners during the course of 
the study must agree to use a double method of contraception including condom plus 
diaphragm, or condom plus stable insertable (implant or IUD), injectable, 
transdermal or combination oral contraceptive by the female partner, from the time 
of informed consent through to 90 days after the last dose of the IMP (covering a full 
spermatogenesis cycle of 60 days starting after 5 half-lives of last dose of IMP. This 
duration is based on the predicted half-life of IMP, and may be amended once the 
actual half-life is calculated during this study). Abstinent male participants must 
agree to start a double method if they begin a sexual relationship with a female during 
the trial, and through to 90 days after the last dose of the IMP. Male participants with 
female partners that are surgically sterile or post-menopausal (defined as being 
amenorrhoeic for at least 12 months without an alternative medical cause), or male 
participants who have undergone sterilisation and have had testing to confirm the 
success of the sterilisation, may also be included and will not be required to use above 
described methods of contraception. Male participants must also agree not to donate 
sperm up to 3 months after dosing with the IMP.  
5. Total body weight greater than or equal to 50 kg, and body mass index (BMI) 
between 18 and 32 kg/m2 inclusive. 
6. Certified as healthy by a comprehensive clinical assessment (detailed medical history 
and complete physical examination).  
7. Vital signs after 5 minutes resting in supine position: 
• Systolic blood pressure (SBP) – 90-140 mmHg, 
• Diastolic blood pressure (DBP) – 40-90 mmHg, 
• Heart rate (HR) 40-100 bpm.  

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DBP 40-49 mmHg and HR 40-49 bpm are outside the study normal ranges but are 
acceptable for eligibility (including Screening, Day -1 and Day 1 pre-dose) if 
considered not clinically significant by the Principal Investigator or delegate.  
8. Standard 12-lead electrocardiogram (ECG) parameters after 10 minutes resting in 
supine position in the following ranges for both males and females, irrespective of 
clinical significance of out-of-range value(s):  
• QRS 50 – 120 msec,  
• QT ≤ 500 msec,  
• QTcF ≤ 450 msec,  
• QTcB ≤ 450 msec, and  
• PR interval ≤ 210 msec. 
The ECG tracing must be normal unless the Principal Investigator or delegate 
considers an ECG tracing abnormality to be not clinically significant. 
9. Having given written informed consent prior to undertaking any study-related 
procedure. 
10. Available for the duration of the study and for 2 weeks following the End of Study 
visit.  
11. In the opinion of the Principal Investigator or delegate, the individual has a high 
probability of adherence with and completion of the study, and willing and able to 
withdraw and refrain from restricted medications. 
12. Fluent in English and able to understand and comply with written and verbal 
protocol-related requirements.  
13. Willing to defer blood donations to a blood service for a minimum of 6 months after 
the End of Study visit.   
4.3.2 Exclusion Criteria 
If any of the following exclusion criteria apply, the potential participant will not be 
permitted to participate in the study: 
1. Haematology, biochemistry or urinalysis results that are abnormal/outside of 
laboratory normal reference ranges AND are either:  
• Considered clinically significant by the Principal Investigator or delegate; OR  
• Considered not clinically significant by the Principal Investigator or delegate 
BUT ARE ALSO outside of the Sponsor-approved clinically acceptable 
laboratory ranges in Appendix 1.  
NOTE: Participants are not excluded if abnormal/out of laboratory normal reference 
range results are considered not clinically significant by the Principal Investigator or 
delegate AND are within the ranges specified in Appendix 1. 
2. Positive serum pregnancy test at screening, positive urine pregnancy test upon 
admission or at other timepoints as specified by schedule of assessments.  
3. Male participants with a female partner(s) who is (are) pregnant or lactating from the 
time of the administration of study medication.  
4. Any history or presence of clinically relevant cardiovascular, broncho-pulmonary, 
gastrointestinal, hepatic/ gallbladder*/ bile duct, renal, metablic, haematological, 

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neurological, musculoskeletal/rheumatologic,  systemic, ocular, gynaecologic (if 
female), or infectious disease, or signs of acute illness. *including medical history of 
asymptomatic gallbladder stones. 
5. Any gastrointestinal surgery or any condition or disease that could affect drug 
absorption, distribution or excretion (eg, gastrectomy, cholecystectomy, diarrhoea). 
6. Severe recurring headache (cluster or migrainous headaches) requiring prescription 
medication/s. History of recurrent nausea and/or vomiting (for vomiting only: more 
than twice a month).  
7. Participation in any research study involving blood sampling (more than 450 mL/unit 
of blood) or blood donation during the 8 weeks prior to IMP administration (Parts 1 
and 2). 
8. Any documented evidence of current or past cardiovascular disease including cardiac 
arrhythmias or family history of congenital long QT syndrome, Brugada syndrome, 
or unexplained sudden cardiac death. Symptomatic postural hypotension at screening 
(confirmed 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 min when changing from supine to standing position. 
9. History or presence of diagnosed (by an allergist/immunologist) or treated (by a 
physician) food or known drug allergies, or any history of anaphylaxis or other severe 
allergic reactions including face, mouth, or throat swelling or any difficulty breathing. 
Participants with seasonal allergies/hay fever or allergy to animal or house dust mite 
that are untreated and asymptomatic at the time of dosing can be enrolled in the trial.   
10. History of convulsion (including drug or vaccine-induced episodes). A medical 
history of a single febrile convulsion during childhood is not an exclusion criterion.  
11. History of substance use disorder(s) within 5 years of screening, including alcohol 
consumption of more than 40g/4 units/4 standard drinks per day or any prior 
intravenous use of an illicit substance.  
12. Smoked >1 pack of cigarettes per day for >10 years, or who currently (within 14 days 
prior to IMP administration (Parts 1 and 2) smokes >5 cigarettes per day.  
13. Any vitamin supplements within 7 days prior to IMP administration (Parts 1 and 2). 
14. Any other medication (including herbal such as St John’s Wort and over the counter 
[OTC]) within 5 half-lives prior to IMP administration (Parts 1 and 2) except 
occasional intakes (for acute pain) of ibuprofen at doses up to 1.8g/day, paracetamol 
at doses up to 4g/day, acetyl salicylic acid (300 to 650 mg orally every 4 to 6 hours as 
needed, maximum dose: 4 g in 24 hours), diclofenac (diclofenac potassium liquid-
filled capsules: 25mg orally 4 times a day; diclofenac free acid capsules: 18 or 35 mg 
orally 3 times a day; diclofenac potassium immediate-release tablets: 50mg orally 3 
times a day [initial dose of 100mg orally followed by 50mg oral doses acceptable if 
required for better relief]) and contraceptives.  
15. Any individual who, in the judgement of the Principal Investigator or delegate, is 
likely to be noncompliant during the study, or unable to cooperate because of a 
language problem or poor mental development.  
16. Any individual in the exclusion period of a previous study according to applicable 
regulations.  

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17. Any individual who cannot be contacted in case of emergency.  
18. Any individual who is the Investigator, or delegates, research assistant, pharmacist, 
study coordinator, project manager, or other staff thereof, directly involved in 
conducting the study.  
19. Any individual without a good peripheral venous access.   
20. Participation in any investigational product study within the 12 weeks preceding IMP 
administration (Parts 1 and 2) or 5 times the half-life of the Investigational product, 
whichever is longer.  
21. Positive serology test for hepatitis B (positive HB sAG or anti-HBc Ab), hepatitis C 
(anti-HCV) or human immune deficiency virus (HIV) (positive for anti-HIV1 and 
anti-HIV2 Ab).  
22. Positive drug test at screening or prior to IMP dosing. Any drug from the list of drugs 
tested unless there is an acceptable explanation to the Principal Investigator or 
delegate (eg, participant has stated in advance that they consumed a prescription of 
over the counter product which contained the detected drug) and/or the participant has 
a negative urine drug screen on retest. Any participant tested positive for serum 
paracetamol at screening may still be eligible for study participation, at the Principal 
Investigator’s or delegate’s discretion.  
23. Positive alcohol screen at screening or prior to IMP dosing.  
24. Any consumption of citrus fruits (grapefruit, Seville oranges) or their juices within 5 
days prior to IMP administration.    
25. Use of antidepressant medication in the past 12 months prior to IMP administration in 
Part 1 and 2. 
26. Individuals with history of schizophrenia, bipolar disorder psychoses, disorders 
requiring lithium, attempted or planned suicide, or any other severe (disabling) 
chronic psychiatric diagnosis including generalised anxiety and obsessive-compulsive 
disorders.   
27. Individuals who have been hospitalized within five years prior to enrolment for either 
a psychiatric illness or due to danger to self or others.  
28. History of an episode of mild/moderate depression lasting more than 6 months that 
required pharmacological therapy and/or psychotherapy within the last 5 years; or any 
episode of major depression. The Beck Depression Inventory (BDI-II) will be used as 
a validated tool for the assessment of depression at screening. In addition to the 
conditions above, individuals with a score of 20 or more on the BDI-II 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 individuals will be referred to a general practitioner 
or medical specialist as appropriate. Individuals with a BDI-II score of 17-19 may be 
enrolled at the discretion of an 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 individual or to the execution of 
the trial and interpretation of the data gathered.  
29. History of malignancy of any organ system (other than localized basal cell carcinoma 
of the skin or in situ cervical cancer considered treated and cured), treated or untreated, 

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within 5 years of screening, regardless of whether there is no evidence of local 
recurrence or metastases.  
30. Any COVID-19 vaccine within 14 days of IMP intake, any other vaccination within 
28 days of IMP intake, and any vaccination (including COVID-19 initial or second 
dose) planned up to the final follow-up visit.  
31. Any medical condition that in the opinion of the Principal Investigator or delegate 
would jeopardize the individual’s involvement in the study.  
Specific to Part 2 only: 
32. Any individual who, in the opinion of the Principal Investigator or delegate, would 
be unwilling or unable to consume the pre-dose test meal during the fed arm.  
33. Individuals with food intolerance or food allergy are excluded. Vegetarian 
individuals must be excluded, unless they agree to eat a full diet during the study. 
4.3.3 Lifestyle Considerations 
Participants will be requested to follow a stable lifestyle while participating in the study, 
with no increased physical activity compared to their usual habits. The participants will 
also be requested to adhere to the following restrictions, and should be reminded of them 
throughout the study.  
4.3.3.1 Parts 1 and 2 
Throughout Parts 1 and 2, the participant should not: 
• Consume grapefruit or Seville oranges during the study including 5 days prior to IMP 
administration;  
• Consume poppy seeds in the 24 hours prior to screening and first day of confinement 
for IMP administration (Part 1 and Part 2 Period 1 Day -1, and Part 2 Period 2 Day 
21);  
• Consume food or beverages containing alcohol 24 hours prior to each alcohol breath 
test and for the entire confinement period (Part 1 and Part 2 Period 1 Day -1 to Day 
5, and Part 2 Period 2 Day 21 to Day 26).  
o After discharge from the clinical unit (Part 1 and Part 2 Period 1 Day 5 and 
Part 2 Period 2 Day 26), participants should not drink more than 2 standard 
drinks per day until the end of the study (Part 1 Day 28±24 hours and Part 
2 Day 42)  
• Consume beverages containing xanthine bases (eg, Red Bull, coffee) during the 
entire confinement period (Part 1 and Part 2 Period 1 Day -1 to Day 5, and Part 2 
Period 2 Day 21 to Day 26).  
o After discharge from the clinical unit (Part 1 and Part 2 Period 1 Day 5 and 
Part 2 Period 2 Day 26), participants should not consume more than 400 
mg caffeine per day (equivalent to 4 cups of coffee) until the end of the 
study (Part 1 Day 28±24 hours and Part 2 Day 42)  
• Use tobacco during the entire confinement period (Part 1 and Part 2 Period 1 Day -1 
to Day 5, and Part 2 Period 2 Day 21 to Day 26).  
o After discharge from the clinical unit (Part 1 and Part 2 Period 1 Day 5 and 
Part 2 Period 2 Day 26), participants should not smoke more than 5 
cigarettes (or equivalent) per day until the end of the study (Part 1 Day 
28±24 hours and Part 2 Day 42).  

