Conditions: Malaria
Keywords: Safety Tolerability
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 72
Healthy volunteers: yes

Brief summary:
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.

Detailed description:
Part 1:

Double-blind, randomized, placebo-controlled, sequential ascending single dose study in healthy adult participants, 7 cohorts, and 1 additional cohort may be considered if needed according to the observed safety, tolerability, and pharmacokinetics results.

A sentinel dosing strategy will be implemented at each dose level to ensure the best conditions of safety. Each cohort will be divided into at least 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 safety and tolerability data from the sentinel cohort up to and including 96 hours post-dose will be reviewed by the Principal Investigator, the Medical Monitor and the Sponsor´s Medical Director. Following a satisfactory safety review, dosing of the remaining participants in the cohort may proceed.

Part 2:

Open label, 2-period cross-over, randomized, pilot food effect study to provide preliminary information on the effect of a high-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. 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.

Arms:
arm 1: 5 mg MMV533 with single ascending dose arm 2: Single ascending dose to be determined after SRC review of previous cohort. arm 3: Single ascending dose to be determined after SRC review of previous cohort. arm 4: Single ascending dose to be determined after SRC review of previous cohort. arm 5: Single ascending dose to be determined after SRC review of previous cohort. arm 6: Single ascending dose to be determined after SRC review of previous cohort. arm 7: Single ascending dose to be determined determine after SRT review of previous cohort. Dose will not exceed 400 mg. arm 8: Open label, 2-period cross-over, randomized, pilot food effect study to provide preliminary information on the effect of a high-fat meal on the pharmacokinetics of a single-dose oral administration of MMV533 determined to be safe in Part 1.

Interventions: intervention 1: MMV688533
Intervention descriptions: intervention 1: Investigational medicinal product

Protocol document:
ICF_002.pdf: 
 
Study drug - MMV533 
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Page 1 of 26 
Document No. SPFMA001-02 
Implementation Date: 07-Oct-2019 
 
 
 
Participant Information and Consent Form 
Alfred Project Number: 
97/20 
Full Study 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.  
Protocol Number: 
MMV-MMV533_19_01 
Test Drug Code: 
MMV533 
International Sponsor: 
Medicines for Malaria Venture (MMV) 
Local Sponsor: 
Southern Star Research Pty Ltd (SSR) 
Principal Investigator: 
Dr Jason Lickliter 
Location: 
Nucleus Network Pty Ltd, Melbourne, Victoria 
 
PART 1 - What does my participation involve? 
 
1. 
Introduction 
You are invited to take part in this research study because you are a healthy male or female 
aged 18-55 years old who potentially meets the study participation requirements.  
This project is testing the safety, tolerability, pharmacokinetics (the amount of study drug in your 
blood and any metabolites (break down products)) of a single (Part 1)/multiple (Part 2) oral dose 
of a new drug called MMV533.   
This Participant Information and Consent Form (PICF) tells you about the research study. It also 
explains the tests and treatments that will be completed during study participation. This information 
is given to you to help you decide if you want to take part in this research study. Please read this 
information carefully and ask the study doctor questions about anything that you don’t understand 
or want to know more about before deciding whether or not you want to take part. If you wish to do 
so, please take the time to talk about it with a relative, friend or your local doctor before making a 
decision to participate. 
Once you understand what the study is about and if you agree to take part in it, you will be asked 
to sign a Consent Form attached to this document.  By signing the Consent Form, you indicate that 
you understand the information and that you give your consent to participate in the research study. 
Your information regarding participation in the study will be provided to your preferred doctor if 
you opt to provide their contact details to study staff. 
Participation in this research is voluntary. If you don’t wish to take part, you don’t have to. 


 
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If you decide you want to take part in the research study, you will be asked to sign the consent 
section. By signing it you are telling us that you: 
• 
understand the information you have read; 
• 
consent to take part in the research study; 
• 
consent to follow the study requirements 
• 
consent to have the tests and treatments that are described; 
• 
consent to follow the study requirements and to keep follow-up appointments that are 
described; 
• 
consent to the use of your personal and health information as described. 
A description of this clinical trial is available on https://clinicaltrials.gov/. This website will not 
include information that can identify you. At most, the website will include a summary of the 
results after the trial is completed. You can search this website at any time. 
You will be given a signed copy of the Participant Information and Consent Form to keep. 
 
2. 
What is the purpose of this research? 
MMV533 is being developed for the curative treatment of mild malaria caused by P. falciparum in 
adults and children.  
Malaria is an infectious disease caused by Plasmodium parasites that are carried by Anopheles 
mosquitoes. At least five types of Plasmodium parasites can cause malaria in humans. In natural 
infections, the malaria parasite is injected into the blood when an infected Anopheles mosquito 
bites its victim. Anopheles mosquitoes are mostly found in hot and humid regions of the world. 
Current approaches to controlling malaria are failing because the malaria parasites have become 
resistant or are becoming resistant to the antimalarial drugs we have available (this means the 
parasites are no longer killed by the drugs or they take longer to be killed by the drugs). Therefore 
we need to develop and test new antimalarial drugs or combinations of drugs.  
Medicines for Malaria Venture (MMV) is developing the study drug MMV533 as one such potential 
new treatment for the treatment of malaria.  
Medications, drugs and devices must be approved for use by the Australian Federal Government; 
the Therapeutic Goods Administration (TGA). MMV533 has not been approved for marketing by 
the TGA in Australia (and is not yet approved anywhere else in the world). Therefore, the use of 
MMV533 in this study is experimental. 
This is the first time MMV533 will be given to humans.  Although unlikely, there is a risk of 
death in first in human studies such as this study. 
In other studies, some unexpected serious, life-threatening side effects have occurred following 
the administration of new experimental treatments. It is unknown, whether some unexpected, 
serious, life threatening side effects could occur with MMV533. Whilst these are considered 
unlikely, you will be monitored closely for them and treated if they occur.  
Part 1 and 2 of this study are being conducted at Nucleus Network Pty. Ltd., Melbourne, Victoria. 
The Clinical Research Organisation involved in monitoring the study and acting as the local 


 
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Document No. SPFMA001-02 
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sponsor is Southern Star Research and the study is sponsored by Medicines for Malaria Venture 
(hereafter referred to as MMV).   
 
3. 
What does participation in this research involve? 
Before you begin the study, you will be given detailed information about MMV533, the study, and 
any other relevant information by research staff. You are encouraged to ask questions until you 
are sure that you fully understand the nature of and requirements of the study. 
If you decide to be assessed for inclusion in the study, you will be asked to visit the Nucleus 
Network Pty Ltd for an initial assessment visit (screening visit). Before any procedures are 
undertaken, you will be asked to sign a consent form. You will then have some tests to check that 
the study is suitable for you. The screening visit may take between 3 and 3½ hours.  
This study will enrol approximately 64 participants, in two parts: 
Part 1 of the study will enrol approximately 56 participants in up to 7 cohorts (groups) with 
approximately 8 participants in each cohort. You will be enrolled in a single cohort of this study 
only. Each cohort will be divided into at least 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 safety profile will be reviewed by a medical team (safety 
review committee) and if deemed safe the rest of the remaining participants in the cohort may 
proceed.  
As this is a dose escalation study, the first cohort (group) enrolled will receive the lowest dose 
and once it is considered to be safe, the next group will be enrolled and will receive the next 
higher dose. Dose escalation will only proceed following a review of all available safety data by 
the Principal Investigator in consultation with the sponsor and if there is confirmation that this is 
safe to continue with the next higher does in the next group. The study can be stopped at any 
time, based on evaluation of the side effects of the study drug/experimental drug.  
The study is placebo controlled, meaning that some participants will receive a tablet containing 
study drug and some will receive a tablet containing placebo. The tablet containing the placebo 
will look the same as the tablet containing the active study drug but will not contain any active 
ingredients in it. You will not have a choice as to whether you receive the study drug or placebo 
(you will be assigned randomly, like flipping a coin).  Neither you nor the study staff will know if 
you are assigned to receive the active study drug or the placebo, although in an emergency, the 
study staff can find out. In each cohort (group) 6 participants will receive the study drug and 2 
participants will receive placebo. 
Part 2 of the study is a referred to as a ‘crossover study’, as participants will receive a sequence of 
different treatments. In Part 2, one cohort (group) of approximately 8 participants will receive a 
dose of the study drug in two separate dosing periods separated by a washout phase of 21 days. The 
first dose will be administered while fasting and the second dose of the study drug will be 
administered after a high-fat meal (described in the treatment and follow-up period below). A 
vegetarian meal (example: egg, avocado, almonds, toast, hashbrown, whole milk) can be made 
available if discussed with study staff. The range of doses of MMV533 administered in Part 1 of 
this study ranged from 5 to 160mg and the dose for Part 2 will be 30mg. 
 


 
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Study sequence: 
Your total participation in Part 1 of the study will consist of approximately 8 weeks as follows:  
• 
Screening visit: Will occur within 28 days of dosing. You will undergo assessments to 
determine if you are eligible for the study.  
• 
Admission, treatment and follow up period: You will be required to attend the study 
centre for a 5-night in patient stay. 
• 
Follow up visits: You will be required to attend the study centre on Days 8, 14, 21 and 
day 28 for follow up visits.  
 
Below is a schematic outlining the study schedule: 
 
 
Your total participation in Part 2 of the study will consist of approximately 10 weeks as follows:  
• 
Screening visit: Will occur within 28 days of your first dose. You will undergo assessments 
to determine if you are eligible for the study.  
• 
Admission and treatment period: You will be required to attend the study centre for two 
inpatient periods of 5 days each, with a washout period of 21 days in-between study drug 
administration. One dose of the study drug will be with food and one will be administered 
without food.  
• 
Follow up visits: You will be required to attend the study centre on several days following 
each inpatient period. 
 
Below is a schematic outlining the study schedule: 
 
 
Screening visit (between Day -28 to Day -2) 
If you decide to be assessed for inclusion into the study, you will be asked to visit the Nucleus 
Network Pty Ltd for the screening visit. The first screening visit may take between 3 and 3½  hours.  
After reading this information sheet and if you agree to participate in the study, you will be asked 
to sign the attached consent form. The study doctor will perform a medical examination to ensure 
that it is appropriate for you to be part of the study. You will undergo the following assessments: 
• 
You will be asked about your current health status and about your medical history, 
including all medications, over-the-counter and herbal medications that you have been, and 
Screening Visit: 
Within 28 days
Admission and treatment period
Admit: Day -1
Dose: Day 1
Discharge: Day 5
Follow up Visits
Day 8, 14, 21 and 28
Screening 
Visit: 
Within 28 days
Period 1
Admit: Day -1
Dose: Day 1
Discharge: Day 5
Follow Up 
period
Visits on;
Day 8 and Day 
14
Period 2
Admit: Day 21
Dose: Day 22
Discharge: Day 
26
Follow up 
Visits
Day 29, 35, and 
42


 
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Document No. SPFMA001-02 
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are currently taking. The study doctor will also ask you to complete a questionnaire related 
to your current mental health.  
• 
You will be asked some personal details about yourself, including your date of birth. 
• 
You will be asked about your alcohol history and you will undergo an alcohol breath test.  
• 
You will be asked to provide a urine and blood sample to assess your general health and 
to test for medications of addiction as listed below: 
- 
to test for drugs of addiction (such as methamphetamine, cocaine, cannabinoids, 
opiates, phencyclidine, barbiturates, benzodiazepines, methadone, and amphetamine). 
This is a study requirement and the results will remain confidential. The tests may reveal 
that you have previously used illegal medications. That information will be stored in a 
re-identifiable (or coded) format. If the Nucleus Network Pty Ltd is ordered by a court of 
law to disclose the information regarding the use of illegal medications or illegal alcohol 
breath test levels, it may be used against you in legal proceedings or otherwise as the 
court directs. If you test positive for any of these substances, you may be excluded from 
further participation in this study. 
- 
to test for use of paracetamol  
• 
Your vital signs such as blood pressure, heart rate, respiratory rate and tympanic (ear) 
temperature will be measured.  
• 
You will have a full physical examination (PE), your height and weight will be measured 
to determine your body mass index (BMI). 
• 
You will have electrocardiograms (ECG) (recording of your heart’s electrical activity and 
rhythm).   
• 
Safety Lab Test Blood sample (approximately 20mL / 4 teaspoons) will be collected to 
provide information on your general health and to screen for pregnancy, HIV (AIDS virus), 
and hepatitis B and C. This is because the study doctors need to know about your health 
and the health of your immune system. 
o You will receive information and counselling before the HIV and hepatitis tests. If a 
test shows you have HIV or hepatitis you will not be included in this study, but you 
will have follow-up counselling and medical advice. If your test results are positive, 
the researchers are required by law to notify the relevant state government. Signing 
the consent form means you agree to have this testing. It will not be done without 
your consent. 
If for any reason, the trial is found to not be suitable for you, staff from the Nucleus Network Pty 
Ltd will contact you and provide follow-up treatment advice where applicable. 
 
Treatment and Follow-up Period 
If you are eligible to enter the study, you will be admitted to the clinical unit the day before the 
planned dosing day (Day -1). On this day you will undergo a number of procedures to confirm your 
suitability for participation in the trial (see table below). Participants in Part 2 will also undergo 
procedures to ensure continued eligibility when they admit to the clinical unit for their second dosing 
period on Day 21. 
To ensure sufficient number of participants are available for Day-1, additional volunteers called 
‘alternates’ will be recruited and admitted to the clinical unit. If you are an alternate, you may be 
asked to participate in the study if someone is not included in the dosing group. You will be informed 
if you are an alternate on Day 1 before treatment is given. 


 
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In the clinical unit a cannula will be inserted into a vein in your arm prior to dosing. This is a small, 
flexible tube which will allow blood to be collected easily throughout your unit stay and prevents 
the need for repeated needles to be inserted in your vein to collect each sample. The location of 
the cannula may need to be repositioned if required. 
You will undergo the following procedures at various times during the study:  
• 
Vital signs: tympanic (ear) temperature, heart rate and blood pressure will be measured. 
• 
12-Lead Electrocardiogram (ECG): will be performed to assess your heart rhythm. 
• 
Physical Examination: will be performed to assess your general health. This will include 
measuring your body weight. 
• 
Safety blood and urine samples: approximately 15 ml (approx. 3 teaspoons) of blood and 
a urine sample will be collected to assess your general health and to screen for pregnancy. 
When you check in, the urine sample will also be collected to test for drugs of addiction. A 
positive test will exclude you from further participation in the trial. Additional safety samples 
may also be collected if required by the study doctor. You will be required to fast prior to 
some safety blood samples; study personnel will let you know when this is required and 
what length the fasting period will be. 
• 
Alcohol breath test: You will undergo an alcohol breath test when you check into the 
clinical unit to see if you have been drinking any alcohol in the past 24 hours. A positive 
test will exclude you from further participation in the trial. 
• 
Study drug administration:  
Part 1: The study drug will be administered as an oral tablet with 240ml of water under 
fasting conditions (10 hrs overnight). 
Part 2: You will receive the study drug with and without food in either of the two inpatient 
periods. When you receive the dose with food, you will need to fast overnight for 10 hours 
followed by a high fat meal.  
 
The high-fat meal will include 2 x pieces of toast, full cream milk, fried hash brown potatoes 
and animal products (egg, bacon, butter) and must be completed prior to dosing. Please 
talk to the study staff if you have any questions about the meal. A vegetarian meal 
(example: egg, avocado, almonds, toast, hashbrown, whole milk) can be made available if 
discussed with study staff.  
 
You will be required to eat the whole meal within 30 minutes and be dosed 30 minutes after 
you start eating.  
When you receive the drug without food you will need to fast overnight for 10 hours before 
receiving the drug. 
• 
Pharmacokinetic (PK) samples: will be collected to measure the amount of MMV533 in 
your blood, the break down products and to assess the effect it has on your body. 4mL of 
blood (approx. 1 teaspoon) will be collected at various time points during your inpatient stay 
and study visits.  
Additional PK sample may be collected if your safety blood results show out of range 
results.   
• 
Pharmacogenetic Sample: An additional blood sample for mandatory genetic testing, 2ml 
of blood will be collected prior to your dose of the study drug (MMV533). This test is 
intended to evaluate how various genes are involved in the distribution, metabolism and 
elimination of the drug from your body. 


 
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Document No. SPFMA001-02 
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• 
Concomitant Medication (medications taken at same time or almost the same time) 
review: you will be asked if you have recently taken any medications as this may interact 
with the study.  
• 
Adverse Events: You will be asked about how you are feeling (whether you feel alright, 
different from normal or unwell) at regular intervals, please tell a study team member if you 
have any changes in your health or concerns. 
 
You will be discharged from the clinical unit once all study procedures are complete and the clinical 
staff sees no changes in your health which would prevent your discharge from the clinical unit.  
 
Follow up visits 
Part 1: On days 8, 14, 21 and day 28, you will be required to attend the Nucleus Network Pty Ltd 
for follow up visits. These visits will take approximately 1-2 hours for follow-up assessments as 
outlined above and in the table below.  
Part 2: After Period 1, you will need to attend follow up visits on Day 8 and 14. After Period 2, you 
will be asked to attend follow up visits on days 29, 35, and 42.  
The study doctor will ask you to return to the research unit on these days and may ask you to return 
in between these visits days or after this period, if he/she feels it is necessary. Additional safety 
assessments may be carried out when you return for a visit if the study doctor feels it is necessary. 
In the event it is necessary to further evaluate the safety or effects of the medication, it may be 
necessary to have access to additional information about your health status. Your study doctor 
may attempt to obtain study-related information about your health from you or from other sources, 
including your primary care physician. This may include contacting you again by phone or letter. 
 


 
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Document No. SPFMA001-02 
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The table below outlines the assessments that will be performed in Part 1: 
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  
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 test 
X 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs  
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 
Body temperature (ºCelcius) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haematology, biochemistry, urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test/ FSH 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
Adverse event collection 
< 
- 
- 
- 
- 
- 
 
- 
- 
- 
> 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
MMV533 plasma samples 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MMV533 urine samples 
 
 
X 
X 
X 
 
 
 
 
 
 
 
Pharmacogenetics 
 
 
 
 
 
 
 
 
 
 
 
 
DME/T DNA blood sample 
 
 
X 
 
 
 
 
 
 
 
 
 
ABBREVIATIONS: DME = drug metabolizing enzymes; ECG = Electrocardiogram; exam = examination; FSH = follicle stimulating hormone; IMP= Investigational Medicinal 
Product (study drug); BDI = Beck Depression Inventory; ET – early termination 
 


 
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Document No. SPFMA001-02 
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The table below outlines the assessments that will be performed in Part 2: 
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  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history/BDI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
< 
- 
- 
- 
- 
- 
 
 
 
 
 
- 
 
 
- 
- 
- 
> 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatment administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMV533 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
High fat breakfast when applicable 
 
 
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 test 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Vital signs  
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 
Body temperature (ºCelcius) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haematology, biochemistry, urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test/ FSH 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Adverse event collection 
< 
- 
- 
- 
- 
- 
 
 
 
 
 
- 
 
 
- 
- 
 
> 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMV533 plasma samples 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacogenetics 
 
DME/T DNA blood sample 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ABBREVIATIONS: ECG = electrocardiogram; hCG = human chorionic gonadotropin; WOCBP = woman of childbearing potential; EOS – end of study; ET – early termination; 
BDI = Beck Depression Inventory 


 
 
 
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4. 
What do I have to do? 
It is important for your own safety that you inform the study doctor or staff of your complete 
medical history and all medications, supplements, and/or herbal preparations that you have 
taken within the past 6 months or are currently taking. If you have any health problems, 
please notify your study doctor immediately. As mentioned earlier in this document, if you 
notice any changes in your health or have concerns during your participation in the study, 
also inform your study doctor or study staff as soon as possible. You must always follow the 
instructions of the study doctor and staff. 
Please note that in the days leading up to your admission to the clinical unit, there are a few 
requirements for inclusion in the study: 
1. You must avoid participation in any research study involving blood sampling (more than 
450 mL/unit of blood) or blood donation during the 8 weeks prior to study drug 
administration. 
2. You must have no 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. A positive alcohol screen at screening, or prior 
to study drug dosing, will exclude you from the study. 
3. You must not have smoked >1 pack of cigarettes per day for >10 years, or currently (within 
14 days prior to study drug administration) smoke >5 cigarettes per day. You cannot use 
tobacco during  confinement periods. After discharge from the clinical unit, you should not 
smoke more than 5 cigarettes (or equivalent) per day until after your last study visit. 
4. You must not have taken any vitamin supplements within 7 days prior to study drug 
administration 
5. You cannot take any medications (including herbal such as St John’s Wort and over the 
counter) within 5 half-lives prior (approximately 20 days) to study drug administration 
except occasional intakes of  
- 
ibuprofen (e.g. Nurofen) 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 (e.g. Voltaren) potassium liquid-filled capsules at doses up to 25mg 
orally 4 times a day; diclofenac free acid capsules at doses up to 18 or 35 mg 
orally 3 times a day; diclofenac potassium immediate-release tablets at doses up 
to 50mg orally 3 times a day 
- 
contraceptives.  
You must not have taken any antidepressant medication in the past 12 months prior to 
study drug administration and you must not receive any vaccination within 28 days of 
screening. 
The half-life of a drug is the time it takes for the levels of the drug in your system to 
decrease by half. Your screening doctor can help answer any questions regarding 
medications and clarify how long half-lives of most medications will last. 
6. You must not have a positive urine drug test at screening, or prior to study drug dosing. 
7. You must not consume any citrus fruits (grapefruit, Seville oranges) or their juices during 
the study and within 5 days prior to study drug administration. You must not consume 
poppy seeds in the 24 hours prior to screening and during the first day of confinement for 
study drug administration (Day -1).  