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• Abstain from strenuous exercise sessions for 4 days prior to IMP administration until 
EOS.   
4.3.4 Screen Failures 
Unscheduled visits may be planned to assess, confirm, and follow-up on out-of-range 
clinical laboratory test, vital sign, or ECG values that determine a participant’s eligibility. 
One re-test only is permitted if the original results are considered to not represent the 
expected medical status of the participant (see Section 6.1.1 for further information).  
If a participant does not meet all selection criteria (is a screen failure), but at some point 
in the future is expected to meet the eligibility criteria, the participant may be rescreened 
on one occasion only. Participants who are to be rescreened will undergo the informed 
consent process, be assigned a new participant number, and then restart a new screening 
phase. 
 
4.3.5 Withdrawal of Participants 
Participants are free to withdraw from participating in the trial at any time upon request 
and irrespective of the reason. The Principal Investigator or delegate will endeavour to 
obtain the reason for withdrawal, and will ask the participant to attend an early termination 
visit where procedures planned for EOS will be conducted in agreement with the 
participant (including PK sample if appropriate).   
The Sponsor and/or Principal Investigator or delegate may discontinue or withdraw a 
participant from the trial for one or more of the following reasons: 
• Pregnancy in a female participant (must be withdrawn from the study); 
• Significant non-compliance or major protocol deviation;  
• Any clinical AE, laboratory abnormality or other medical condition or situation 
occurs that would not be in the best interest of the participant to continue to 
participate in the study (see also Section 4.3.8 for toxicity rules);  
• An exclusion criterion newly develops or was not previously recognized that 
precludes the participant from continuing to participate in the study;  
• Participating in any other investigational product study while enrolled in this study; 
• Unblinding of study treatment in Part 1 (on a case by case basis). 
The reason for participant discontinuation or withdrawal from the study will be recorded 
on the eCRF and withdrawn participants will be requested to attend an early termination 
visit (procedures are the same as for EOS).   
The Principal Investigator or delegate will continue to provide medical care for any SAEs 
with the participant’s permission, until symptoms resolve and/or the participant’s 
condition becomes stable.  
4.3.5.1 Replacement of Withdrawn/discontinued Participants 
Participants who have signed the informed consent form and are randomised but have not 
been administered IMP may be replaced. Extra eligible participants are permitted per 
cohort as back-up replacements.  
The replacement of participants who have been administered IMP and subsequently 
withdraw or are withdrawn or discontinued from the trial, must be discussed between the 
Principal Investigator and the Sponsor.   

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4.3.6 Lost to Follow-Up 
The Principal Investigator or delegate will make every effort to contact participants who 
fail to return to the clinical site for visits scheduled in the protocol. All efforts must be 
recorded in source document.  
4.3.7 Study Discontinuation 
The Sponsor, Principal Investigator, approving HREC, and regulatory authorities 
independently reserve the right to discontinue the trial at any time for safety or other 
reasons. Where practical, this will be done in consultation with the Sponsor and all parties 
notified in writing where applicable. The Sponsor and Principal Investigator will ensure 
that participants’ interest and safety are protected, and the Principal Investigator must 
review all participants and complete all records as required.  
4.3.8 Trial Intervention/Treatment Discontinuation – Toxicity Rules 
In addition to the classic assessment of serious adverse events (SAEs) and the 
occurrence/grading of other AEs including AEs of special interest (AESIs)  by the 
Sponsor and Principal Investigator as described in Sections 7.7 and 7.8, the following 
toxicity rules are provided as guidance for the SRC in making decisions to suspend or 
stop dose escalation or suspend or stop IMP administration to additional participants.  
4.3.8.1 Toxicity Rules for Part 1 (Single Ascending Dose)  
Dose escalation in Part 1 or progression to Part 2 will be suspended pending a detailed 
safety review by the SRC if any of the following conditions are met within a given cohort: 
 
1. An SAE in one or more participants which is considered drug-related, 
2. More than 1 adverse event (AE) in two or more participants within the same 
cohort (regardless of organ class or body system) of Grade 3 intensity 
according to NCI-CTCAE V5.0 or as per applied Principal Investigator 
grading for TBA and other AEs where no CTCAE grading is available (see 
Section 7.7.3), which are considered drug-related,  
3. For post-dose fasted Total Bile Acids (TBA) within a full cohort:  
• Over 2 consecutive timepoints at least two participants show an 
elevation of ≥3-fold above upper limit of normal (ULN), or  
• Over 2 consecutive timepoints at least two participants show an 
elevation of  ≥2-fold above ULN AND an elevation of ≥5-fold above 
baseline; if baseline TBA <1 µmol/L, then post-dose TBA must be 
≥  5 µmol/L, or  
• At least one participant shows an elevation of ≥5-fold above ULN. 
4. Any other adverse event (AE) deemed to pose an unacceptable risk to study 
participants and which is considered drug-related. 
5. More than fifty percent of participants having at least 1 adverse event (AE) 
(same organ class or body system) of Grade 2 intensity according to NCI-
CTCAE V5.0 or as per applied Principal Investigator grading for TBA and 
other AEs where no CTCAE grading is available (see Section 7.7.3), which is 
considered drug-related.  
 
If any of the above criteria are met, the double-blind (for Part 1) will be broken by the 
Sponsor for the affected participants and: 

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• Dose-escalation or progression to rest of cohort dosing from sentinel group in Part 
1 will be stopped if one of the criteria 1 to 4 is confirmed. One or more lower 
dose(s) may be administered in new additional cohorts, only if the SRC agree that 
it is safe to do so after reviewing all relevant data (PK and safety), 
• If criterion 5 is met, IMP administration as per protocol may either continue as 
planned or be reconsidered as above, depending on the nature of the affected body 
system, and only if the SRC (and when applicable the HREC) agree that it is safe 
to do so after reviewing all relevant data. 
Local laboratory normal values will be applied for this assessment. In case of suspected 
technical error or reasonable assumption that test results do not reflect the actual status of 
the participant (s), measurements should be repeated whenever feasible and or 
appropriate, prior to grading. Diurnal variations in laboratory variables and other 
measurements as well as baseline status and conditions will be taken into account when 
assessing whether abnormalities constitute a drug related AE and when grading, if 
applicable. 
The SRC may decide to break the double-blind for other reasons supported by a clear 
rationale and/or decide to stop IMP administration based on emerging safety signals not 
described in the above criteria. 
PK exposure criteria 
In addition to the above safety-based rules, progression and escalation in Part 1 will also 
be limited by PK exposure limits. 
Two-week GLP toxicology studies conducted in rat and dogs have shown that the dog is 
the most sensitive species with a NOAEL dose of 1 mg/kg/day.  
Based on the toxicity profile above, the NOAEL in the two species and the ability to 
monitor the observed toxicity, the dog NOAEL is identified as the highest acceptable 
human exposure for this first-in-human study with single dose administration of 
MMV533 to healthy volunteers. The corresponding exposure of 125μg.hr/mL is the 
cumulative AUC0-360h of the parent drug MMV533 over the 2 weeks of the GLP dog study. 
As volunteers will receive only a single dose of MMV533, it is considered that the mean 
exposure in human, AUC0-last, is equivalent to the cumulative AUC0-t PK derived exposure 
limit in the 2-week dog toxicology study. 
In this first-in-human study, preliminary PK of each dose level in Part 1 will be 
analyzed after completion of each cohort to ensure that the mean group exposure of 
the subsequent cohort will not exceed the highest achievable human exposure of 125 
μg.hr/mL. 
 
4.3.8.2 Toxicity rules for Part 2 (Food Effect) 
Toxicity rules provided for Part 1 will also be used in case of safety events occurring in 
the single cohort of Part 2. 
4.3.9 Emergency Unblinding of Study Participants 
Code-break tamper-evident envelopes containing treatment allocation per participant 
were provided to the study site for emergency unblinding if required. For Part 1, the 
treatment allocation of a participant should be unblinded by the Principal Investigator or 
delegate when knowledge of the IMP is required for the treatment of an AE.  The SRC 
may also unblind the treatment allocation of a participant as detailed in Section 4.3.8.1. 

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Refer to the Safety Plan and/or Randomisation Procedure (if available) for further 
information on the procedures for code-breaking . 
5 TRIAL INTERVENTIONS/TREATMENTS 
5.1 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
Both MMV533 (all Parts) and placebo (for Part 1 only) are defined as the IMP for this 
study. Refer to the Pharmacy Manual for further information on the required handling of 
the IMP.  
Participants will be admitted to the clinical unit for oral dosing of the IMP. 
5.1.1 MMV533 
For both Parts of the study: 
• Participants will fast overnight for at least 10 hours.  
• Efforts should be made to ensure all the study volunteers are dosed after a minimum 
of 10 hours fasting and before 10:00AM.  
• Part 2 participants participating in the fed arm will eat breakfast as described below 
in Section 5.3.1.2. 
• Participants will take a single oral dose of IMP with 240 mL of water. The dose of 
IMP will depend on their cohort (see Section 5.2).  
• Participants will then: 
o Be requested to not drink liquids for 1 hour;  
o Remain seated for 10 minutes, then stay in a semi-recumbent position for 
the next 2 hours (except during assessments that require lying positions);  
o Not be permitted food for at least 4 hours.  
• Lunch and dinner will be provided at approximately 5 hours and 12 hours post IMP 
administration, with snacks available between meals.  
5.1.2 Part 1 Placebo 
Placebo will be administered in Part 1 as described for MMV533 in Section 5.1.1. Part 2 
is open label and does not require a placebo arm.  
5.2 
SELECTION OF DOSE IN THE STUDY  
5.2.1 MMV533 
5.2.1.1 Part 1 
There will be seven ascending single doses of MMV533, starting at 5 mg under fasting 
conditions to be taken as per Section 5.1 (with up to 1 optional dose level). See Table 7 
below for further information. 
A proposed starting dose of 5 mg is predicted to generate in humans mean Cmax and AUC 
values of 4.3 ng/ml and 949 ng∙h/ml, respectively. These estimates provide a predicted 
safety margin of 120- and 139-fold when compared to the Cmax (517 ng/ml) and 
cumulative AUC0-360 (125 µg∙h/ml) in the most sensitive species (dogs) at 1 mg/kg/day.  
 
 

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Table 7: AUCinf and Safety Ratio calculated for the Starting Dose of 5 mg MMV533 
and Potential Escalated Doses 
Dose (mg) 
AUCinf (µg*hr /mL) 
Safety Ratio (fold) - 
Dog NOAEL 
5 
3.13* 
138 
10 
7.25* 
69.1 
20 
10.06* 
34.6 
50 
28.25#  
4.4 
100 
56.50# 
2.2 
200 
113.0# 
1.1 
400 
226.0#  
0.55  
*Arithmetic mean AUCinf from observed data available at the time of third SRC meeting. 
#Predicted arithmetic mean AUCinf from observed PK data at 5-20mg. 
Based on observed human PK data and modeling, and taking into account the AUC cap 
identified for this First In Human study, the maximum dose is now expected to be 200 
mg. These predictions will be refined when PK data at 50 mg and 100 mg will be 
available.  
The proposed doses from 50 mg listed in Table 7 are based on observed human PK at 5-
20mg and could be modified based on additional observed human PK data.Increments 
between doses will be maintained and the highest target human mean exposure at the 
highest dose will not exceed the AUCcap identified for this project (AUC0-inf=125 
µg∙h/ml). This AUC cap corresponds to the cumulative AUC0-360 observed at the NOAEL 
in the most sensitive species (dog). 
Currently, the highest single dose is set at 200 mg, the safety ratio is 1.1 and this dose is 
approximately 4.4 to 10 times above the predictive active dose based on MPC determined 
from SCID models. 
The Safety Review Committee (SRC) will determine whether progression to the next dose 
cohort is indicated as outlined in Section 7.9. All doses administered will be determined 
by the SRC in accordance with PK, safety and tolerability data collected up to the 
decision-making time-point from the preceding cohort/s as outlined above. This will allow 
dose selection to take into account the predicted safety margins and any unexpected drug 
exposure levels or safety signals observed in human participants.  
5.2.1.2 Part 2 
The dose for the food effect cohort will be selected by the SRC based on PK and safety 
results obtained in Part 1, taking into account the human efficacious dose/exposure 
predicted from preclinical efficacy studies in rodent malaria models.  The dose will be at 
least 3-fold less than a dose that was determined to be safe in Part 1 in order to cover for 
a possible increased exposure when the drug is given in a fed state. Choice of the dose to 
be administered will be also made based on the review of available PK data.  