 
 
 
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8. You must not consume food or beverages containing alcohol 24 hours prior to each alcohol 
breath test and during confinement periods. After discharge from the clinical unit, you 
should not drink more than 2 standard drinks per day until after your last study visit.  
9. You will not be able to consume beverages containing xanthine bases (eg, Red Bull, 
coffee) during confinement periods. After discharge from the clinical unit, you should not 
consume more than 400 mg caffeine per day (equivalent to 4 cups of coffee) until after 
your last study visit.  
10. You must abstain from strenuous exercise sessions for 4 days prior to study drug 
administration until Day 10 following study drug administration. 
11. You should not have participated in other clinical trials within 3 months before dosing or 5 
times the half-life of the IP (whichever is longer). Your screening doctor can help determine 
this. 
12. Please refrain from any COVID-19 vaccine within 14 days of dose administration until the 
completion of the study and any other vaccination within 28 days of dose administration 
until the completion of the study.  
 
In case of emergency, you must be easily contactable by phone and/or email. You will be 
given a Participant Wallet Card which contains emergency contact information and information 
about your study commitments. You must always carry the Participant Wallet Card with you 
until the end of the study. 
 
5. 
Other relevant information about the research study 
This study is being conducted at the Nucleus Network Pty Ltd in Victoria for Part 1 and 2. 
Researchers from Nucleus Network Pty Ltd. (located in Melbourne and Geelong, Victoria) 
and Q-Pharm Pty Ltd (located in Brisbane, Queensland), both Nucleus Network companies, 
will be working together. 
A representative of MMV (study sponsor) may be present for inspections in the unit during 
the study.  
 
6. 
Do I have to take part in this research study? 
Participation in any research study is voluntary. If you do not wish to take part, you don’t have 
to. If you decide to take part and later change your mind, you are free to withdraw from the 
study at any time without providing any reason. Your study doctor may ask you the reason for 
your withdrawal, you can answer or not.  
Your decision whether to take part or not, or to take part and then withdraw, will not affect your 
relationship with the Nucleus Network Pty Ltd and will not involve any penalty or loss of 
benefits to which you would be otherwise entitled. Should you withdraw from the study before 
the final visit you will receive a partial payment according to the number of visits you have 
attended. 
Before you make your decision, a member of the research team will be available so that you 
can ask any questions you have about the research study. You can ask for any information 
you want. Sign the Consent Form only if you agree to participate and only after you have had 
a chance to ask your questions and have received satisfactory answers. 


 
 
 
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7. 
What are the alternatives to participation? 
Since this study is intended only to evaluate the safety, tolerability and pharmacokinetics of 
MMV533, your alternative to be a volunteer in this study is to choose not to participate in the 
study. 
 
8. 
What are the possible benefits of taking part? 
If you agree to take part in this study, there will be no direct benefit to you. However, your 
participation in this study may help develop important scientific knowledge that could 
contribute to the development of a treatment for Malaria. We hope the information learned 
from this study will benefit others in the future. 
 
9. 
What are the possible risks and disadvantages of taking part? 
MMV533 is an experimental medication, therefore the risks to human participants have not 
been fully evaluated. 
Medical treatments often cause side effects. You may have none, some or all of the effects 
listed below, and they may be mild, moderate or severe. If you have any of these side 
effects, or are worried about them, talk with a study doctor. Your study doctor and study staff 
will also be watching you closely for side effects. 
Many side effects go away shortly after treatment ends. However, sometimes side effects 
can be serious, long lasting or permanent. If a severe side effect or reaction occurs, your 
study doctor may need to stop your participation in the trial. Tell your study doctor or site 
staff if you notice any changes in your health or have concerns. Your study doctor will 
discuss the best way of managing any side effects with you. 
There may also be side effects that are not expected or are not known that may be serious. 
Tell your study doctor immediately about any new or unusual symptoms or changes in your 
health that you become aware of. The treatment of the side effects will depend on the type 
and severity of the symptom(s). 
If during screening or participation in this research study a previously unknown medical 
condition is discovered the study doctor will discuss: 
• 
whether you are eligible for study participation  
• 
if you require referral to your usual physician or to a specialist 
This research study involves the collection of information about your use of drugs and 
alcohol.  Participation in the research study includes blood and/or urine analysis to 
determine the presence of amphetamines, methamphetamines, barbiturates, 
benzodiazepines, cocaine, methadone, opiates, phencyclidine, tetrahydrocannabinol, 
paracetamol and tricyclic antidepressants. The test may reveal that you have previously 
used illegal drugs or illegal alcohol breath test levels. That information will be stored in a re-
identifiable (or coded) format.  In the event that the Nucleus Network Pty Ltd is required to 
disclose that information, it may be used against you in legal proceedings or otherwise. 
 


 
 
 
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Risks of Study Drug: 
Risks of the study drug (MMV533) based on related drugs and animal studies 
The mechanism of action of MMV533 against the malaria parasite is unknown and there are 
no other licensed medications on the market that act in a similar way. To assess the 
potential risk of treating humans with MMV533, non-clinical (i.e. animal) studies were 
conducted in two species (rats and dogs).  
In these studies, some unexpected serious side effects have occurred following the 
administration of MMV533 at drug levels that are higher than levels that will be reached in 
this current study. These side effects observed in rats and dogs are considered unlikely to 
occur in humans; however, you will be monitored closely for all side effects and treated if 
they occur. 
Studies were conducted with repeated dose of MMV533. In these studies where animals 
were treated for 2 weeks, there were some transient changes in blood tests (liver enzymes 
and bile acids) without symptoms. There were minor changes seen in the bile ducts of dogs 
receiving MMV533 (called hyperplasia) which where reversible when the drug was stopped.  
MMV533 may have side effects in humans, including side effects which are currently 
unknown. 
Based on the animal observations, the following effects may occur after single dose 
administration of MMV533: 
  
• 
Elevated liver enzymes and bile acids in your blood, 
• 
Temporary changes in liver tissue (a consequence of increased levels of bile acids), 
• 
Changes in cardiac activity on electrocardiograms (called “QTc prolongation”), a 
condition which may lead to irregular heart beat (cardiac arrythmia). Your heart 
activity will be monitored closely during the study for any adverse cardiac activity. 
Risks of the study drug (MMV533) based on preliminary human data 
 
Single dose administration of MMV533 was recently evaluated in the First-in-Human study 
MMV_MMV533_19_01 in Melbourne, Australia. Six dose levels, 5, 10, 20, 50, 100, and 160 
mg MMV533, have been fully evaluated in six cohorts of 8 healthy volunteers (6 active 
drug/2 placebo). Although safety observations are still blinded (i.e. we do not know who 
received placebo and who received the drug), preliminary data did not show serious or 
severe adverse events nor any clinically concerning events from electrocardiograms, vital 
signs (blood pressure/heart rate, body temperature) and safety laboratory tests. At this time 
in point, reported adverse events after MMV553/placebo observed in these first 48 
volunteers (i.e. with 5, 10, 20, 50, 100 and 160 mg) and considered as "drug-related" are: 
mild transient elevation of total bile acids (blood tests changes, no symptoms), headache, 
palpitations and contact dermatitis. 
 
As a further precaution you will not be included on the study if you have any conditions that 
may put you at an increased risk of developing any of these effects. We will monitor these 
risks through regular blood samples and recordings of your cardiac activity. 
 
 


 
 
 
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Could I Have An Allergic Reaction? 
There is a risk of allergic reaction. If you have a very serious allergic reaction, you may be at 
risk of death.  
Symptoms may include difficulty in breathing, dizziness, itching, swelling of the lips, tongue 
or throat, coughing, rash. 
In general, most symptoms are manageable. They are mild to moderate in severity. But life-
threatening reactions may occur at any drug dose. If you believe you are having a serious 
allergic reaction after you have been discharged, you should seek emergency medical 
assistance immediately by dialling the emergency services on 000. 
Please notify the study doctor immediately if you experience any of these symptoms. Some 
symptoms of allergic reactions are: 
• 
Rash 
• 
Wheezing and difficulty breathing 
• 
Dizziness and fainting 
• 
Swelling around the mouth, throat or eyes 
• 
Fast pulse 
• 
Sweating 
You will be monitored very carefully for any signs or symptoms that you may be having an 
allergic reaction and appropriate care will be taken by the study doctor and nursing staff.  
If you do not understand what some of these side effects or risks mean, ask the study doctor 
or the study staff to explain them to you. 
Blood Draw/ Cannula Insertion Risks: 
You may have pain or bruising at the site where blood is drawn or a cannula (a temporary 
small plastic tube) is inserted. An infection at the site of blood draws or cannula insertion is 
also possible. The insertion of the cannula (small plastic tube) or the drawing of blood may be 
associated with some pain. Possible side effects from blood drawing include faintness, 
inflammation of the vein, pain, bruising or bleeding at the site of puncture. These will normally 
disappear a few days after the procedure.  
 
Blood Pressure Measurement Risks: 
There is no risk to your health when having your blood pressure tested. You may experience 
some feeling on discomfort as the cuff inflates and squeezes your arm, but it should only last 
a few seconds. Sometimes, there are tiny red spots that appear after the test just below the 
location of the cuff, they should be painless.  
 
Electrocardiogram (ECG) risks: 
The ECG test is a recording of the electrical activity of your heart. The sticky pads used may 
be cold when applied and sometimes cause some discomfort such as redness or itching. If 
there is hair in the area where patches need to be applied, this area will be shaved in order 
to complete the ECG. Shaving may result in irritation. 