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5.3 
SELECTION AND TIMING OF DOSE FOR EACH PARTICIPANT 
5.3.1 MMV533 
5.3.1.1 Part 1 
There will be seven ascending single oral doses of IMP (one dose per cohort) to be taken 
on Day 1, starting at 5 mg. There is an additional one optional dose level, if considered 
required by the SRC.   
Participants will be randomised to receive either MMV533 or placebo on Day 1 (in a 
cohort, 6 will receive MMV533 and 2 will receive placebo). In the sentinel groups, one 
participant will receive MMV533 and the other placebo (double-blind, randomised).  The 
procedures for IMP administration will be as described above in Section 5.1. 
5.3.1.2 Part 2 
In Part 2, the SRC will decide the dose to be used for all participants in the single cohort. 
The dose will be at least 3-fold less than the highest dose determined to be safe in Part 1.  
Part 2 is open label. All participants will receive a single oral dose of MMV533 on Days 
1 and 22, with participants randomised on Day 1 to the fed or fasted arm for that day (ratio 
1:1). The participants will then cross over to the opposite arm on Day 22. 
All participants will be fasted overnight for at least 10 hours.  
For the fasted arm, the procedures for IMP administration will be the same as described 
above in Section 5.1.1.  
For the fed arm, the procedures for IMP administration will be the same as described 
above in Section 5.1.1 except that: 
• 30 minutes prior to IMP administration participants will be provided with a 
standardized 800 kcal high-fat breakfast consisting of: 
o  2 eggs fried in butter, 2 slices of bacon, 2 slices of toast with butter, 100g 
fried hash brown potatoes and 250 mL whole milk.   
• Participants will be required to finish eating the entire breakfast within the timeframe 
of 30 minutes, and will be monitored by clinical unit staff to ensure this.  The start 
and completion times of eating will be recorded in the eCRF.   
• After administration of IMP, the procedures are as described above in Section 5.1.1. 
5.4 
DOSE INTERRUPTIONS AND REDUCTIONS  
Dose interruptions per participant are not applicable to IMP as it will be administered in 
a single dose. Dose adjustments will be made as outlined above in Section 5.3 and as 
recommended on an ongoing basis cohort by cohort by the SRC as outlined in Section 
7.9.  
5.5 
SUPPLY, PACKAGING AND LABELLING OF STUDY TREATMENTS 
The IMP and other study medications/interventions (non-IMP) will be manufactured and 
packaged according to Good Manufacturing Practice (GMP), all local regulations and 
labelled for clinical trial use in accordance with Australian requirements. The IMP will 
be supplied to the clinical unit with an acknowledgement of receipt form.  
5.5.1 MMV533 
MMV533 will be supplied  by Piramal (Pharmaceutical Development Services, Piramal 
Enterprises Ltd. Ahmedabad). Two film-coated tablets will be used in the clinical study 

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at the following strength: 5 mg and 50 mg (identical is shape and size), and a matching 
placebo.  The tablets are white to off-white, round, biconvex, film-coated tablets.  
5.5.2 Placebo 
Placebo will be supplied by Piramal (Pharmaceutical Development Services, Piramal 
Enterprises Ltd. Ahmedabad) to exactly match the MMV533 tablets in appearance. 
5.6 
STORAGE OF STUDY TREATMENTS 
Prior to dispensing, the IMP must be stored in a secure and locked storage area with 
limited access, and under monitored, temperature controlled conditions as appropriate. 
All storage requirements are detailed in the respective Investigator Brochures or product 
information/CMI. 
The Pharmacist or Designee will be responsible for the correct storage and handling of 
IMP. Deviations from the storage requirements, including corrective action, must be 
documented. Refer to the Pharmacy Manual for further information.  
5.7 
ACCOUNTABILITY, RECONCILIATION AND RETURN OF THE STUDY 
TREATMENTS 
The Principal Investigator or delegate will only dispense the IMP to eligible participants 
enrolled in this study and will ensure that complete and current dispensing and inventory 
records are maintained. The site’s dispensing logs must record every episode of 
dispensing of the IMP.   
The logs must contain the following information: 
• Date of receipt. 
• Number of tablets. 
• Batch number(s). 
• The identification of the participant to whom the tablets was dispensed. 
• The date(s), time and quantity dispensed to the participant. 
• The cumulative total of IMP at site. 
• Tablets damaged, destroyed, or returned. 
Supplies of the IMP will be shipped to the clinical unit prior to study start. The study 
monitor will perform drug accountability during routine monitoring visits.   
Once the study has completed or has been discontinued, final accountability and 
reconciliation will be performed. Any discrepancies will be investigated and the 
resolution documented.  All full, partially full, and empty containers of IMP must be 
returned to the Pharmacy, Manufacturer or Sponsor for destruction, and the appropriate 
form sent to the Sponsor. Please refer to the Pharmacy Manual for further details on the 
storage, handling, and dispensing of IMP. 
5.8 
PROHIBITED CONCOMITANT THERAPY 
Permitted and prohibitied prior and concomitant prescribed medications, over-the-counter 
medications and supplements are outlined in the exclusion criteria in Section 4.3.2. Before 
use of any non-study medication during this study, the participant should discuss with the 
Principal Investigator or delegate.  
Ibuprofen may be permitted for use at doses up to 1.8g/day or paracetamol at doses up to 
4g/day only after the participants discusses with the Principal Investigator or delegate. 
Ibuprofen is the preferred treatment, however paracetamol may be used if ibuprofen does 

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not relieve the participant’s symptoms. Acetyl salicylic acid (300 to 650 mg orally every 
4 to 6 hours as needed, maximum dose: 4 g in 24 hours), diclofenac (diclofenac potassium 
liquid-filled capsules: 25mg orally 4 times a day; diclofenac free acid capsules: 18 or 35 
mg orally 3 times a day; diclofenac potassium immediate-release tablets: 50mg orally 3 
times a day [initial dose of 100mg orally followed by 50mg oral doses may provide better 
relief in some participants]) may also be permitted after discussion with the Principal 
Investigator or delegate. Contraceptives are permitted. 
Any use of concomitant medication including name of medication, daily dosage and 
duration of use must be recorded in source documents and in the eCRF.  
5.9 
TREATMENT COMPLIANCE  
Participants will be administered IMP under medical supervision while confined at the 
clinical unit.  
5.10 MEASURES TO MINIMIZE BIAS 
5.10.1 Randomisation Procedures 
Randomisation procedures for Parts 1 and 2 will be as described in the Randomisation 
Plan and/or Randomisation Procedure. A randomisation number will be allocated to each 
participants as per the randomisation schedule.   
Part 1: Eligible participants in Part 1 will be randomised on Day 1 to be administered 
either MMV533 or placebo in a ratio of 3:1 overall (a ratio of 1:1 in the sentinel group 
and 5:1 in the rest of the cohort). Randomisation will be double-blind.  
Part 2: this part of the study is open-label, but eligible participants in Part 2 will be 
randomised on Day 1 to either the fed or fasted arm for Period 1 in a ratio of 1:1. On Day 
22, the participants will cross over to the opposite arm.  
5.10.2 Blinding 
Part 1: 
The double blind for Part 1 will be maintained as the placebo will be identical in 
appearance to the MMV533 tablets. The randomisation list will remain strictly 
confidential until the time of unblinding and will be accessible only to study personnel 
authorised to be unblinded.   
A participant’s treatment allocation should not be unblinded except as described above in 
Section 4.3.9 or as outlined in Section 4.3.8.1.   
Otherwise, blinding of Part 1 will be maintained during the trial until all final clinical data 
has been entered into the database, all data queries have been resolved and the assignment 
of participants to analysis sets has been completed.  
SRC meetings will be performed blinded, except if unblinding is required as described in 
Sections 4.3.8.1 and 4.3.9.  
Part 2 is open label.  
 
 

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6 STUDY ASSESSMENTS AND PROCEDURES  
6.1 
STUDY CONDUCT SCHEDULE 
The schedules for all assessments and study activities are summarised in the Schedule of 
Activities for each part (Part 1 Table 1 and Part 2 Table 2) and shown in more detail in 
the Detailed Schedule of Activities for each part (Part 1 Table 3, Part 2 Table 4 and Table 
5). All study assessments and procedures are as described below and in Section 7. 
Protocol waivers or exemptions are not permitted. 
6.1.1 Screening 
• The screening period for both parts of the study will be between Day -28 and Day -
1. During this time, the participant will sign the patient information consent form 
(PICF) prior to any study-related procedures or assessments and eligibility will be 
assessed.  
• Any 
screening 
visit(s) 
will 
be 
prior 
to 
and 
separate 
from 
the 
safety/eligibility/confinement visit on Day -1 (see Section 6.1.2).  
• Review of screening/eligibility laboratory testing is as follows:  
o If results are normal/within the laboratory normal reference ranges, the 
participant may be included (if all inclusion criteria fulfilled and no other 
exclusion criteria are met).  
o If results are abnormal or outside of the laboratory normal reference 
ranges, then clinical significance must be assigned by the Principal 
Investigator or delegate:  
 If clinically significant, the participant is excluded as per Exclusion 
criterion #1.  
 If not clinically significant, the parameter(s) must be checked 
against Appendix 1: Sponsor Approved Clinically Acceptable 
Inclusion Laboratory Ranges:  
• If outside the ranges in Appendix 1, the participant is 
excluded as per Exclusion criterion #1.  
• If within the ranges in Appendix 1, the participant may be 
included (if all inclusion criteria fulfilled and no other 
exclusion criteria are met). 
• Retesting of any screening parameters (for example if a lab error is suspected) can 
be conducted once only.  
• A positive urine drug screen should only be re-tested once if there is a strong rationale 
for doing so (for example, false positive).  
• The result of any re-tests must be considered for participant eligibility and must be 
available prior to IMP administration. Findings made during unscheduled visits 
should be reported in the source document and electronic case report form (eCRF). 
6.1.2 Inclusion/Eligibility/Confinement Visit  
• For both Parts, participants will attend the clinical unit on Day -1 prior to IMP 
administration on Day 1 for completion of screening procedures, to confirm 
eligibility and for admission to the clinical unit for the confinement period.  
• NOTE: Informed consent and initial screening procedures should be completed prior 
to Day -1, so that the eligibility procedures required on Day -1 are in addition to those 
conducted for Screening.  

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• See Section 6.1.1 for review of laboratory test results for eligibility purposes and the 
use of Appendix 1. 
• Part 2 participants will attend the clinical unit on Day 21 for admission to the clinical 
unit for the Period 2 confinement period, in addition to completing the scheduled 
assessments for Day 21. Safety laboratory test results from Day 21 sampling (except 
TBA results) must be available for review prior to IMP administration on Day 22.  
• For each cohort, eligible additional participants may be available as back-up 
replacements, in the event planned cohort participants withdraw or are withdrawn 
prior to IMP administration.   
6.1.3 General Further Information: 
• An indwelling cannula may be inserted into a peripheral vein of the participant’s 
forearm either upon admission to the clinical unit for confinement on Day -1 or on 
Day 1 prior to dosing to obtain blood samples (both Parts) and on Day 21 or Day 22 
prior to dosing for Part 2 Period 2. The cannula will be locked with a mandrel 
between blood samples.  
• Only one re-test of any Day 1 pre-dose parameter is permitted, and only if the result 
can be available for review prior to IMP administration. Assessment results that are 
available prior to dosing on Day 1 must satisfy the relevant inclusion/exclusion 
criteria (for ECG intervals, the mean of each triplicate ECG will be used). 
• Only participants who meet all of the inclusion criteria and none of the exclusion 
criteria will be eligible to receive IMP on Day 1 for both Parts.  
• For Part 2 Period 2, the Principal Investigator or delegate will review safety 
assessments from Day 21 and Day 22 pre-IMP administration (except TBA results) 
before confirming IMP administration on Day 22 can proceed. The Principal 
Investigator or delegate may discuss clinically significant abnormal findings with the 
study Medical Monitor and/or Sponsor Medical Director before deciding to proceed.  
• Participants will be administered the IMP as described in Section 5.1. Efforts should 
be made to ensure all the study volunteers are dosed after a minimum of 10 hours 
fasting and before 10:00AM.  
• Participants will only be discharged from the clinical unit a minimum of 96 hours 
post-IMP administration after the Principal Investigator or delegate has performed a 
complete review of the available safety data.  
• During outpatient periods of the study, participants should immediately contact the 
Principal Investigator or delegate if they experience any unexpected symptom, effect 
or event. Participants will be informed that they can contact the clinical unit by 
telephone 24 hours a day and will be provided with a participant card listing the study 
number and appropriate clinical unit telephone contact details. The participant must 
also provide telephone contact details so that they can be contacted in an emergency.  
6.2 
PHARMACOGENETICS 
In Part 1 and Part 2 (Period 1 only), one mandatory blood sample per participant will be 
collected on Day 1 prior to IMP administration to investigate allelic variants related to 
drug metabolism enzymes and drug transporters (DME/T) that are potentially involved in 
the MMV533 ADME. Special procedures for the collection, storage and shipping of the 
samples are described in a separate laboratory manual.   
The objective is to identify genetic factors which may predict response to treatment, and 
predict susceptibility to drug-drug interactions. No other testing will be conducted and 
these tests may not diagnose any unknown illness or medical condition. The participant’s 

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confidentiality must be protected, and the sample will be used only for this specific 
analysis. The blood sample and the extracted DNA will be kept until the end of study and 
will only be analysed under specific circumstances, including abnormal or unexpected PK 
or safety results. The decision to conduct the analysis will be taken once all data is 
available after LPLV. The blood sample and extracted DNA will be destroyed either upon 
completion of analysis or when it is confirmed they will not be required for analysis.  
6.3 
PHARMACOKINETICS 
Blood and urine sample handling for PK analysis is described in the Laboratory Manual.  
Plasma samples will be obtained for both Parts of the study and urine samples will be 
collected for PK analysis in Part 1 only.  
Exact timing of PK sampling is to be respected. The actual time of sampling must be 
recorded in source document and the eCRF. If other assessments or activities are required 
at the same timepoint, they should be conducted ahead of the scheduled time (see Section 
7.3 below for required time windows for ECGs). The following order is recommended if 
required at the same timepoint: urine sampling for PK/urinalysis, vital signs, ECG, blood 
sampling, IMP administration, meal (each where applicable).   
The following time windows will be permitted for blood sampling for PK assay: 
Table 8: Permitted Time Windows for Pharmacokinetic Blood Sampling 
Time point  
Tolerance window 
Pharmacokinetic Blood Samples 
In confinement 
Pre-dose (T=0 h) 
- 60 min to 0 h, taking into account the pre-
dose triplicate ECGs to be conducted prior 
0.5-4 
hours 
inclusive 
after 
initial 
IMP 
administration  
± 2 min 
6-12 
hours 
inclusive 
after 
initial 
IMP 
administration  
± 5 min 
24-96 hours inclusive after initial IMP 
administration  
± 30 min 
Outpatient care 
168 hours-480 hours (including EOS Part 2) 
± 120 min 
EOS (Part 1 only) 
± 24 h 
 
6.3.1 Part 1 
For Part 1, blood and urine samples will be collected for PK analysis as scheduled on the 
detailed Part 1 Detailed Schedule of Activities Table 3 with time windows as indicated in 
Table 8 above.  
Blood collection will commence on Day 1 during confinement at the clinical unit pre-
dose, then 30, 60, 90 minutes post-IMP administration, and then 2, 3, 4, 6, 8, 10, 12, 24, 
48, 72, and 96 hours post-IMP administration. After discharge from the clinical unit, blood 
samples will be collected on Day 8 (168 hours), Day 14 (312 hours), Day 21 (480 hours) 
and EOS Day 28 (648 hours). 
NOTE: An unscheduled PK blood sample will be taken if ALT or AST values >2x ULN 
as described in Section 7.4.1.2. 

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Urine will be collected during the following time ranges (hours) post-IMP administration: 
-2 to 0 (U00 pre-dose); 0-4 (U01); 4-8 (U02); 8-12 (U03); 12-24 (U04), 24-48 (U05) and 
48-72 (U06). During these time ranges, all urine will be collected and pooled, except for 
samples required for safety urinalysis (Section 7.4.6). 
6.3.2 Part 2 
For Part 2, blood samples will be collected for PK analysis in Periods 1 and 2 as scheduled 
on the detailed Part 2 Detailed Schedule of Activities Table 4 (Period 1) and Table 5 
(Period 2), with permitted time windows for sampling as indicated above in Table 8. 
NOTE: An unscheduled PK sample will be taken if ALT or AST values >2x ULN as 
described in Section 7.4.1.2. 
6.3.2.1 Period 1 
Blood collection will commence on Day 1 during confinement at the clinical unit pre-
dose, then 30, 60, 90 minutes post-IMP administration, and then 2, 3, 4, 6, 8, 10, 12, 24, 
48, 72, and 96 hours post-IMP administration. After discharge from the clinical unit, blood 
samples will be collected on Day 8 (168 hours), Day 14 (312 hours) and Day 21 (480 
hours).  Day 21 is also the first day of confinement for Period 2.  
6.3.2.2 Period 2 
Blood collection will commence on Day 22 during confinement at the clinical unit pre-
dose, then 30, 60, 90 minutes post-IMP administration, and then 2, 3, 4, 6, 8, 10, 12, 24, 
48, 72, and 96 hours post-IMP administration. After discharge from the clinical unit, blood 
samples will be collected on Day 29 (168 hours), Day 35 (312 hours) and EOS Day 42 
(480 hours).  
 
 

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7 SAFETY ASSESSMENTS 
• The schedules for all safety assessments/activities are summarised in the Schedule 
of Activities for each part (general overview in Part 1 Table 1 and Part 2 Table 2, 
and in more detail in the Detailed Schedule of Activities for each Part (Part 1 Table 
3, Part 2 Table 4 and Table 5).  
• Protocol waivers or exemptions are not permitted.   
• All safety assessments may be conducted at unscheduled visits or timepoints if 
required for the participant’s safety at the discretion of the Principal Investigator or 
delegate.  
• When several assessments/activities are scheduled to take place at the same 
timepoint, the recommended order is: urine sampling (urinalysis and urine collection 
for PK), vital signs, ECG, blood sampling, IMP administration, meal (where 
applicable/appropriate).  
• Exact timing for PK blood sampling is to be maintained - see Section 6.3 Table 8 
above for permitted PK sampling time windows.  
• See Section 7.3 below for required time windows for ECGs.  
• Date/time of all assessment/activities must be recorded in source document.  
• Clinical significance of any out-of-range or abnormal result or finding must be 
recorded by the Principal Investigator or delegate. Clinically significant results or 
findings must be recorded as an AE or indicated as a symptom of a recorded AE.  
7.1 
PHYSICAL EXAMINATION 
Physical examination will include at a minimum: heart and respiratory auscultation; 
peripheral arterial pulse; pupil, knee, Achilles and plantar reflexes; peripheral lymph 
nodes and abdomen examination. 
Symptom directed physical examination: body systems will be reviewed only if clinically 
indicated and at the discretion of the Principal Investigator or delegate. Symptom directed 
physical examination may be performed as required by the Principal Investigator or 
delegate throughout the study except where a full physical examination is required.  
7.1.1 Part 1 
In Part 1, full physical examination will be performed at Screening, Day -1 and EOS.  
Symptom-directed physical examination may be performed at the discretion of the 
Principal Investigator or delegate if clinically indicated at any time during confinement. 
Prior to the discharge of participants from confinement at the clinical unit at least 96 hours 
post-IMP administration on Day 5, clinical staff will check with the Principal Investigator 
or delegate to clarify if any participant will require a symptom directed physical 
examination.  
Symptom-directed physical examination may be performed at the discretion of the 
Principal Investigator or delegate if clinically indicated during outpatient visits to the 
clinical unit on Days 8, 14 and 21.   
7.1.2 Part 2 
In Part 2, full physical examination will be performed at Screening, Day -1, Day 21 and 
EOS Day 42.  
Symptom-directed physical examination may be performed at the discretion of the 
Principal Investigator or delegate if clinically indicated at any time during confinement. 

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Prior to the discharge of participants from confinement at the clinical unit at least 96 hours 
post-IMP administration on Day 5 and Day 26, clinical staff will check with the Principal 
Investigator or delegate to clarify if any participant will require a symptom directed 
physical examination.  
Symptom-directed physical examination may be performed at the discretion of the 
Principal Investigator or delegate if clinically indicated during outpatient visits to the 
clinical unit on Days 8, 14, 29, and 35.  Similarly, the Principal Investigator or delegate 
may decide to perform a symptom-directed physical examination at any time during the 
study. 
7.2 
VITAL SIGNS AND BODY MEASUREMENTS 
7.2.1 Body Measurements 
For Parts 1 and 2, Body weight (kg) and height (cm) will be measured at screening, and 
body weight (kg) will be measured again on Day -1. For Part 2, body weight (kg) will also 
be measured at EOS Day 42.  
7.2.2 Vital signs 
• Vital signs: heart rate (beats per minute), systolic and diastolic blood pressure 
(millimetres of mercury [mmHg]), respiratory rate (breaths per minute), and 
tympanic body temperature (°Celcius): 
o For Part 1 and Part 2 Screening, Part 1 EOS and Part 2 EOS Day 42, heart 
rate, systolic and diastolic blood pressure and respiratory rate will be 
measured after 5 minutes in supine resting position, and after 3 minutes in 
standing position.  
o At all other timepoints vital signs (heart rate, systolic and diastolic blood 
pressure and respiratory rate) will be measured only after 5 minutes in the 
supine resting position.  
• Permitted time windows for vital sign measurements:  
o Pre-dose: ≤ 2 hours before IMP administration;  
o Post-dose during confinement (where applicable): ± 15 minutes of the 
nominal timepoint up to and including 12 hours post-dose, and then as per 
PK blood sampling time windows in Table 8; 
o Post-dose during outpatient visit period: as per PK blood sampling time 
windows in Table 8.  
In Part 1:  
• Vital signs excluding tympanic body temperature (°C) will be measured at 
Screening, on Day -1 upon admission to the clinical unit for confinement, from Day 
1 pre-dose and then at the following hours post-IMP administration: 0.5, 1, 1.5, 2, 3, 
4, 6, 8, 10, 12, 24, 48, 72 and 96 hours (prior to discharge from the clinical unit). 
After discharge, vital signs will be measured at outpatient visits to the clinical unit 
on Days 8, 14, 21  and EOS Day 28 (±24 hours).   
• Tympanic body temperature (°C) will be measured at Screening, Day -1 upon 
admission to the clinical unit for confinement, Day 1 pre-dose and then at the 
following hours post-IMP administration: 6, 12, 24, 48, 72 and 96 hours (prior to 
discharge from the clinical unit). After discharge from the clinical unit, tympanic 
body temperature (°C) will be measured at the same timepoints as the other vital 
signs.  

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In Part 2, Period 1:  
• Vital signs excluding tympanic body temperature (°C) will be measured at 
Screening, on Day -1 upon admission to the clinical unit for confinement, from Day 
1 pre-dose and then at the following hours post-IMP administration: 0.5, 1, 1.5, 2, 3, 
4, 6, 8, 10, 12, 24, 48, 72 and 96 hours (prior to discharge from the clinical unit). 
After discharge, vital signs will be measured at outpatient visits to the clinical unit 
on Days 8, 14  and 21 (also day of admission to the clinical unit for Period 2 
confinement).  
• Tympanic body temperature (°C) will be measured at Screening, Day -1 upon 
admission to the clinical unit for confinement, Day 1 pre-dose and then at the 
following hours post-IMP administration: 6, 12, 24, 48, 72 and 96 hours (prior to 
discharge from the clinical unit). After discharge until Day 21, tympanic body 
temperature (°C) will be measured at the same timepoints as the other vital signs. 
In Part 2, Period 2:  
• Vital signs excluding tympanic body temperature (°C) will be measured from Day 
22 pre-dose and then at the following hours post-IMP administration: 0.5, 1, 1.5, 2, 
3, 4, 6, 8, 10, 12, 24, 48, 72 and 96 hours (prior to discharge from the clinical unit). 
After discharge, vital signs will be measured at outpatient visits to the clinical unit 
on Days 29, 35, and EOS Day 42.  
• Tympanic body temperature (°C) will be measured at Day 21 upon admission to the 
clinical unit for confinement, Day 22 pre-dose and then at the following hours post-
IMP administration: 6, 12, 24, 48, 72 and 96 hours (prior to discharge from the 
clinical unit). After discharge, tympanic body temperature (°C) will be measured at 
the same timepoints as the other vital signs.   
For both Parts, assessment results available prior to dosing on Day 1 must satisfy relevant 
inclusion/exclusion criteria. 
 