 
 
 
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Pregnancy Risk: 
Risks related to Pregnancy 
Reproductive and developmental toxicity studies to evaluate the potential impact of MMV553 
during pregnancy have not been performed. Taking the study drug may involve some risks 
to a human unborn baby or nursing infant. Therefore, you cannot join this study if you are 
pregnant, if you are planning to become pregnant in the next two months, or if you are 
breast-feeding.   
All women of childbearing potential willing to be enrolled in a clinical study with MMV533 will 
have pregnancy tests at screening and during the study. 
Female participants 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 study drug.  
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 study drug.  
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 either 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 study drug. 
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,  
- 
intrauterine hormone-releasing system,  
- 
bilateral tubal occlusion,  
- 
vasectomised partner,  
- 
or sexual abstinence or same sex relationship. 
You will need discuss methods of effective contraception with your study doctor to be enrolled 
in this study. 
Please ask you study doctor if you have any questions regarding the forms of birth 
control that must be used while participating in this study. 
If you/your partner becomes pregnant during the study or up to 60 days (female participants) 
or 90 days (female partners of male participants) after the last dose of study medication, 
please tell your study doctor or staff immediately as we would like to request permission to 


 
 
 
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follow this pregnancy and its outcome. The study doctor will also report the pregnancy to the 
Human Research Ethics Committee and to the study Sponsor.  
Allowing the pregnancy and outcome to be followed is optional. If you/you partner agree to 
have this pregnancy followed, then you/she will be asked to sign a separate Pregnancy 
Follow-Up Participant Information and Consent Form. The information collected is similar to 
that which would be routinely collected during a typical pregnancy consultation. The 
consultation will be done in person at the Nucleus Network Pty Ltd, and/or by telephone.  
In addition, you/she will be asked to notify the study doctor about the outcome of the 
pregnancy. If you/she forgets, you/she will be contacted to obtain this information. This 
outcome data collected includes: pregnancy complications and outcome, birth weight, birth 
defects (if any), and additional factors that may have had an impact on the outcome of the 
pregnancy (drugs, infections, family history etc.).  
The study doctor may also need to contact the obstetrician of your partner. 
 
10. 
What will happen to my test samples? 
By consenting to take part in this study, you also consent to the collection and testing of your 
urine and blood samples for this research. The total volume of blood taken for for the study 
will not exceed 500mL (approx. 2 cups) .For comparison, a standard blood donation is 
approximately 470mL (approx. 2 cups). Additional blood samples may also be collected for 
safety reasons.  
The blood and urine samples collected for the assessment of your health status (e.g. liver 
and kidney function tests) will be processed by a local pathology laboratory. These samples 
will be labelled with your unique study participant number, your initials and date of birth, and 
will not contain any information that can identify you personally. These samples will be 
destroyed following analysis. 
Blood samples collected for pharmacokinetic testing will be sent to Switzerland. These 
samples will be labelled with your unique study participant number and will not contain any 
information that can identify you personally. These samples will be stored during the study at 
a secure premise and the samples will be destroyed following analysis at the end of the 
study. 
Blood samples collected for pharmacogenetics will be sent to various Sponsor-approved 
laboratories in the United Kingdom. These samples will be analysed to better understand 
how genes encoding for enzymes and transporters may influence the distribution and 
elimination of the drug in your body. Samples will be labelled with your unique study 
participant number and will not contain any information that can identify you personally. 
These samples will be stored during the study at a secure premise and the samples will be 
destroyed following analysis at the end of the study. 
The pharmacogenetic testing to be performed as part of the study is not a routine evaluation 
but research testing (as opposed to medical testing) to help the study sponsor interpreting 
the data.  As such, the medical impact of pharmacogenetic research results will not be 
systematically assessed for any individual subject and results of exploratory analysis will not 
be returned to individual participants unless specifically requested. Extra precautions are 


 
 
 
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taken to preserve confidentiality and prevent genetic data being linked to the identity of the 
participant. Samples will be linked to subject ID number. Only the clinical site will be able to 
link individual subject ID numbers with identities. The results from this genetic research may 
be reported in a separate report from the Clinical Study Report or published in scientific 
journals. 
The proposed blood tests include a screening test for HIV (also called the ‘AIDS” virus) and 
Hepatitis.  You will receive information and counselling before the test.  If a test shows you 
have HIV or Hepatitis, you will have follow-up counselling and medical advice.  If your test 
results are positive, the study doctors are required by law to notify government health 
authorities.  Signing the consent form means that you agree to have this testing; it will not be 
done without your consent.  
 
11. 
What if new information arises during this research study? 
Sometimes during a research study, new information becomes available about the treatment 
that is being studied. If this happens, your study doctor will tell you about it and discuss with 
you whether you want to continue in the research study. If you decide to continue in the 
research study, you will be asked to sign an updated consent form. 
Also, on receiving new information, your study doctor might consider it to be in your best 
interests to withdraw you from the research study. If this happens, he/she will explain the 
reasons and arrange for your regular health care to continue. 
 
12. 
Can I have other treatments during this research study? 
Whilst you are participating in this research study, you are not able to take any medications 
or treatments other than those agreed upon at the start of your participation in the study. 
However, if you develop a new illness (unrelated to MMV533) that requires treatment, 
participation in the trial will not prevent appropriate treatment. 
It is important to tell your study doctor and the study staff, at each clinic visit, about any 
treatments or medications you may have taken, including over-the-counter medications, 
vitamins or herbal remedies, acupuncture or other alternative treatments.  
 
13. 
What if I withdraw from this research study? 
If you decide to withdraw from the study, please notify your study doctor or staff before you 
withdraw. This notice will allow the study doctor to discuss any health risks or special 
requirements linked to withdrawing. Before you withdraw, the study doctor will want to conduct 
one last study visit known as an early termination visit to check your health. The assessments 
completed at this visit are the same as those completed at the end of study visit. Please refer 
to the assessment tables above.  
If you do withdraw your consent during the research study, any information collected on you 
up to the point of withdrawal will be used. Data collected after your withdrawal, if any, may 
be used: 


 
 
 
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• If you decide to withdraw from the study, any adverse event not resolved at this time 
will be followed until its resolution by your study doctor to ensure your medical follow-
up. You may also contact your study doctor if you experience a new adverse event. 
• If you withdraw from the study for a reason other than your own decision, your study 
doctor may contact you to request any relevant information and / or documentation 
regarding your medical care. 
• If you withdraw your consent, all your biological sample(s) will be destroyed without 
disclosing your identity. If safety or PK/PD analysis is required for the study, it will be 
analysed before destroying your samples.  
 
14. 
Could this research be stopped unexpectedly? 
This research study or your participation in the study may be stopped unexpectedly for the 
reasons listed below.   
• 
Unacceptable side effects 
• 
The drug being shown not to be safe 
• 
Decisions made in the commercial interests of the sponsor or by local regulatory/health 
authorities 
• 
If you don’t follow the instructions of the clinical unit staff; or 
• 
If the study doctor decides it is in the best interest of your health and welfare to stop. 
 
15. 
What will happen when the research study ends? 
The study drug will not be available to you following completion of participation.  
The study data will be analysed, and a final report provided to the study doctor, who will share 
the results with you when requested. The disclosure and/or any published results will be 
available to you when requested. It is usual for a number of years to elapse before definitive 
results of this type of study are available. These may be published in medical journals that are 
available to the public. You should feel free to ask the study staff about this. 
 
 
16. 
What will happen to information about me? 
Any information and data obtained/retained in connection with this research study that can 
identify you will remain confidential and will only be used for this research study. 
Information about you may be obtained from your health records held at other health 
services for the purpose of this research. By signing the consent form, you agree to the 
study team, including Sponsor delegates, accessing health records if they are relevant to 
your participation in this research study to ensure data accuracy. Whilst every effort will be 
made to keep your personal information confidential, the data gathered for this study will 
also be reviewed by a Sponsor delegate. This delegate will have access to your medical 
records, without violating your confidentiality to the extent permitted by local laws and 
regulations, to verify the data are correct and complete. 


 
 
 
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The data collected as part of this research study may be reviewed by representatives of the 
international sponsor, MMV, its affiliated companies and/or subcontractors, the local 
sponsor, Southern Star Research, Members of the Alfred Hospital Ethics Committee, by 
authorised representatives of the Australian Therapeutic Goods Administration or other 
regulatory agencies. Information may be transferred to parties in countries (and regions) 
other than Australia including the US, and Europe for these purposes. Southern Star 
Research, MMV representatives, collaborators and contracted agencies comply with internal 
procedures to protect personal information even in countries whose data privacy laws are 
less strict than those of this country. In all cases when dealing with your personal (coded) 
information. MMV, and any of their agents will comply with the Privacy Act 1988. If you have 
any concerns on how your information is handled, please feel free to ask a member of the 
study team for more information. 
By signing the consent section, you authorise release of, or access to, this confidential 
information to the relevant study personnel and regulatory authorities as noted above. 
 
Study Medical Records 
Data from your study medical record will be identifiable and stored in secured offices at the 
Nucleus Network Pty Ltd. Only research team members and authorised representatives from 
the Sponsor, the Ethics Committee or regulatory agencies will have access to your medical 
records. 
In accordance with relevant Australian and/or state privacy and other relevant laws, you 
have the right to request access to your information collected and stored by the research 
team. You also have the right to request that any information with which you disagree be 
corrected. Please contact the study team member named at the end of this document if you 
would like to access your information. 
Information about your participation in this research study will be recorded in your study 
records at the Nucleus Network Pty Ltd.  
 
Case Report Form (CRF) 
Information you provide us will be recorded in electronic case report forms (CRF).  Your 
information will be coded by your unique study number, your gender and birth year only and 
thus will be considered re-identifiable. The recorded data will be kept in an electronic 
database which will be managed throughout the study by Southern Star Research. 
Information from these CRFs will form part of the study results, which may be published.  
A copy of the database entries and your medical record will be kept securely in accordance 
with ICH GCP requirements with all other study related documents.  
This information will be reviewed by authorised individuals from the contract research 
organisation, MMV or affiliates, contractors and/or Health Authorities or Government 
Agencies (including the Therapeutic Goods Administration, as well as health authorities in 
USA and other countries) and delegates of the Ethics Committee for confirming the accuracy 
of the research study data.  


 
 
 
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By signing the consent section, you authorise release of, or access to, this confidential 
information to the relevant study personnel and regulatory authorities as noted above. 
 
Publications 
A report of the study results may be submitted for publication. In any publication and/or 
presentation, information will be provided in such a way that you cannot be identified, except 
with your permission).  
If you want to know more about the Nucleus Network Pty Ltd’ approach to privacy or access 
any of your information held by the Nucleus Network Pty Ltd, you can contact the privacy 
officer at privacyofficer@nucleusnetwork.com.au . 
It is desirable that your local doctor be advised of your decision to participate in this research 
study. By signing the consent section, you agree to your local doctor being notified of your 
decision to participate in this research study. 
 