For both Parts, the study normal ranges for supine and standing vital signs are: 
Parameter 
Range 
Systolic blood pressure             
90-140 mmHg 
Diastolic blood pressure           
50-90 mmHg 
Heart rate                                 
50-100 bpm 
Respiratory rate                        
10-25 breaths/min 
Temperature                             
35.0-37.5°C 
If results are out of these ranges, the Principal Investigator or delegate must assess, assign 
and document clinical significance.  
Please note for Inclusion critierion #7: vital signs in supine position for eligibility prior to 
IMP dosing (including at screening, Day -1 and Day 1 pre-dose), an out of range value of 
40-49 bpm for heart rate and/or 40-49 mmHg for diastolic blood pressure will be 
acceptable if considered not clinically significant (NCS) by the Principal Investigator or 
delegate.  
7.3 
12-LEAD ELECTROCARDIOGRAM (ECG) 
Standard 12-lead ECGs (safety ECGs) will be recorded after at least 10 minutes in supine 
position using a validated electrocardiographic device. The electrodes will be positioned 

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at the same place for each ECG recording throughout the study (attachment sites of the 
leads will be marked with an indelible pen). See also manual supplied by the central ECG 
reading Vendor.  
When triplicate ECGs are required, 3 ECGs will be recorded within 5 minutes with at 
least 1 minute between 2 replicates. Each ECG consists of a 10-second recording of the 
12 leads simultaneously, leading to:  
• A single 12-lead ECG (25 mm/s, 10mm/mV) printout with heart rate, PR, QRS, QT, 
QTcB and QTcF automatic correction evaluation (by the ECG device) and at least 3 
complexes for each lead. The Principal Investigator’s or delegate’s medical opinion 
and automatic values will be recorded in the eCRF. This printout will be retained at 
the site,  
• A digital storage that enables eventual further reading by an ECG central laboratory: 
each digital file will be identified by theoretical time, real date and real time (recorder 
time), Sponsor study code, participant number (i.e., 3 digits), and site and country 
numbers, if relevant. The digital recording, data storage, and transmission (whenever 
requested) need to comply with all applicable regulatory requirements (i.e., FDA 21 
CFR, part 11). 
Part 1: 
• Single standard 12-lead ECGs will be recorded at Screening and on Day -1 upon 
admission to the clinical unit for confinement.  
• From Day 1, standard 12-lead ECGs will be performed in triplicate as described 
above: 
o pre-dose: three lots of triplicate baseline ECGs [ie 9 conducted pre-dose]  
within one hour prior to dosing with IMP, with triplicates performed at 
least 10 minutes apart from last one to the first one of the next set, and all 
to be completed prior to blood sampling; 
o then at the following hours post-IMP administration: 0.5, 1, 1.5,  2, 3, 4, 6, 
8, 10, 12, 24, 48, 72 and 96 hours [triplicates will be performed within 15 
minutes prior to the actual time of PK blood sampling]; 
o The triplicate ECGs will be centrally read.  
• After discharge from the clinical unit, single standard 12-lead ECGs will be recorded 
at outpatient visits to the clinical unit on Days 8, 14, 21 (all ± 2 hours of the actual 
PK blood sampling time) and EOS Day 28 as permitted for PK blood sampling (±24 
hours – see Table 8). 
Part 2: 
• Single standard 12-lead ECGs will be recorded at Screening, Day -1 and Day 21 
upon admission to the clinical unit for confinement.  
• From Period 1 Day 1 and Period 2 Day 22, standard 12-lead ECGs will be performed 
in triplicate as described above: 
o pre-dose: three lots of triplicate baseline ECGs [ie 9 conducted pre-dose]  
within 90 minutes prior to dosing with IMP, with triplicates performed at 
least 10 minutes apart from last one to the first one of the next set, and all 
to be completed prior to blood sampling; 
o then at the following hours post-IMP administration: 0.5, 1, 1.5,  2, 3, 4, 6, 
8, 10, 12, 24, 48, 72 and 96 hours [triplicates performed within 15 minutes 
prior to the actual time of PK blood sampling]; 

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o The triplicate ECGs will be centrally read.  
• After discharge from the clinical unit, single standard 12-lead ECGs will be recorded 
at outpatient visits to the clinical unit on Days 8, 21, 29 and EOS Day 42 (all ± 2 
hours of the actual PK blood sampling time). 
For both Parts, results available prior to dosing on Day 1 must satisfy relevant 
inclusion/exclusion criteria. For ECG intervals, the mean of each triplicate ECG will be 
used.  
For both Parts, the study normal ranges for ECG parameters are: 
ECG Parameter 
Range 
PR interval             
≤210 msec 
QRS           
50–120 msec 
QTcB/QTcF                            
≤450 msec for males and females 
QT 
≤500 msec for males and females 
For study eligibility as per Inclusion criterion #8 (including at Screening, Day -1 and Day 
1 pre-dose), results out of these ranges are exclusionary irrespective of the clinical 
significance of any out-of-range value.  
If results are out of these ranges post-IMP dosing, the Principal Investigator or delegate 
must assess, assign and document clinical significance. See also Section 7.7.5.2. 
7.4 
CLINICAL LABORATORY TESTS 
• Blood and urine will be collected for clinical laboratory safety tests. Handling of 
samples is described in the Pathology Vendor Laboratory Manual.  
• See Section 6.1.1 for information on the review of results of all screening and 
eligibility clinical laboratory tests.  
• Results of all safety laboratory tests (except TBA results from Part 2 Day 21) on 
samples collected on Day -1 Part 1, Day -1 Part 2 Period 1, and Day 21 Part 2 Period 
2, must be available and reviewed by the Principal Investigator or delegate prior to 
dosing with IMP on Day 1 Part 1, Day 1 Part 2 Period 1, and Day 22 in Part 2 
respectively. NOTE: Day -1 test results (and any Day 1 results available prior to 
dosing) must satisfy relevant inclusion/exclusion criteria.  
• NOTE: Participants must have fasted for at least 10 hours prior to collecting safety 
blood samples when scheduled in the morning. Participants must have fasted for 
Screening and for all biochemistry safety blood tests that include TBA (must be 
collected in the morning before breakfast).   
7.4.1 Safety Blood Tests 
• Permitted time windows for collecting safety blood samples:  
o Pre-dose: as per PK blood sampling in Table 8;  
o Post-dose during confinement (where applicable): ± 15 minutes for the 6-
12 hour post-IMP timepoints; then as per PK blood sampling in Table 8;  
o Post-dose during outpatient visit period: as per PK blood sampling in Table 
8. 
• Blood for standard safety blood tests will be collected: 
Part 1: Screening, Day -1, Day 1 prior to IMP administration, and then at the following 
hours post-IMP administration: 6, 12, 24, 48, 72 and 96 hours prior to discharge from the 
clinical unit. After discharge from the clinical unit, blood will be collected on Days 8, 14, 
21 and EOS Day 28.  

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• Fasting total bile acids (TBA) will also be part of the safety blood tests in Part 1 
at the following time-points: Day 1 pre-dose, then at the following hours post-
dose: 24, 48, 72, 96, then on Days 8, 14, 21 and EOS.  
• Blood samples collected at 6 and 12 hours post-IMP administration on Day 1 are 
not required to be fasting (TBA not required for these samples). 
Part 2 Period 1: Screening, Day -1, Day 1 prior to IMP administration, Day 2 (24 hours), 
Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 8, Day 14 and Day 21.  
• Fasting TBA will be part of the safety blood tests in Part 2 Period 1 at the following 
time points: pre-dose Day 1, then at the following hours post-dose: 24, 48, 72, 96, 
and then on Days 8, 14 and 21.  
Part 2 Period 2: Day 22 prior to IMP administration, Day 23 (24 hours), Day 24 (48 hours), 
Day 25 (72 hours), Day 26 (96 hours), Day 29, Day 35 and EOS Day 42. 
• Fasting TBA will be part of the safety blood tests in Part 2 Period 2 at the following 
time points: pre-dose Day 22, and then at the following hours post-dose: 24, 48 72, 
96, and then on Days 29, 35 and EOS Day 42.  
7.4.1.1 Haematology  
Red blood cell count, haematocrit, haemoglobin, white blood cell count with differential 
count (neutrophils, eosinophils, basophils, monocytes, and lymphocytes), platelets. 
NOTE: blood will also be collected for an unscheduled haematology assessment if ALT 
or AST >2x ULN as described in Section 7.4.1.2. 
7.4.1.2 Biochemistry  
• Plasma/serum electrolytes (sodium, potassium, chloride, calcium (corrected), 
magnesium);  
• Liver function tests (AST, ALT, alkaline phosphatase (ALP), gamma-glutamyl 
transferase (GGT), lactate dehydrogenase (LDH), total and direct bilirubin; TBA to 
be included at timepoints detailed in Section 7.4.1)  
• Renal function (urea, creatinine)  
• Metabolism (glucose, albumin, total proteins, cholesterol, triglycerides)  
• Potential muscle toxicity (creatine kinase)  
NOTE: If ALT or AST values >2 xULN at any time post-IMP administration (see Section 
7.7.5.1 and, if applicable, Section 4.3.8), then:  
• blood must be collected for the following tests within 24-48 hours: 
o Coagulation (see Section 7.4.2; see also Section 7.7.5.1) 
o Liver panel (ALT, AST, LDH, ALP, GGT, total and direct bilirubin)  
o CK 
o Haematology (see Section 7.4.1.1) 
o Unscheduled PK sample (see Section 6.3).  
• Collect 
additional 
recent 
history 
of 
potentially 
hepatoxic 
concomitant 
medications/substances (including paracetamol and alcohol) and exercise. 
7.4.2 Coagulation 
Blood will be collected for coagulation studies only at Screening for both Parts, and will 
include international normalized ratio (INR) and activated partial thromboplastin time 
(APTT). Additional coagulation tests (including INR) may be requested for safety at the 

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discretion of the Principal Investigator or delegate, and must be requested if ALT or AST 
> 2x ULN as described in Section 7.7.5.1 and Section 7.4.1.2. 
7.4.3 Serology 
Blood will be collected for serology tests at Screening for both Parts, and will include: 
hepatitis B surface antigen (HB sAG), anti-hepatitis B core antibodies (anti-HBc Ab), 
hepatitis C antibodies, anti-HIV1 and anti-HIV2 antibodies.  
7.4.4 Pregnancy Testing 
Blood will be collected from all female participants for serum β-human chorionic 
gonadotropin (β-hCG) testing at Screening for both Parts of the study.  Blood will be 
collected from WOCBP for serum β-hCG testing at EOS both Parts of the study.   
Urine will be collected from WOCBP for β-hCG testing: for Part 1 Day -1 prior to IMP 
administration; Part 2 Day -1 and Day 21 prior to IMP administration. 
Blood will also be collected from a female participant for unscheduled serum β-hCG 
testing if their urine β-hCG test returns a positive result. 
7.4.5 Confirming Menopause 
Blood will be collected from post-menopausal female participants for follicle stimulating 
hormone (FSH) testing at Screening for both Parts of the study.  
7.4.6 Urinalysis 
Urine will be collected as part of the clinical laboratory safety testing at the same 
timepoints as for safety blood tests above in Section 7.4.1.  
• Permitted time windows for collecting safety urinalysis samples:  
o Pre-dose: ≤ 2 hours before IMP administration;  
o Post-dose during confinement (where applicable): ± 1 hour of the nominal 
urine sampling timepoint.  
o Post-dose during outpatient visit period: as per PK blood sampling time 
windows in Table 8.  
Qualitative: a dipstick test will be performed on a freshly voided urine sample including 
tests for proteins, glucose, blood (erythrocytes), leucocytes, ketone bodies, nitrate, 
bilirubin, urobilinogen, and pH. 
Quantitative: any urine dip stick result of more than traces (pH will not trigger quantitative 
analysis) will trigger a quantitative analysis for all of the following parameters: protein, 
protein/creatinine ratio, glucose, red blood cells, white blood cells, and organism. If 
available, the quantitative result will be the leading one over the dip stick results for 
decision making e.g. for study inclusion/exclusion or clinical assessment.  
7.5 
ALCOHOL AND DRUG SCREENING 
Alcohol will be measured by breath test at the clinical unit.  
Drug screening will be conducted both in urine and in serum as per below specifications.  
Urine 
will 
be 
collected, 
using 
suitable 
dipstick 
test 
for: 
amphetamines, 
methamphetamines, barbiturates, benzodiazepines, cocaine, methadone, opiates, 
phencyclidine, tetrahydrocannabinol, tricyclic antidepressants.  