17. 
Complaints and compensation 
If you suffer any injuries or complications because of this research study, you should contact 
the study doctor or study team as soon as possible and you will be assisted with arranging 
appropriate medical treatment. If you are eligible for Medicare, you can receive any medical 
treatment required to treat the injury or complication, free of charge, as a public patient in 
any Australian public hospital. 
If you are not eligible for Medicare, the Sponsor and/or Nucleus Network Pty Ltd will cover 
the cost of any and all health care service costs incurred by you in respect of any injury or 
complication that has been independently determined to have been incurred as a result of 
the study drug or study procedure. 
There are two avenues that may be available to you for seeking compensation if you suffer an 
injury because of your participation in this research study: 
• 
The sponsor MMV has set up a compensation process, with which the local sponsor 
of this research study, Southern Star Research, has agreed to comply. Details of this 
process and conditions are set out in the Medicines Australia Guidelines for 
Compensation for Injury Resulting from Participation in a Company-Sponsored Clinical 
Trial. In accordance with these Guidelines, the sponsor will determine whether to pay 
compensation to you, and if so, how much. The research staff can give you a copy of 
the Guidelines together with this Participant Information and Consent Form or it can 
be accessed online; 
https://medicinesaustralia.com.au/wp-content/uploads/sites/52/2010/09/Clnical-
Trials-Compensation-Guidelines-1.pdf. If you have any questions about the 
Guidelines, please contact Dr Jason Lickliter on j.lickliter@nucleusnetwork.com.au. 
• 
You may be able to seek compensation through the courts. 
If you are not satisfied with how your personal information has been handled (as laid out in 
the Privacy Act, 1988), then you can make a complaint to the Office of the Australian 
Information Commissioner (OAIC). It is free to lodge a complaint and you do not need a lawyer, 
however if you do decide to hire a lawyer, you must pay for the lawyer yourself. You can 


 
 
 
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choose 
to 
withdraw 
your 
complaint 
at 
any 
time. 
Please 
refer 
to 
http://www.oaic.gov.au/privacy/privacy-complaints for more information. 
 
18 
Who is organising and funding the research? 
This research is being conducted by MMV based in Geneva and sponsored in Australia by 
Southern Star Research. MMV may benefit financially from this research study if, for example, 
the study assists to obtain approval for a new drug. 
By taking part in this research study you agree that samples of your blood (or data generated 
from analysis of these materials) may be provided to MMV. 
MMV may directly or indirectly benefit from knowledge acquired through analysis of your 
samples. 
If knowledge acquired through this research leads to discoveries that are of commercial value 
to MMV, the study doctor or their institutions, there will be no financial benefit to you or your 
family from these discoveries. 
MMV, other researchers, or research companies may patent or sell discoveries that result 
from this research. Neither MMV nor the study doctor will compensate you if this happens. 
Contractors engaged by MMV will receive a payment from MMV for undertaking this research 
study. 
No member of the research team will receive a personal financial benefit from your 
involvement in this research study (other than their ordinary wages). 
 
19. 
Will I be reimbursed to take part in this research study? 
Participants in Part 1 will be reimbursed $150.00 for the screening and follow-up visits, and 
at a daily rate of $480.00 per day for the in-clinic stay part of this study. Please note that 
admission and discharge days will be reimbursed at half-day rates. The total reimbursement 
for participants who complete the entire Part 1 study will be approximately $3,150.00. If you 
are an alternate for Part 1, and do not complete the entire study, you will receive a partial 
reimbursement of $630.00. 
Participants in Part 2 will be reimbursed $200.00 for the screening and follow-up visits, and 
at a daily rate of $450.00 per day for the in-clinic stay part of this study. Please note that 
admission and discharge days will be reimbursed at half-day rates. The total reimbursement 
for participants who complete the entire Part 2 study will be approximately $5700.00. If you 
are an alternate for Part 2, and do not complete the entire study, you will receive a partial 
reimbursement of $650.00. 
You will be reimbursed within 10 business days of the end of study visit via electronic funds 
transfer directly into your bank account. Should you withdraw yourself from the study before 
the final visit, or your participation is halted early (refer to section 14), you will receive a 
partial reimbursement according to the number of visits you have attended. 
If you are an eligible alternate, and do not get dosed, you will receive a partial 
reimbursement as mentioned above. If you are deemed to be ineligible after your screening 
visit due to a medical result that is independent from your direct actions, you will receive a 


 
 
 
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reimbursement for your screening visit. This payment will be made within a month of your 
screening appointment. Screening visit will not be reimbursed if your ineligibility is due to a 
positive drug of abuse or alcohol testing. 
Reimbursement compensates for your time, travel expenses, parking and inconvenience. 
This reimbursement is not made for undergoing risk nor is it to compensate you for any loss 
of earnings as a result of your participation. 
It is not anticipated that participation in this research study will result in any additional cost to 
you. 
20. 
Who has reviewed the research study? 
All research in Australia involving humans is reviewed by an independent group of people 
called a Human Research Ethics Committee (HREC) who make sure that the rights, safety 
and well-being of participants in a study are protected. The ethical aspects of this research 
study have been approved by the Alfred Hospital Ethics Committee. 
This study will be carried out according to the National Statement on Ethical Conduct in 
Human Research (March 2007) produced by the National Health and Medical Research 
Council of Australia. This statement has been developed to protect the interests of people 
who agree to participate in human research studies. 
21. 
Further information and who to contact 
The person you may need to contact will depend on the nature of your query. If you want 
any further information concerning this study, please contact the below; 
General Enquiries:  
1800 243 733 
After hours contact (Nucleus Network Pty Ltd) 24 hours 7 days a week 
On-call mobile:  
 
0429 353 069 
If you have any medical questions/problems which may be related to your involvement in the 
study (for example, any side effects), you can contact the principal study doctor (Dr Jason 
Lickliter) on j.lickliter@nucleusnetwork.com.au. Please also refer to your participant card 
with your study specific contact numbers.  
For matters relating to research at the site at which you are participating, the details of the 
local site complaints person are: 
Complaints contact person 
Position 
Complaints Officer 
Email 
complaintsofficer@nucleusnetwork.com.au  
Privacy contact person 
Position 
Privacy Officer 
Email 
privacyofficer@nucleusnetwork.com.au  
If you have any complaints about any aspect of the study, the way it is being conducted or 
any questions about being a research participant in general, then you may contact: 


 
 
 
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Document No. SPFMA001-02 
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Reviewing HREC approving this research and HREC Executive Officer details 
Please reference the following Alfred HREC project number: 97/20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reviewing HREC name 
Alfred Hospital Ethics Committee 
Position 
Governance Officer, Ethics and Research Governance, Alfred Health 
Telephone 
(03) 9076 3619  
Email 
research@alfred.org.au  


 
 
 
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CONSENT 
Alfred Project Number: 
97/20 
Full Study 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.  
Protocol Number: 
MMV-MMV533_19_01 
Test Drug Code: 
MMV533 
International Sponsor: 
Medicines for Malaria Venture (MMV) 
Local Sponsor: 
Southern Star Research Pty Ltd (SSR) 
Principal Investigator: 
Dr Jason Lickliter 
Location: 
Nucleus Network Pty Ltd, Melbourne, Victoria 
 
➢ I have read the Participant Information Sheet, or someone has read it to me in a 
language that I understand. 
➢ I have had an opportunity to ask questions and I am satisfied with the answers I have 
received. 
➢ I understand the purposes, procedures and risks of the research described for this 
study. 
➢ I give permission for my doctors, other health professionals, hospitals or laboratories 
outside this hospital to release information to the Nucleus Network Pty Ltd for the 
purposes of this study. I understand that such information will remain confidential.  
➢ I freely agree to participate in this research study as described and understand that I 
am free to withdraw at any stage during the study without affecting my future health 
care. 
➢ I understand that I will be given a signed copy of this document to keep. 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Participant’s First Name 
(printed)  …………………….…Middle Initial..……Surname…….………....... 
Signature 
 
 
 
Date _____/______/________ 
Time _____:_____ 
Declaration by Study Doctor/Senior Researcher 
I have given a verbal explanation of the research study; its procedures and risks and I believe that 
the participant has understood that explanation. 
Study Doctor/Researcher’s 
First Name (printed)  ……….………………Middle Initial……..Surname……….……....... 
Signature 
 
 
Date _____/______/________ 
Time _____:_____ 
A senior member of the research team must provide the explanation of, and information concerning, 
the research study. 
Note: All parties signing the consent section must date their own signature. 
 
 


 
 
 
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FORM FOR WITHDRAWAL OF PARTICIPATION 
Alfred Project Number: 
97/20 
Full Study 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.  
Protocol Number: 
MMV-MMV533_19_01 
Test Drug Code: 
MMV533 
International Sponsor: 
Medicines for Malaria Venture (MMV) 
Local Sponsor: 
Southern Star Research Pty Ltd (SSR) 
Principal Investigator: 
Dr Jason Lickliter 
Location: 
Nucleus Network Pty Ltd, Melbourne, Victoria 
 
Declaration by Participant 
I wish to withdraw from participation in the above research study and understand that such withdrawal 
will not affect my routine treatment, my relationship with those treating me or my relationship with the 
Nucleus Network Pty Ltd. 
Participant’s First Name (printed)  ……………………….Middle Initial…..…Surname….…………....... 
Signature  
Date _____/______/________ 
Time 
_____:_____ 
Study Doctor to include a description of the circumstances for withdrawal, if provided by the participant. 
 
 
Declaration by Study Doctor 
I have given a verbal explanation of the implications of withdrawal from the research study and I 
believe that the participant has understood that explanation. 
Study Doctor/Researcher’s First 
Name (printed)  ……………….………Middle Initial……..Surname….…………....... 
Signature  
Date _____/______/________ 
Time 
_____:_____ 
Note: All parties signing the consent section must date their own signature. 

Prot_000.pdf: 
Medicines for Malaria Venture 
 
Version 7.0     
Protocol No: MMV_MMV533_19_01 
 
Date: 27 October 2021 
CONFIDENTIAL  
 
Page 1 of 91 
 
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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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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 


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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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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 
pregnancy. 
 


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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 


Medicines for Malaria Venture 
 
Version 7.0     
Protocol No: MMV_MMV533_19_01 
 
Date: 27 October 2021 
CONFIDENTIAL  
 
Page 90 of 91 
 
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. 
 


Medicines for Malaria Venture 
 
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Protocol No: MMV_MMV533_19_01 
 
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Page 91 of 91 
 
APPENDIX 2: SEVERITY GRADING FOR FASTING TBA IN PHASE 1 
VOLUNTEERS 
 
 
 

SAP_001.pdf: 
Protocol Number: MMV-MMV533_19_01 
 
18 November 2022 
Document status: SAP Version 1.1 (FINAL) 
BM S01-A, v2.0 
Statistical Analysis Plan 
Template Effective: 18/JAN/2018 
CONFIDENTIAL 
Page 1 of 22 
 
 
 
STATISTICAL ANALYSIS PLAN 
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 No.: MMV-MMV533_19_01 
Product Codes: MMV533 
 
PREPARED FOR: 
 
Medicines for Malaria Venture (MMV) 
20, Route de Pré-Bois 
1215 Geneva 15 
Switzerland 
 
PREPARED BY: 
 
Southern Star Research 
Level 1, 1 Merriwa St 
Gordon, NSW, 2072  
Australia  
 
DATE OF ISSUE: 
 
18 November 2022  
 
VERSION/STATUS: 
 
Version 1.1 (FINAL) 
 
AUTHOR: 
 
Locadiah Kuwanda 
 
 
 


Protocol Number: MMV-MMV533_19_01 
 
18 November 2022 
Document status: SAP Version 1.1 (FINAL) 
BM S01-A, v2.0 
Statistical Analysis Plan 
Template Effective: 18/JAN/2018 
CONFIDENTIAL 
Page 2 of 22 
 
CHANGES TO SAP  
The original SAP was Version 1.0, 9 June 2021 and was approved and signed by MMV and SSR. 
The amendments made are: 
Details of Amendment 
Reason for Amendment 
Definition for summary table columns. 
Change Fasting/ Fed to Fasted/Fed 
Label as in protocol 
Add time points for visit tabulations: 
Day 14/ Day 35 and Day 21/ Day 42 
Visits are in protocol 
Adverse Events starting prior to drug 
administration are considered Medical 
History 
Definition as per protocol 
Added Protocol deviations before Drug 
administration as occurring during 
screening period 
As per protocol and CRF 
Deleted Eligibility listing section 
Screening failures not recorded 
in CRF 
Added only IMP related TEAE tables 
and Procedure related TEAE 
As per protocol 
 
SAP APPROVAL 
 
By my signature, I confirm that this SAP has been reviewed and has been approved for use on the 
MMV-MMV533_19_01 study: 
 
Name 
Title / Company 
Signature 
Date 
Denis Gossen 
Clinical Science Lead / 
MMV 
 
 
Stephan Chalon 
VP - Experimental Med. / 
MMV 
 
 
Locadiah Kuwanda 
Manager, Statistics / 
Southern Star Research 
 
 
 
21 Nov 2022
Denis Gossen 
(Signature)
Digitally signed by Denis Gossen 
(Signature) 
Date: 2022.11.22 09:45:12 +01'00'
Locadiah Kuwanda
Electronically signed by:
Locadiah Kuwanda
Reason: I have authored
this document.
Date: Nov 23, 2022
12:16 GMT+11
23-Nov-2022


Protocol Number: MMV-MMV533_19_01 
 
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Page 3 of 22 
 
TABLE OF CONTENTS 
 
1 
INTRODUCTION ............................................................................................................................... 5 
2 
PROJECT OVERVIEW ....................................................................................................................... 5 
2.1 
Study Design ......................................................................................................................................... 5 
2.2 
Sample Size ........................................................................................................................................... 7 
2.3 
Treatment Assignment and Randomization ......................................................................................... 7 
2.4 
Study Objectives and Endpoints ........................................................................................................... 8 
3 
STATISTICAL CONSIDERATIONS ....................................................................................................... 9 
3.1 
Data Capture ....................................................................................................................................... 10 
3.2 
Statistical Programming...................................................................................................................... 11 
4 
ANALYSIS SETS .............................................................................................................................. 13 
4.1 
Analysis Set Descriptions .................................................................................................................... 13 
5 
PARTICIPANT DISPOSITION ........................................................................................................... 13 
5.1 
Disposition .......................................................................................................................................... 13 
5.2 
Clinical Trial Unit Admission, Confinement and Discharge ................................................................ 13 
6 
PROTOCOL DEVIATIONS ................................................................................................................ 14 
7 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ...................................................................... 14 
7.1 
Demographics ..................................................................................................................................... 14 
7.2 
Medical and surgical history ............................................................................................................... 15 
7.3 
Prior Medications ............................................................................................................................... 15 
7.4 
Drug Screen ........................................................................................................................................ 15 
7.5 
Alcohol Screen .................................................................................................................................... 15 
7.6 
Beck Depression Inventory ................................................................................................................. 15 
8 
TREATMENT EXPOSURE ................................................................................................................ 15 
8.1 
Study Drug Administration ................................................................................................................. 15 
8.2 
Standardised Breakfast ....................................................................................................................... 15 
9 
PHARMACOKINETICS .................................................................................................................... 15 
10 
PHARMACODYNAMICS.............................................................................................................. 15 
11 
SAFETY ....................................................................................................................................... 16 
11.1 
Safety Endpoints ................................................................................................................................. 16 
11.2 
Adverse Events ................................................................................................................................... 16 
11.3 
Concomitant Medications .................................................................................................................. 17 
11.4 
Laboratory .......................................................................................................................................... 19 
11.5 
Body Measurements .......................................................................................................................... 20 
11.6 
Vital Signs............................................................................................................................................ 20 
11.7 
Physical Examination .......................................................................................................................... 21 
11.8 
12-Lead ECG ........................................................................................................................................ 21 
12 
Exploratory Parameters ............................................................................................................ 22 
12.1 
Pharmacogenetics: Drug Metabolism Enzymes and Drug Transporters (DME/T) ............................. 22 
13 
HANDLING OF MISSING DATA ................................................................................................... 22 
14 
CHANGES AND CLARIFICATIONS TO THE PLANNED ANALYSIS .................................................. 22 
15 
INTERIM ANALYSES ................................................................................................................... 22 
16 
SOFTWARE ................................................................................................................................ 22 
17 
REFERENCES .............................................................................................................................. 22 
 
 
 
 


Protocol Number: MMV-MMV533_19_01 
 
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ABBREVIATIONS 
 
ADaM 
Analysis Data Model 
ADME 
Absorption, distribution, metabolism and excretion 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine Aminotransferase 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
β-HCG 
β-Human Chorionic Gonadotropin 
BDI 
Beck Depression Inventory 
BMI 
Body Mass Index 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CK 
Creatine Kinase 
CRA 
Clinical Research Associate 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic Blood Pressure 
DME/T 
Drug metabolism enzymes and drug transporters 
DTS 
Data Transfer Specification 
ECG 
Electrocardiography 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data capture 
EOS 
End of Study 
FAS 
Full Analysis Set 
FSH 
Follicular Stimulating Hormone 
fTBA 
Fasting Total Bile Acids 
GGT 
Gamma Glutamyl Transpeptidase 
HBsAg 
Hepatitis B Surface Antigen 
HDL 
High Density Lipoprotein 
HEENT 
Head, Eyes, Ears, Nose, Throat 
HIV 
Human Immunodefiniciency Virus 
HR 
Heart Rate 
IMP 
Investigational Medicinal Product 
LDH 
Lactate Dehydrogenase 
LDL 
Low Density Lipoprotein 
LPLV 
Last Participant Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PN 
Preferred Name 
PT 
Preferred Term 
QTcB 
Corrected QT interval with Bazett’s Formula 
QTcF 
Corrected QT interval with Fridericia’s Formula 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SBP 
Systolic Blood Pressure 
SBQ 
Swiss BioQuant Central 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SRC 
Safety Review Committee 
SSR 
Southern Star Research 
TEAE 
Treatment Emergent Adverse Event 
WHODRL 
World Health Organization-Drug Reference List 
 


Protocol Number: MMV-MMV533_19_01 
 
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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides the outline for the statistical analysis deliverables 
required for the MMV-MMV533_19_01 study. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. In addition, post hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data.  Any post hoc, or 
unplanned, exploratory analyses performed will be clearly identified as such in the final CSR. 
Any significant changes from planned analyses will also be described in the final CSR. 
A separate pharmacokinetic (PK) analysis plan will be prepared to detail the PK related analyses. 
2 
PROJECT OVERVIEW 
2.1 
Study Design 
This is a phase 1, single -centre study in 2 parts.  
2.1.1 Part 1 
Part 1 is a double-blind, randomized, placebo-controlled, sequential ascending single dose study in 
healthy adult participants,  consisting of 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). 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. 
 
Figure 1: Part 1 Schema 
 


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2.1.2 Part 2 
Part 2 is an open label, 2-period cross-over, randomised, pilot food effect study to provide 
preliminary information on the effect of a high-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.  
Part 2 may be conducted in parallel to or after completion of Part 1 at the discretion of the Safety 
Review Committee (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. 
 
Figure 2: Part 2 Schema 
 


Protocol Number: MMV-MMV533_19_01 
 
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2.2 
Sample Size 
2.2.1 Part 1 (SAD) 
Up to 64 participants: 7 groups (7 incremental doses) with 8 participants each with one additional 
optional cohort of 8 participants (6 participants receiving MMV533 and 2 participants receiving 
placebo in each cohort).  
2.2.2 Part 2 (Pilot food effect) 
1 cohort of 8 participants all receiving MMV533 (same dose for all the participants). 
2.3 
Treatment Assignment and Randomization 
Randomisation procedures for Parts 1 and 2 are described in the Randomisation Plan and 
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. 
2.3.1 Replacement of Withdrawn/Discontinued Participants 
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.  


Protocol Number: MMV-MMV533_19_01 
 
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2.4 
Study Objectives and Endpoints 
Primary Objective  
Primary Endpoints 
• 
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 Objectives 
Secondary Endpoints 
• 
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 
Exploratory Objectives 
Exploratory Endpoints 
• 
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.   
 
 
 


Protocol Number: MMV-MMV533_19_01 
 
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3 
STATISTICAL CONSIDERATIONS 
Data analysis will be performed according to Southern Star Research’s Standard Operating 
Procedures (SOPs). 
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 population 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. 
 
 


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3.1 
Data Capture 
3.1.1 Database 
The primary method of data collection is via the study database, developed within the chosen 
Electronic Data Capture (EDC) platform, IBM Clinical Development. The database has been 
designed based on the final protocol, the system/core configuration, electronic Case Report Form 
(eCRF) specifications and/or mock eCRF and consistency check specifications. 
Data will  be entered directly into the EDC system. Site-collected data will be entered directly from 
source notes at the site and will be verified by Clinical Research Associates (CRAs) to ensure data 
integrity.  
Refer to the Data Management Plan for further details. 
3.1.2 Third Party Data 
3.1.2.1 Safety Laboratory (ACL, Australia) 
Central safety laboratory data will be received from ACL as specified in the ACL Data Transfer 
Specification (DTS).  An initial transfer will be delivered prior to database lock and reconciled against 
CRF data.  Following successful reconciliation and resolution of any data issues, the data will be 
incorporated into the End of Study analysis. 
No unit conversion of laboratory data will be performed. 
3.1.2.2 Central ECG Data (Cardiabase - Banook, France) 
Whilst single standard 12-lead ECG results will be recorded directly in the eCRF, triplicate ECG 
readings will be sent to a central ECG laboratory for assessment.  Central ECG data will be 
transferred to SSR as specified in the relevant DTS. 
3.1.2.3 PK Laboratory (SBQ, Switzerland) 
PK samples will be analysed by Swiss BioQuant Central (SBQ).  Final PK assay data will be 
transferred to SSR, as specified in the SBQ DTS, for incorporation into the PC SDTM. 
3.1.2.4 PK  Analysis  
PK analysis will be performed by a third party, to be confirmed by MMV. SSR will be required to 
provide the selected vendor(s) with PK concentration data as well as any CRF datasets required by 
the vendor ro complete their analyses (e.g. demographics, drug administration data).   
 