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Drug screening will also include testing for serum paracetamol using blood sample(s) 
collected at the timepoints below for clinical laboratory tests (see Section 7.4) (NOTE: 
paracetamol is not exclusionary. A subject may still be eligible for study participation, at 
the Principal Investigator’s or delegate’s discretion). Based on the quantitative results of 
the serum paracetamol assay, the following binary classification will be used: 
• Negative test: serum levels < 20 µmol/L 
• Positive test: serum levels  ≥ 20 µmol/L 
Alcohol and drug screening will be conducted: 
Part 1: Screening and Day -1. 
Part 2: Screening, Day -1 and Day 21. 
If considered necessary to confirm lifestyle considerations are being adhered to during the 
study (Section 4.3.3), alcohol and drug screening may also be conducted at other 
unscheduled timepoints at the discretion of the Principal Investigator or delegate.  
7.6 
BECK DEPRESSION INVENTORY 
Originally described by Beck et al (1961), the Beck Depression Inventory (BDI) is a 
validated objective tool for the assessment of depression.7 Updated in 1996, the BDI II is 
21-item, self-report rating inventory that measures characteristic attitudes and symptoms 
of depression, and participants will be required to complete the BDI-II at Screening for 
both parts of the study.8 The BDI II takes approximately 10 minutes to complete, although 
clients require a fifth – sixth grade reading level to adequately understand the questions. 
A score of >20 at screening and/or a response of 1, 2 or 3 for item 9 indicating current 
suicidal ideation is exclusionary. A BDI score of 17 to 19 may be enrolled at the discretion 
of the Principal Investigator if they do not have a history of the psychiatric conditions 
mentioned in exclusion criterion 26 and their mental state is not considered to pose 
additional risk to the health of the volunteer or the execution of the study and 
interpretation of the data gathered.  
7.7 
ADVERSE EVENTS (AEs) 
The Principal Investigator or delegate and clinical unit staff are responsible for detecting 
recording and reporting events that meet the criteria and definition of adverse events as 
described below. Adverse events may be reported by the participant  or observed by the 
Principal Investigator, delegate or other clinical site staff.   
All AEs will be followed until the event has resolved, no further medically relevant 
information from the event can be expected and it is acceptable to discontinue follow-up 
of the event in the assessment of the Principal Investigator. The Principal Investigator 
should continue to follow up AEs that were unresolved at the participant’s EOS as long 
as medically required or until the participant has been satisfactorily referred to a general 
practitioner or medical specialist as appropriate.  
Medically untoward events occurring in participants between the time of consent 
(Screening) and the time of IMP administration (for Part 1 and Part 2 Period 1) will be 
considered medical history and not recorded as AEs. 
7.7.1 Definitions 
An adverse event (AE) is any untoward medical occurrence in a clinical trial participant 
administered a medicinal product, and that does not necessarily have a causal relationship 
with this treatment.  

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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/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 finding) 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 
(e.g., CTCAE grade 2 or above), 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. 
Abnormal laboratory findings and other objective assessments should NOT be routinely 
captured and reported as AEs. 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 IMP dosing, or discontinuation from the study, significant 
additional concomitant drug treatment, or other therapy, and/or 
• It is considered by the Principal Investigator (or delegate) or Sponsor to be clinically 
significant or represent a clinically significant change from baseline. 
AEs will not include: 
• A medical or surgical procedure such as surgery, endoscopy, tooth extraction, or 
transfusion (although the condition that leads to the procedure may be an AE).  
• A pre-existing disease or condition present at the start of the study that does not 
worsen during the study. 
• Any situation where an untoward medical occurrence has not occurred (for example, 
hospitalizations for cosmetic elective surgery or social admissions). 
7.7.2 Causal Relationship to Investigational Medicinal Product and Other Study 
Treatments 
The Investigator or delegate is required to assess the causality for all AEs, and must 
indicate this in the source document and eCRF. An adverse event with reasonable causal 
relationship to the IMP means there is evidence or argument to suggest a causal 
relationship.  
If considered related: 
• The temporal relationship between the event and the administration of the IMP is 
compelling and/or follows a known or suspected response pattern to that product, 
and the event cannot be explained by the participant’s medical condition, other 
therapies or accident.  

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If considered not related: 
• The event can be readily explained by other factors such as the participant’s 
underlying medical condition, concomitant therapy or accident and no plausible 
temporal or biologic relationship exists between the IMP and the event.  
7.7.3 Severity Grading of Adverse Events 
The severity of AEs (except for elevated fasting TBA) will be recorded in accordance 
with the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, published 27 
November 2017 where available. A severity grading system has been developed 
specifically for elevated fasting TBA to be implemented for this study from 14 April 2021. 
See Appendix 2: Severity Grading for Fasting TBA in Phase 1 Volunteers. The Principal 
Investigator will provide severity assessment as per below should there be no CTCAE 
grading available for a  specific AE. 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 AEs. 
The severity of AEs will be graded as follows:  
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
• Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living. 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; limiting 
self-care activities of daily living. 
• Grade 4: Life-threatening consequences; urgent intervention indicated. 
• Grade 5: Death related to AE. 
An AE that is assessed as severe is not the same as a serious AE. Severity is a category 
utilized for rating the intensity of an event and both AEs and SAEs can be assessed as 
severe. An AE is defined as ‘serious’ when it meets one of the pre-defined serious 
outcomes as described below in Section 7.8.1. 
7.7.4 Documentation of Adverse Events 
The Principal Investigator or delegate is responsible for reviewing all documentation 
related to each AE, and for recording all relevant AE/SAE information in source 
document and in the CRF. The Principal Investigator or delegate will attempt to establish 
a diagnosis of the AE based on signs, symptoms and/or other clinical information, and 
where possible the diagnosis will be documented as the AE/SAE (and not individual signs 
or symptoms).   
The following information should be recorded for all AEs: 
• Description 
• Dates and times of onset and resolution 
• Duration in hours 
• Time of onset relative to IMP administration 
• Seriousness  
• Severity 
o In the source data, the description of the AE will report the various 
severities observed over time. If the severity of an AE increases, separate 
AEs per severity grading will be recorded into the eCRF. 

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o If the AE resolves and then reoccurs, then two AEs will be reported. 
• Action taken in response to the AE regarding IMP: 
o Permanently discontinued, or 
o No action taken, or 
o Unknown/not applicable.  
• Outcome of AE: 
o Recovered/resolved, or 
o Recovering/resolving, or 
o Not recovered/not resolved, or 
o Recovered with sequelae/resolved with sequelae 
o Fatal 
o Unknown  
• Relationship to the IMP or procedures conducted during the trial (causality 
assessment of related or not related.  
7.7.5 Adverse Events of Special Interest (AESI) 
Adverse Events of Special Interest (AESIs) may be serious or non-serious, and are defined 
by the Sponsor as being of specific scientific and/or medical concern to the Sponsor’s 
product or programme. Documentation and reporting of AESIs are applicable only post-
first dose of IMP and will be required to be monitored and reported promptly to the 
Sponsor by the Principal Investigator or delegate. Such an event may require further 
investigation in order to characterise and understand it. 
All AESIs (both serious and non-serious) must be notified to the pharmacovigilance 
provider (Prime Vigilance) within 24 hours of the clinical study staff becoming aware of 
the event (see Section 7.8.3 below). Reporting should be via a Serious Adverse Event 
Report Form marked as ‘AE of special interest’. Follow-up information will be submitted 
in a timely fashion as it becomes available.  
7.7.5.1 Hepatic AEs of Special Interest 
• Any ALT or AST above 5×ULN, 
• An elevation in bilirubin of  2×ULN or more, 
• An elevation in fasting total bile acids (TBA) of  >1 x ULN 
• Any AST or ALT above 2×ULN (see Section 7.4.1.2) and:  
o Total Bilirubin Level (TBL) >1.5×ULN OR  
o INR >1.4 (see Section 7.4.2) 
• Any AST or ALT above 2×ULN 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). 
7.7.5.2 Cardiac AEs of Special Interest 
• 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: 
o Sinus bradycardia that is clinically asymptomatic, and not associated with 
any other relevant ECG abnormalities, 
o sinus tachycardia that is clinically asymptomatic, and associated with a 
body temperature >38.0°C, and not associated with any other relevant 
ECG abnormalities, 

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o Respiratory sinus arrhythmia, 
o Wandering atrial pacemaker, 
o 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. 
7.7.5.3 Haematological AEs of Special Interest 
• Absolute neutrophil count <0.5 × 109/L, 
• Platelet count <75 × 109/L. 
7.7.5.4 Dermatological AEs of Special Interest 
Clinical signs of possible cutaneous adverse reactions such as:  
• Dermatitis, 
• Rash, including erythematous, macular, papular, maculopapular, pruritic, pustular, 
and vesicular. 
If one of these cutaneous reaction is observed and when feasible, pictures of the lesions 
should be obtained. 
Dermatological AEs do not need to be reported as AESIs if clearly unrelated to study drug 
(e.g. rash from cannula dressing or ECG dots). 
7.7.6 Treatment of Overdose 
Overdose of IMP is considered unlikely as it is a single dose administered under 
supervision at the clinical unit. However symptomatic overdose of IMP is an event 
suspected by the Principal Investigator or delegate, or notified by the participant, and 
defined as at least twice the intended dose within the intended therapeutic interval adjusted 
according to the tested drug. Such an event should be reported promptly to the Sponsor 
as for AESIs.  Asymptomatic overdose will be reported as a standard AE.   
7.8 
SERIOUS ADVERSE EVENTS (SAES) 
7.8.1 Definitions of Serious Adverse Events (SAEs) 
A serious adverse event (SAE) is any AE that: 
• Results in death, or 
• Is life-threatening, and/or 
• Requires inpatient hospitalisation or prolongs existing hospitalisation, and/or 
• Results in persistent or significant disability or incapacity, and/or 
• Is a congenital anomaly or birth defect, and/or  
• Constitutes a possible Hy’s Law case: 
o Hy’s Law case is defined as a participant 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]). 
Note: Life-threatening in the definition of an SAE refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe. 
Note: Medical and scientific judgement should be exercised in deciding whether an AE 
should be classified as serious in other situations. Important medical events that are not 

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immediately life-threatening or do not result in death or hospitalization, but may 
jeopardise the participant or may require intervention to prevent one of the other outcomes 
above should also be considered serious.  
Planned procedures that require admission to hospital for this study, or any planned 
elective procedure that requires hospitalization are not considered SAEs unless the 
underlying condition has worsened or the participant’s condition worsens after the 
procedure.  
7.8.2 Pregnancy 
Pregnancy itself is not defined as an AE/SAE. Any complication  or termination of 
pregnancy for medical reasons are to be reported as an AE/SAE. Spontaneous abortion, 
still birth or congenital anomaly must be reported as an SAE.  
Any WOCBP (Woman of Child-Bearing Potential) enrolled in the study who becomes 
pregnant during the study and the following 60 days after the dosing should be followed 
through delivery or termination of the pregnancy. The Investigator will collect pregnancy 
information and report as for an SAE (see Section 7.8.3) within 24 hours of becoming 
aware of a participant’s pregnancy. Follow-up will generally not be required for longer 
than 6 to 8 weeks beyond the estimated delivery date. Once pregnancy is confirmed, 
pregnant female participants will be immediately withdrawn from the study as outlined in 
Section 4.3.5.   
Where possible, the Investigator will also attempt to collect and report information 
regarding pregnancy outcomes of female partners of any male participants who were 
administered IMP in this study and the following 60 days after the last dosing. Appropriate 
signed informed consent will be required directly from the pregnant female partner to 
obtain and report this information.  Any participant’s female partner who becomes 
pregnant during the study should be followed through delivery or termination of the 
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7.8.3 Reporting for Serious Adverse Events (24 hours) 
If any SAE occurs, the Investigator will take immediate appropriate action and strive to 
identify the causes of the event/s. The Investigator must notify the SAE to the 
pharmacovigilance provider (Prime Vigilance) by email within 24 hours of becoming 
aware of the event. 
All reports must be signed by the Principal Investigator or delegate and notified to Prime 
Vigilance preferably by email or fax to: 
Email: MMV@primevigilance.com 
Back-up fax number: +44 800 471 5694 
Prime Vigilance Contact:  
Andreja Baricevic 
e-mail: andreja.baricevic@primevigilance.com 
Phone: +44 385 1 46 28 183 
Mobile: +44 385 99 2680 787 
Head Office: +44 1483 307920 
Any copies of participant’s medical records provided for SAE reporting must have all 
participant identifiers redacted before submission.   
The SAE report form will always be completed as thoroughly as possible with all 
available details of the event and signed by the Principal Investigator or delegate. If the 
Principal Investigator or delegate does not have all information regarding an SAE, he/she 
will not wait to receive additional information before reporting the event. A follow-up 
SAE report should be completed within 14 days, or if there is no new information the 
SAE report form should be updated when additional information is received. 
The Principal Investigator or delegate will always provide an assessment of causality at 
the time of the initial report. 
Email transmission of the SAE report form is the preferred method to transmit this 
information to Prime Vigilance. In rare circumstances notification by telephone is 
acceptable, with a copy of the SAE report form sent by overnight mail.  
The Principal Investigator or delegate, or responsible person according to local 
requirements, will comply with the applicable local regulatory requirements related to the 
reporting of SAEs to regulatory authorities and the HREC.  
7.9 
SAFETY REVIEW COMMITTEE (SRC) 
The SRC will be responsible for decisions related to the safety of participants and to 
inform decision making on trial progression and details will be outlined in the SRC 
Charter. The required data (blinded for Part 1) to be reviewed will be detailed in the SRC 
Charter and will be sent to the SRC prior to all scheduled and any ad hoc SRC meetings 
associated with the trial.  
The Safety Review Committee (SRC) will be composed at a minimum of the Sponsor’s 
Medical Director, the Principal Investigator, an Independent Clinical Pharmacology 
Physician and the study Medical Monitor. Representative/s for PK analysis will also be 
included. The study will proceed cohort by cohort with SRC review in between each 
cohort, with some parallel overlap for the subsequent Parts if deemed safe to do so by the 
SRC. In the event of an incomplete cohort, a minimum number of 7 participants in a 

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cohort is required for SRC review and decision to dose-escalate. The SRC may decide to 
discontinue a Part or the study after any of the cohort reviews.  
Part 1: 
The SRC will evaluate all available blinded safety data up to and including Day 14 and 
PK data up to and including Day 8 for Cohorts 1 to 3. The SRC will then decide if the 
subsequent dose cohort should proceed. For Cohorts 4 onwards, the SRC will review 
safety and PK data up to and including Day 21 before deciding to proceed with the next 
cohort. The SRC may unblind treatment allocation if an AE or AEs occur that stop dose 
escalation as per Section 4.3.8. 
All doses administered in Part 1 will be determined by the SRC in this manner, and each 
cohort will not proceed until the SRC has reviewed the previous cohort’s data as described 
above. This will ensure that the selected doses take into account the predicted pre-clinical 
safety margins and any unexpected drug exposure levels or safety signals observed in the 
participants of this study.  
The minutes of each SRC meeting will be shared with the GSB (Global Safety Board 
[MMV Safety Board]) for their information. Initial study HREC approval required that 
after completion of the cohort dosed with 200 mg, a comprehensive preliminary data 
report with observed safety/tolerability and PK data was to be provided to the HREC 
before progressing to the next dose level. As 200 mg is now likely to be the final dose 
level, the report will instead be provided to the HREC before progressing to the 200 mg 
cohort and after completion of the previous cohort. Before proceeding with the last 
planned dose at 200 mg, all available safety data up to and including Day 14 and PK data 
up to and including Day 21 will be shared with the GSB for their approval to test the dose 
of 200 mg.  
Part 2: 
The dose for Part 2 will be decided by the SRC based on data from Part 1. Wash-out 
periods may be adjusted by the SRC if required.  Safety and PK data from Part 2 will be 
reviewed by the SRC after completion of the second period of the food effect study. 
 
 

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8 STATISTICAL ANALYSES 
8.1 
GENERAL APPROACH 
The following sections describe the statistical analysis as it is foreseen during the planning 
phase of trial. 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. A 
separate Analysis Plan will be provided for PK analysis. The study Sponsor may decide 
to conduct an MMV533 concentration – QTcB and/or QTcF analysis after 
completion/review of the study (see Section 8.9.2). This analysis, if to be conducted, will 
be described in a separate companion SAP and reported in a dedicated companion CSR.  
The general analytical approach for all safety endpoints will be descriptive in nature. 
Unless otherwise stated, the following statistical approaches will be taken: 
Continuous variables:   
Descriptive statistics will include the number of 
non-missing values, mean, standard deviation (SD), 
median, minimum, and maximum.  The minimum and 
maximum values will be presented to the same number of 
decimal places as recorded in the raw data; mean, median 
and SD will be presented to one more decimal place than 
the raw data. 
Categorical variables:   
Descriptive statistics will include frequency counts and 
percentages per category. Percentages will be rounded to 
one decimal place, with the denominator being the number 
of participants in the relevant cohort with non-missing data. 
Imputation:   
No missing data will be imputed. 
Confidence intervals (CIs):  If required, CIs will be two sided and will use 95% 
confidence levels. Any analyses requiring significance 
testing will use a two-sided test at the 5% significance level. 
 
Unscheduled assessments: 
Unscheduled visits will be excluded from visit-based 
summary tables. 
 
Early termination visits: 
Assessments conducted at Early Termination will be 
excluded from visit based summary tables. 
8.2 
SAMPLE SIZE AND JUSTIFICATION 
Sample size for this study was based upon empirical considerations. No sample size 
calculation was performed. The food effect evaluation is a pilot one and will be followed by 
a definitive powered food effect study in the future if this NCE moves into further 
development.  
Part 1 (SAD) 
Up to 64 participants including up to one optional cohort: up to 8 cohorts with 8 
participants each (6 participants receiving MMV533 and 2 participants receiving placebo 
in each cohort).  
Part 2 (Pilot food effect) 

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1 cohort of 8 participants all receiving MMV533. 
8.3 
ANALYSIS SETS AND SUB-SETS 
8.3.1 Analysis Sets 
In the first instance, two (2) analysis datasets will be used for study analyses: Full Analysis 
Set (FAS) and Safety Set.   
Additional analysis populations may be defined in the SAP or the PK Analysis Plan. 
The number of participants in each analysis set will be summarised, with a corresponding 
listing. 
8.3.1.1 Full Analysis Set 
The Full Analysis Set (FAS) will consist of all enrolled participants.  The FAS will be 
used to assess all participant disposition, baseline, demographic and protocol deviation 
data. 
8.3.1.2 Safety Set 
The Safety Set will include all enrolled participants who received at least one dose (full 
or partial) of IMP. The Safety Set will be used to assess all safety data.  
8.4 
PARTICIPANT DISPOSITION 
A listing of participant disposition will present participant dates of informed consent, 
enrolment, randomisation, key visits as well as study completion details. Early 
termination data, including the reason for early termination will be listed in an additional 
listing.  
A participant disposition summary table will present, at a minimum, the number of 
participants who completed the study and the number of participants who discontinued 
classified by reason for early termination.   
8.5 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
8.5.1 Demographics 
Demographic data will be listed for all enrolled participants and summarised by cohort 
and overall.  
8.5.2 Medical History 
All medical history data will be listed, grouped by participant. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities and 
summarised by system organ class (SOC) and preferred term (PT). 
8.5.3 Prior Medications 
Prior medications will be listed for all enrolled participants. Prior medications are defined 
as any medication that is started before administration of IMP, regardless of when it 
ended. If a medication has a missing or partial missing start/end date or time and it cannot 
be determined whether it was taken before IMP or concomitantly, it will be considered as 
prior and concomitant. 
8.5.4 Eligibility 
Eligibility will be listed for all enrolled participants. 

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8.6 
PROTOCOL DEVIATIONS 
All protocol deviations will be listed. A protocol deviation summary table will present the 
total number of protocol deviations as well as the number of participants who reported at 
least one protocol deviation, broken down by deviation type including (but not limited 
to): 
• Informed consent  
• Eligibility  
• Visit not done 
• Visit performed out of window 
• Study procedure not done 
• Study procedure done out of window 
• Safety reporting 
• Investigational Product 
• Privacy and Data Protection 
• Concomitant Medication  
• COVID 19 
• Other 
8.7 
TREATMENT EXPOSURE 
Participant exposure to all protocol-specified treatments will be listed and summarised.   
8.8 
SAFETY (PRIMARY ENDPOINT) 
8.8.1 Safety Endpoints 
Safety and tolerability will be assessed by clinical review of the following parameters:  
• AEs (including SAEs and AESIs) 
• Vital signs  
• 12-lead ECG 
• Haematology, chemistry, urinalysis 
• Physical examination 
All descriptive statistics for safety parameters will be evaluated using the Safety Set. 
8.8.2 Adverse Events 
All AE data will be listed for each participant, including severity, relationship to IMPs, 
relationship to non-IMP protocol-specific treatments, outcome and actions taken. In 
addition, listings of AEs leading to discontinuation of the study, SAEs and deaths, will be 
provided as applicable.  
All AE summaries will be restricted to TEAEs only, where a TEAE is defined as an AE 
that commences on, or after, the first administration of IMP up to EOS (inclusive). TEAEs 
without an onset date or time will be defined as treatment emergent except if an 
incomplete date (e.g., month and year) clearly indicates that the event started prior to first 
administration of IMP, or if the AE stop date indicates that the event started and/or 
stopped prior to the first administration of IMP.  
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) and grouped by system organ class (SOC) and preferred terms (PT).  Their 
severity will be graded according NCI-CTCAE v5.0. 
At a minimum, the following AE summary tables will be provided: 

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• Overall summary of TEAEs 
• All TEAEs 
• TEAEs by severity 
• TEAEs by relationship 
• Serious TEAEs  
• TEAEs leading to study withdrawal  
8.8.3 Concomitant Medications 
Medications used in this study will be coded using WHO-DDE. 
Concomitant medications are defined as medications continued or newly received at or 
after administration of IMP, through to the End of Study visit. 
If a medication has a missing or partial missing start/end date or time and it cannot be 
determined whether it was taken before initial treatment or concomitantly, it will be 
considered as prior and concomitant. 
Concomitant medications will be summarised by Anatomical Therapeutic Class (ATC) 
and preferred name (PN). The summary tables will show the number and percentage of 
participants taking each medication by ATC and PN. 
For the summaries of prior and concomitant medications, participants who take the same 
medication (in terms of the ATC and PN) more than once will only be counted once for 
that medication. 
8.8.4 Laboratory Findings 
Laboratory parameters will be listed by participant and visit, including: 
• haematology, 
• biochemistry, 
• urinalysis, 
• serology, 
• drug screening, 
• alcohol screening 
• FSH, and 
• pregnancy test. 
Haematology, biochemistry and continuous urinalysis laboratory data will be summarised 
for each scheduled visit, including observed values, absolute change from each baseline. 
Categorical urinalysis results will be summarised for each scheduled visit using frequency 
tabulations. Shift tables may be provided.  
8.8.5 Physical Examination 
Physical examination parameters will be listed for all participants and visits. 
8.8.6 Body Measurements 
Height and weight will be listed for all participants and visits.   
For Part 2, observed values (including changes from each baseline) will be summarised 
for weight. 
8.8.7 Vital Signs 
Vital sign parameters will be listed for all participants and visits.  