 
 


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3.2 
Statistical Programming 
3.2.1 Programming Specifications 
Programming specifications will be prepared to detail the SAS programming of CDISC (SDTM and 
ADaM) datasets and listings, tables and figures. 
3.2.2 Baseline 
Baseline will be defined as the last available assessment prior to the first IMP administration. For 
part 2, baseline will be assigned separately for the two treatment periods.  
3.2.3 Change from Baseline 
Change from Baseline will be calculated as: 
Part 1:  𝑐ℎ𝑎𝑛𝑔𝑒 𝑓𝑟𝑜𝑚 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒= (𝑝𝑜𝑠𝑡𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑣𝑎𝑙𝑢𝑒) −𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑣𝑎𝑙𝑢𝑒 
Part 2, Period 1:  𝑐ℎ𝑎𝑛𝑔𝑒 𝑓𝑟𝑜𝑚 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒= (𝑝𝑜𝑠𝑡𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑣𝑎𝑙𝑢𝑒) −𝑝𝑒𝑟𝑖𝑜𝑑 1 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑣𝑎𝑙𝑢𝑒 
Part 2, Period 2:  𝑐ℎ𝑎𝑛𝑔𝑒 𝑓𝑟𝑜𝑚 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒= (𝑝𝑜𝑠𝑡𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑣𝑎𝑙𝑢𝑒) −𝑝𝑒𝑟𝑖𝑜𝑑 2 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑣𝑎𝑙𝑢𝑒 
3.2.4 Study Day 
Study Day will be derived as the number of days relative to date of first administration of study drug, 
where the day of first administration = 1. 
3.2.5 Listings, Tables and Figures 
Listings, tables and figures will be delivered as individual .rtf files in accordance with the mock 
listings, tables and figures, with separate sets of outputs for each study part. 
Data listings will present all data, with subjects grouped by treatment regimen (part 1) or treatment 
sequence (part 2). 
3.2.6 Treatment Groups – Part 1 
Tabulations for part 1 will summarise data by the following treatment groups:  
• 
MMV 533 (5 mg) 
• 
MMV 533 (xx mg) 
• 
MMV 533 (xx mg) 
• 
MMV 533 (xx mg)  
• 
MMV 533 (xx mg) 
• 
MMV 533 (xx mg) 
• 
MMV 533 (xx mg) 
• 
Total Active 
• 
Placebo 
• 
Overall 
 
 


Protocol Number: MMV-MMV533_19_01 
 
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3.2.7 Treatment Groups – Part 2 
Tabulations for part 2 will summarise data as follows: 
• 
Demographics and baseline characteristic data, will be summarised by: 
o MMV533 Fasted/Fed 
o MMV533 Fed/Fasted 
o Total 
• 
Visit based tabulations will be summarised by treatment received (MMV533 Fasted or 
MMV533 Fed) and total, and timepoint relative to within period dosing.  Treatment will be 
assigned to individual records based on the treatment period.  Timepoints will be: 
o Screening (summarised as total only) 
o Day -1 (summarised as total only) 
o Day 1/Day 22 (combination of Day 1 and Day 22, summarised by treatment) 
o Day 2/Day 23 (combination of Day 2 and Day 23, summarised by treatment) 
o Day 3/Day 24 (combination of Day 3 and Day 24, summarised by treatment) 
o Day 4/Day 25 (combination of Day 4 and Day 25, summarised by treatment) 
o Day 5/Day 26 (combination of Day 4 and Day 26, summarised by treatment) 
o Day 8/Day 29 (combination of Day 8 and Day 29, summarised by treatment) 
o 
Day 14/Day 35 (combination of Day 14 and Day 35, summarised by treatment) 
o Day 21/Day 42 (combination of Day 21 and Day 42, summarised by treatment) 
 
• 
Event based tabulations (e.g. adverse events, concomitant medications and deviations) will 
be summarised by treatment and total.  Treatment will be assigned to individual records 
based on the treatment period of the start date of the event.   
o Adverse Events:  
▪ 
Events started prior to the Day 1 study drug administration will only be 
considered as Medical History.  
▪ 
If start date is after Day 1 study drug administration, then it will be assigned to 
the treatment received in Period 1. 
▪ 
If start date is after the Day 22 study drug administration, then it will be 
assigned to the treatment received in Period 2. 
o Protocol Deviations:  
▪ 
If date is before Day 1 then it will be assigned to Screening 
▪ 
If date of deviation is after Day 1 study drug administration,then it will be 
assigned to the treatment received in Period 1. 
▪ 
If start date is after the Day 22 study drug administration, then it will be 
assigned to the treatment received Period 2.  
o Prior Medications: 
▪ 
Summarised by treatment sequence and total. 
o Concomitant Medications: 
▪ 
Based on start and end dates – if subject was on medication within a given 
period then that medication will be summarised within that period.  If subject 
took medication across both periods then it would be counted in both 
treatment columns.  
• 
Treatment Exposure will be summarised by sequence and total 
 
 


Protocol Number: MMV-MMV533_19_01 
 
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4 
ANALYSIS SETS 
In the first instance, two (2) analysis sets will be used for the analyses: Full Analyses Set (FAS), and 
Safety Set.   
The number of participants in each analysis set will be summarised, with a corresponding listing. 
4.1 
Analysis Set Descriptions 
4.1.1 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. 
4.1.2 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.  
5 
PARTICIPANT DISPOSITION 
5.1 
Disposition 
Analysis Set: FAS 
A listing of participant disposition will present: 
• 
Date of informed consent 
• 
Date of randomisation 
• 
Date of first dose of IMP administration 
• 
Did the participant complete the study? 
• 
Date of completion / early withdrawal 
• 
Primary reason for early withdrawal (including instances where early termination was related 
to COVID-19) 
Detailed early withdrawal information will also be listed in a separate listing. 
If there are any deaths reported, a separate death listing will be prepared. 
The number and percentage of participants entering and discontinuing the study will be summarised 
along with the reason for discontinuation.  The participant disposition summary table will include: 
• 
Number of participants randomised 
• 
Number of participants who received one dose (Part 1) or at least one dose (Part 2) of study 
medication 
• 
Number of participants who completed the full study 
• 
Number of participants withdrawn from the study early 
• 
Reason for early withdrawal 
5.2 
Clinical Trial Unit Admission, Confinement and Discharge 
All  admission, confinement and discharge data will be listed. 
 


Protocol Number: MMV-MMV533_19_01 
 
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6 
PROTOCOL DEVIATIONS 
Analysis Set: FAS 
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 classification and type. 
6.1.1 Definition of variables 
• 
Date deviation detected 
• 
Date of deviation 
• 
Deviation classification 
o Minor 
o Major 
• 
Deviation type 
o Informed consent 
o Eligibility 
o Visit not done 
o Visit performed out of window 
o Assessment not done 
o Assessment out of window 
o Safety reporting 
o Investigational Product 
o Privacy and Data Protection 
o Prohibited Medication 
o Standardised meal not completed 
o Blood collected not under fasting condition 
o COVID 19 
o Other 
• 
Deviation description 
• 
Preventative action taken 
7 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Analysis Set: FAS 
7.1 
Demographics 
Demographic data will be listed for all enrolled participants and summarised by treatment arm and 
overall.  Data includes: 
• 
Age 
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
Women of Child-bearing potential 
 
 


Protocol Number: MMV-MMV533_19_01 
 
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7.2 
Medical and surgical history 
All medical history data will be listed, grouped by participant. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedRA) and 
summarised by system organ class (SOC) and preferred term (PT).  
7.3 
Prior Medications 
Prior medications will be coded using the World Health Organization-Drug Reference List 
(WHODRL), the version of which will be included in the footnote of the listing. 
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. 
7.4 
Eligibility 
Eligibility will be listed for all enrolled participants. 
7.5 
Drug Screen 
Drug screen data will be listed for all participants. 
7.6 
Alcohol Screen 
Alcohol screening data will be listed for all participants. 
7.7 
Beck Depression Inventory 
Beck Depression Inventory (BDI-II) data will be listed for all participants, including answers to the 
individual questions as well as the total scores, which are auto-calculated within the CRF. 
8 
TREATMENT EXPOSURE 
Analysis Set: Safety Set 
8.1 
Study Drug Administration 
Participant exposure to all protocol-specified treatments will be listed and summarised.  
8.2 
Standardised Breakfast 
Meal data for the standardised high fat breakfast provided for the fed treatment during part 2, will be 
listed for all part 2 participants. 
9 
PHARMACOKINETICS 
PK parameters will be estimated using non-compartmental methods from plasma concentration-time 
data. Refer to the PK Analysis Plan, Appendix 1, as prepared by SBQ. A formal analysis report will 
be prepared at the completion of the work and included in the CSR appendices. 
Dose-proportionality analyses will also be conducted. Please refer to the Dose Proportionality 
Analysis Plan.  An analysis report will be prepared at the completion of the work and will be included 
in the CSR appendices. 
10 PHARMACODYNAMICS 
Not applicable 
 
 


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11 SAFETY  
11.1 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 (including fasting Total Bile Acids [fTBA]), urinalysis 
• 
Physical examination 
All descriptive statistics for safety parameters will be evaluated using the Safety Set.    
11.2 Adverse Events 
11.2.1 Definitions 
• 
Treatment Emergent Adverse Event (TEAE) 
o A TEAE is defined as an AE that commences on, or after, the first administration of 
IMP.  AEs 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. 
• 
Adverse Events of Special Interest (AESI) 
o 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. 
11.2.2 Parameters 
• 
Event Term 
• 
Dates and times of onset and resolution 
• 
Severity (CTCAE Grades 1 to 5) 
• 
Outcome (Recovered/resolved, Recovering/resolving, Not recovered/not resolved, 
Recovered/resolved with sequelae, Fatal, Unknown) 
• 
Relationship of AE to Investigational medicinal product (Not Related, Related) 
• 
Relationship of AE to Trial Procedures (Not Related, Related) 
• 
Action taken with Investigational medicinal product  (Permanently discontinued, No action 
taken, Not applicable, Unknown) 
• 
Other actions taken (including withdrawal from the study) 
• 
Seriousness (and Serious Adverse Event (SAE) category) 
• 
AESI status (Yes/No) 
• 
Relatedness to COVID-19  
Derived parameters: 
• 
Duration in hours  
• 
Time of onset relative to first IMP administration 
 