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Observed values, as well as absolute changes from each baseline, will be summarised 
descriptively for all vital sign parameters by visit.  
8.8.8 12-lead ECG 
ECG parameters will be listed for all participants and visits. Triplicate ECGs will be 
presented in listings for individual readings as well as the mean for each triplicate.  The 
triplicate means will be used for the summary table. 
Observed values, as well as absolute changes from each baseline, will be summarised 
descriptively for all ECG parameters by visit.  Safety analysis of ECGs will include in 
particular the number of participants during the study with:  
• QTcF or QTcB prolongation of more than 30 msec and 60 msec, and/or  
• QTcB and/or QTcF  > 450 msec.  
8.9 
PHARMACOKINETIC ENDPOINTS 
8.9.1 Pharmacokinetic Parameters 
For both Parts, MMV533 PK profiles will be plotted individually and summarized by dose 
group and by food intake. 
For both Parts, MMV533 PK parameters calculated in plasma will be summarized by dose 
group and by food intake using descriptive statistics. All the statistical analyses described 
below will be done on plasma parameters. 
The tmax values will be represented by histogram plots for each dose level. Dose 
proportionality will be assessed using a power model on Cmax, AUClast and AUC.  
For Part 2 only, impact of food effect on Cmax, tmax AUClast and AUC and t1/2 will be 
assessed. 
8.9.2 Concentration-ECG Analysis 
This pharmacokinetic-pharmacodynamic (PK-PD) analysis will be performed after 
finalization of the study CSR and reported in a separate report.  
Exposure-response analysis between the change from baseline in centrally-read ECG 
intervals and corresponding drug concentrations will be performed using graphical tools 
and regression methods. Estimate and 90% CI of change from baseline in ECG parameters 
(HR, PR, QRS, QTcB and QTcF) at the observed geometric mean of Cmax will be 
computed from the final model chosen. 
8.10 EXPLORATORY PARAMETERS 
If applicable, exploratory parameters will be summarized by treatment group using 
descriptive statistics and may be reported separately. 
8.11 INTERIM ANALYSIS 
This trial has no formal interim analysis. 
 

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9 STUDY ADMINISTRATION 
9.1 
ETHICAL CONSIDERATIONS 
9.1.1 Ethical Principles 
This clinical study was designed and shall be implemented and reported in accordance 
with the Declaration of Helsinki, the Integrated Addendum to ICH E6(R1): Guideline for 
Good Clinical Practice E6(R2) dated 09 November 2016 and the National Statement on 
Ethical Conduct in Human Research, (2007 – updated 2018). 
9.1.2 Informed Consent 
Eligible participants may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC-approved informed consent. Informed 
consent must be obtained before conducting any study-specific procedures (i.e. all of the 
procedures described in the protocol). The process of obtaining informed consent should 
be documented in the participant source documents and a copy of the signed patient 
information and consent form provided to the participant. 
9.1.3 Investigator 
and 
Human 
Research 
Ethics 
Committee 
(HREC) 
Responsibilities 
Before initiating a trial, the investigator/institution should obtain approval/favorable 
opinion from the Human Research Ethics Committee (HREC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures 
(e.g., advertisements) and any other written information to be provided to participants.  
Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents 
and all of the instructions and procedures found in this protocol and to give access to all 
relevant data and records to the Sponsor appointed monitors, auditors, Quality Assurance 
representatives, HREC representatives, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must 
inform the Sponsor immediately that this request has been made. 
9.2 
PROTOCOL ADHERENCE 
This protocol defines the study objectives, the study procedures and the data to be 
collected on study participants. Additional assessments required to ensure safety of 
participants should be administered as deemed necessary on a case by case basis. In this 
instance the Sponsor medical monitor must be advised before or as soon as possible after 
such assessments are conducted.   
Under no circumstances should an Investigator collect additional data or conduct any 
additional procedures for any research related purpose involving any investigational 
drugs. Investigators ascertain they will apply due diligence to avoid protocol deviations. 
If an Investigator feels a protocol deviation would improve the conduct of the study, this 
must be considered a protocol amendment and cannot be implemented unless such an 
amendment is agreed upon by the Sponsor and approved by the HREC. All significant 
protocol deviations will be recorded and reported in the clinical study report (CSR). 
9.3 
PROTOCOL AMENDMENTS 
Any change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by the Sponsor and the HREC prior to implementation. Only 
amendments that are intended to eliminate an apparent immediate hazard to participants 

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may be implemented immediately provided the Sponsors medical monitor is notified as 
soon as possible after the event and the reviewing HREC is subsequently notified. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator 
is expected to take any immediate action required for the safety of any participant included 
in this study, even if this action represents a deviation from the protocol. In such cases, 
the Medical Monitor and Sponsor must be notified immediately. 
9.4 
DATA HANDLING AND RECORD KEEPING 
Participants will be assigned a unique identifier when participating in the study, and any 
participant datasets or records that are transferred to the Sponsor or CRO will only contain 
this identifier. Any other identifiable information about the participant will not be 
transferred.  The Principal Investigator will ensure procedures are in place to appropriately 
protect the confidentiality of the participant records and data, including adequate safe 
guards for digital/computer access. The participants will be informed that their personal 
study-related data will be used by the Sponsor and that their medical records may be 
examined by auditors and regulatory agencies.   
Study-related participant data will be entered into printed or electronic case report forms 
(eCRFs), except for data that may be transmitted to the Sponsor or CRO electronically 
(such as laboratory data). The Principal Investigator is responsible for ensuring that 
accurate source documents for all data entered into the CRF are maintained at the study 
site.  
All study documents including source documents and signed PICFs must be retained by 
the Principal Investigator for at least 15 years and according to local regulatory 
requirements. No study documents may be destroyed or transferred during the retention 
period without the Sponsor being directly notified in writing.  
9.5 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor or CRO maintains responsibility for quality assurance of the data and for 
data management, and retains accountability for actions delegated to other parties 
(including CRO). Study monitors appointed by the Sponsor or CRO will conduct ongoing 
visits to the study sites to confirm the CRF data is accurate according to source documents 
and complete, and that the study is being appropriately conducted according to the 
protocol, ICH GCP and local regulatory requirements. Details will be provided in the 
Monitoring Plan.  
9.6 
PUBLICATION POLICY 
Neither the complete nor partial results of the study achieved under this protocol, nor any 
of the information provided by the Sponsor for the purposes of performing the study, will 
be published or passed on to any third party without the consent of the study 
Sponsor.  Any Investigator involved with this study is obligated to provide the Sponsor 
with complete study results and all data derived from the study. 
Results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.   
 
 

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10 REFERENCES 
 
1 World Health Organisation (WHO) (2019). World Malaria Report 2019. Geneva. 
Licence: CC BY-NC-SA 3.0 IGO.  
2 Malaria – Biology (14 November 2018). CDC Centers for Disease Control and 
Prevention, 
USA, 
accessed 
11 
December 
2019,    
https://www.cdc.gov/malaria/about/biology/index.html  
3 Luo L, Aubrecht J, Dingzhou L, Warner RL, Johnson KJ, Kenny J & Colangelo JL 
(2018). Assessment of serum bile acid profiles as biomarkers of liver injury and liver 
disease in humans. PLoS ONE 13(3): e0193824. 
https://doi.org/10.1371/journal.pone.0193824.  
4 Aleo MD, Aubrecth J, Bonin PD, Burt DA, Colangelo J, Luo L, Schomaker S, Swiss R, 
Kirby S, Rigdon GC & Dua P (2019). Phase I study of PF-04895162, a Kv7 channel 
opener, reveals unexpected hepatotoxiticy in healthy participants, but not rats or 
monkeys: clinical evidence of disrupted bile acid homeostasis. Pharmacology Research 
& Perspectives 2019:e00467. https://doi.org/10.1002/prp2.467  
5 Buoen C, Bjerrum OJ & Thomsen MS (2005). How first-time-in-human studies are 
being performed: a survey of phase 1 dose-escalation trials in healthy volunteers 
published between 1995 and 2004. Journal of Clinical Pharmacology 45(10):1123-
1136.  
6 FDA Guidance for Industry (December 2002). Food-Effect Bioavailability and Fed 
Bioequivalence Studies. 
7 Beck AT, Ward CH, Mendelson M, Mock J & Erbaugh J (1961). An Inventory of 
Measuring Depression. Archives of General Psychiatry. 4(6):561-571.  
8 Beck A T, Steer R A, Ball R & Ranieri W (1996). Comparison of Beck depression 
inventories – IA and II in psychiatric outpatients. Journal of personality assessment 
67(3): 588 – 597.  

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11 APPENDICES 
APPENDIX 
1: 
SPONSOR 
APPROVED 
CLINICALLY 
ACCEPTABLE 
INCLUSION LABORATORY RANGES  
V3.0 24 JUNE 2020 
Test 
Acceptable Inclusion Range 
Low 
High 
Sodium 
130 mmol/L  
150 mmol/L  
Potassium 
3.0 mmol/L  
5.5 mmol/L  
Chloride 
0.95 x LLN  
1.05 x ULN   
Magnesium  
0.95 x LLN  
1.05 x ULN   
Calcium (Corrected) 
0.95 x LLN  
1.05 x ULN  
Glucose Fasted 
N/A 
1.0 x ULN  
Urea 
N/A 
1.75 x ULN 
Creatinine 
N/A 
1.0 x ULN  
Creatine kinase 
N/A 
< 2.5 x ULN 
Total Protein 
≥ 0.85 x LLN  
≤ 1.25 x ULN  
Albumin 
≥ 0.85 x LLN 
≤ 1.25 x ULN 
Total Bilirubin 
N/A 
1.25 x ULN 
Direct Bilirubin 
N/A 
1.25 x ULN 
ALP 
N/A  
1.5 x ULN 
AST 
N/A 
1 x ULN 
ALT 
N/A 
1 x ULN 
GGT 
N/A 
1.5 x ULN 
Lactate Dehydrogenase 
0.9 x LLN 
1.1 x ULN 
Cholesterol 
N/A 
1.2 x ULN  
Triglycerides  
N/A  
1.2 x ULN  
Prothrombin time INR and 
APTT 
1.0 x LLN  
1.0 x ULN  
Haemoglobin 
0.9 x LLN  
1.1.x ULN 

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Test 
Acceptable Inclusion Range 
Low 
High 
Red blood count  
0.9 x LLN 
1.1 x ULN  
Platelets  
0.9 x LLN  
1.1 x ULN  
White Blood Cells 
0.9 x LLN  
1.1 x ULN  
Neutrophils  
1.0 x LLN  
1.0x ULN  
Lymphocytes 
1.0 x LLN  
1.0 x ULN  
Monocytes 
N/A 
1.2 x ULN  
Eosinophils 
N/A 
1.0 x ULN  
Basophils 
N/A 
2.0 x ULN  
Urinalysis  
 
 
Glucose  
(quantitative)  
N/A  
< 3 mmol/L   
Protein  
(quantitative) 
N/A 
< 0.16 g/L  
Protein/creatinine ratio 
(quantitative) 
N/A 
< 21 mg/mmol 
Red Blood Cells (quantitative) N/A 
<20 x 106/L*  
White Blood Cells 
(quantitative) 
N/A 
<10 x 106/L  
Organism   
(quantitative)  
NA  
< 1+  
Ketones (dipstick) 
N/A 
< 1+ 
Nitrate (dipstick) 
NA  
Negative    
Bilirubin (dipstick) 
N/A 
< 1+ 
Urobilinogen (dipstick) 
N/A 
< 1+ 
ABBREVIATIONS: ALP = alkaline phosphatase; ALT = alanine transaminase; APTT = activated 
partial thromboplastin time; AST = aspartate transaminase; GGT = gamma-glutamyl transferase; 
INR = international normalised ratio; LLN = lower limit of normal; N/A = not applicable; ULN 
= upper limit of normal.  
*A result ≥ 20 x 106/L is acceptable for female participants currently menstruating. 
 

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APPENDIX 2: SEVERITY GRADING FOR FASTING TBA IN PHASE 1 
VOLUNTEERS