 


Protocol Number: MMV-MMV533_19_01 
 
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11.2.3 Biostatistical methods 
Adverse events will be coded using MedDRA, and the MedDRA version will be included in the 
footnote of all AE listings and tables. Their severity will be graded according NCI-CTCAE v5.0. 
11.2.3.1 Listings 
All AE data will be listed for each participant, including severity, relationship to IMP, relationship to 
study procedures, outcome and actions taken. In addition, listings of AEs leading to discontinuation 
of the study, SAEs and deaths, will be provided as applicable. 
11.2.3.2 Tables 
AE summary tabulations will be restricted to TEAEs only.  
All reported TEAEs, including SAEs and AESIs, will be mapped to standard MedDRA coding terms 
and grouped by SOC and PT.   
An overview summary table of AEs will be provided by treatment arm including: 
- 
Number of events and number of participants reporting at least one of the following: 
o TEAE 
o IMP related TEAE 
o Procedure related TEAE 
o Serious TEAE 
o IMP related serious TEAE 
o Procedure related serious TEAE 
- 
Number of participants with at least one TEAE by maximum severity 
- 
Number of TEAEs by relationship to IMP 
- 
Number of TEAEs by relationship to procedure 
- 
Number of participants withdrawn from the study due to a TEAE 
- 
Number of deaths 
An duplicate overview summary table will also be presented specifically for the AESIs. 
The number of events, as well as the number and percentage of participants experiencing a TEAE, 
will be summarised for each SOC and PT by treatment arm and overall for the following categories 
of events: 
• 
All TEAEs 
• 
TEAEs by severity 
• 
TEAEs by relationship 
• 
Serious TEAEs  
• 
TEAEs leading to study discontinuation  
• 
TEAEs of Special Interest (AESIs) 
For the summaries of TEAEs, participants who experience the same AE (in terms of the MedDRA 
preferred term) more than once will only be counted once. 
11.3 Concomitant Medications 
Concomitant medications will be coded using the WHODRL, the version of which will be included in 
the footnote of all relevant listings and tables  
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) level 3 and 
preferred name (PN). The summary tables will show the number and percentage of participants 
taking each medication by ATC and PN. 


Protocol Number: MMV-MMV533_19_01 
 
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Participants who take the same medication (in terms of the ATC and PN) more than once will only 
be counted once for that medication.  
 
 


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11.4 Laboratory 
11.4.1 Parameters 
11.4.1.1 Haematology 
• Basophils (absolute) 
• Monocytes (absolute) 
• Eosinophils (absolute) 
• Neutrophils (absolute) 
• Haematocrit 
• Platelet count 
• Haemoglobin 
• Red cell count 
• Lymphocytes (absolute) 
• White cell count 
 Biochemistry 
• Alanine Aminotransferase (ALT) 
• Gamma Glutamyl Transpeptidase (GGT) 
• Albumin 
• Glucose 
• Alkaline phosphatase (ALP) 
• Lactate dehydrogenase (LDH) 
• Aspartate Aminotransferase (AST) 
• Magnesium 
• Bilirubin (direct) 
• Potassium 
• Bilirubin (total) 
• Protein Total 
• Chloride 
• Sodium 
• Cholesterol 
• Fasting - Total Bile Acids (fTBA) 
• Corrected calcium 
• Triglyceride 
• Creatinine 
• Urea 
• Creatine Kinase (CK) 
 
 
 
Pregnancy Test and FSH 
 
• β-Human Chorionic Gonadotropin (β-HCG) (women of child bearing potential only) 
• Follicular Stimulating Hormone (FSH) (post-menopausal women only) 
 Urinalysis  
Dipstick Testing 
Quantitative Assessments 
Urine Chemistry 
• Bilirubin 
• Red blood cells 
• Glucose 
• Blood (erythrocytes) 
• White blood cells 
• Protein 
• Glucose 
• Bacteria 
• Protein:Creatinine Ratio 
• Ketone bodies 
• Budding yeasts 
 
• Leucocyte Esterase 
 
 
• Nitrate 
 
 
• Protein 
 
 
• Urobilinogen 
 
 
• pH 
 
 
11.4.1.2 Coagulation 
• INR 
• Activated partial thromboplastin time (APTT) 
11.4.1.3 Serology 
• Hepatitis B Surface Antigen (HBsAg) 
• Anti-HBc Antibody 
• Hepatitis C Antibody (anti-HCV) 
• Human Immunodefiniciency Virus (HIV) 1/2 (anti-HIV1 and anti-HIV2 Ab) 
 
 
 
 
 


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11.4.2 Biostatistical methods 
 Listings 
All laboratory parameters will be listed with flags for values outside the reference ranges and values 
considered to be clinically significant by the investigator. 
Pregnancy test data will be listed only, for all women of child bearing potential. 
FSH data will be listed only, for all post-menopausal women.    
Coagulation data as well as qualitative and quantitative urinalysis data will be listed only.  
 Tables 
Haematology, biochemistry and continuous dipstick urinalysis laboratory data will be summarised for 
each scheduled visit, including observed values, absolute change from each baseline.  
Categorical dipstick urinalysis results will be summarised for each scheduled visit using frequency 
tabulations.  
Cross-tabulations (shift tables) may be provided. 
11.5 Body Measurements 
Body measurement data will be listed for all participants and visits including height, weight and Body 
Mass Index (BMI) which is auto-calculated within the CRF.  
Observed values, as well as absolute changes from each baseline, will be summarised descriptively 
for weight by visit. 
11.6 Vital Signs 
11.6.1 Parameters 
• 
Systolic Blood Pressure (SBP) (mmHg) 
• 
Diastolic Blood Pressure (DBP) (mmHg) 
• 
Heart Rate (beats/minute) 
• 
Temperature (°C) 
• 
Respiratory Rate (breaths/minute) 
11.6.2 Biostatistical methods 
All vital signs data will be listed for all participants.  Any values outside of the protocol defined 
normal ranges (Table 1) will be flagged, with clinical significance status presented for out of range 
results. 
Table 1: Vital Signs Normal Ranges 
Parameter 
Range 
Systolic blood pressure             
90-140 mmHg 
Diastolic blood pressure           
50-90 mmHg 
Heart rate                                 
50-100 bpm 
Temperature   
35.0-37.5°C 
Respiratory rate                        
10-25 breaths/min 
 
Vital sign parameters will be summarised by presenting summary statistics for observed values and  
change from baseline values for each scheduled visit. 
 
 


Protocol Number: MMV-MMV533_19_01 
 
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11.7 Physical Examination 
11.7.1 Body Systems 
• Heart Auscultation 
• Respiratory Auscultation 
• Peripheral arterial pulse 
• Pupil reflexes 
• Knee reflexes 
• Achilles reflexes 
• Plantar reflexes 
• Peripheral lymph nodes 
• Abdomen 
• Other (free text) 
11.7.2 Biostatistical methods 
Physical examination parameters will be listed for all participants and visits. 
11.8 12-Lead ECG 
11.8.1 Parameters 
• 
RR interval (msec) 
• 
Heart rate (beats/minute) 
• 
PR interval (msec) 
• 
QRS interval (msec) 
• 
QT interval (msec) 
• 
QTcB interval (msec) 
• 
QTcF interval (msec) 
• 
ECG result (Normal, Abnormal, Not Evaluable) 
• 
ECG abnormality (as appropriate) 
• 
Clinical Significance 
11.8.2 Biostatistical methods 
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.  Any values outside of the 
protocol defined normal ranges (Table 1) will be flagged. 
Table 2: ECG Normal Ranges 
Parameter 
Range 
PR interval 
≤210 msec 
QRS interval 
50–120 msec 
QTcB/QTcF       
≤450 msec 
Observed values (or triplicate means where appropriate), as well as absolute changes from each 
baseline, will be summarised descriptively for all ECG parameters by visit.   
An addition table will present the frequencies of participants who fulfill the following criteria, 
considering all scheduled and non-scheduled visit data: 
• 
QTcF prolongation >30 
• 
QTcB prolongation >30 
• 
QTcF prolongation >60 
• 
QTcB prolongation >60 
• 
QTcF >450 msec 
• 
QTcB >450 msec 


Protocol Number: MMV-MMV533_19_01 
 
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12 EXPLORATORY PARAMETERS 
12.1 Pharmacogenetics: Drug Metabolism Enzymes and Drug Transporters (DME/T) 
Allegic variants related drug metabolism enzymes and drug transporters (DME/T) will be 
investigated if deemed necessary based on review of observed PK and safety data at study end.  
Should an analysis be conducted, genotypes for the following DME/T DNA variables will be 
analysed: 
• 
2D6  
• 
CYP1A2 
• 
CYP2C19 
• 
CYP2C9 
• 
CYP3A4 
• 
CYP3A5 
• 
VKORC1 
Genotype data will only be presented if relevant to specific analyses. 
13 HANDLING OF MISSING DATA 
Only recorded data will be analysed/presented and any participants who have missing data will only 
have observed data reported, with no imputation for missing data. 
14 CHANGES AND CLARIFICATIONS TO THE PLANNED ANALYSIS 
Not applicable. 
15 INTERIM ANALYSES 
This trial has no formal interim analyses other than data reviews of safety and tolerability as 
described in the clinical study protocol. 
Analyses for both Parts 1 and 2 will be conducted following the completion of both study parts. 
16 SOFTWARE 
The following software will be used to perform the statistical analyses: Statistical Analysis System 
(SAS®) Version 9.4 (SAS Institute, Cary, North Carolina, USA). 
17 REFERENCES 
1) MMV_MMV533_19_01Clinical Study Protocol, v7.0, 27 October 2021 
2) MMV533_19_01_aCRF 2021-05-12 
 


MMV533_19_01 Statistical Analysis Plan V1.1
(FINAL) 2022-11-18 _SC DG
Final Audit Report
2022-11-23
Created:
2022-11-23 (Australian Eastern Daylight Time (New South Wales))
By:
Ray Lin (rlin@southernstarresearch.com)
Status:
Signed
Transaction ID:
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"MMV533_19_01 Statistical Analysis Plan V1.1 (FINAL) 2022-11
-18 _SC DG" History
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