A First-in-Human, Single-Centre, Single Ascending Dose, Multiple Dose and Pilot Food Effect Study to Assess the Safety, Tolerability and Pharmacokinetics of MMV367 in Healthy Participants
Phase: PHASE1
Conditions: Malaria,Falciparum
Sponsor: Medicines for Malaria Venture

Doc No:DOC-87929                         Doc Name:QSC207031 Clinical Protocol
Project Number:207031                             Version:3.0                             
Status:Approved
Governing SOP: DOC-02642
CLINICAL STUDY PROTOCOL
A First-in-Human, Single-Centre, Single Ascending Dose, 
Multiple Dose and Pilot Food Effect Study to Assess the Safety, 
Tolerability and Pharmacokinetics of MMV367 in Healthy 
Participants
Short Study Title: First-in-Human Study to Assess the Safety, 
Tolerability and Pharmacokinetics of MMV367
Quotient Sciences Study Number:
QSC207031
Sponsor Study Number:
MMV_MMV367_21_01
EudraCT Number:
2022-000918-33
Clinical Study Site:
Quotient Sciences
Mere Way
Ruddington Fields
Ruddington
Nottingham NG11 6JS, UK
Tel: +44 (0)115 974 9000
Sponsor:
Medicines for Malaria Venture
ICC - Block 3, 3rd Floor
20 Route de Pré-Bois 
PO Box 1826
1215 Geneva 15 
Switzerland
Tel. +41 22 555 03 00
Date of Protocol:
08 Sep 2022
Status of Protocol:
Version 3.0
SPONSOR/QUOTIENT SCIENCES CONFIDENTIAL
This clinical protocol may not be reproduced or communicated to a third party 
without the written permission of Medicines for Malaria Venture.
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
QSC207031 Clinical Protocol
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Document History 
Protocol Version Number 
Classification 
Date  
3.0 
Non-substantial Amendment 
08 Sep 2022 
2.0 
Update following feedback from 
the regulatory authorities 
01 Jun 2022 
1.0 
Original Protocol 
28 Apr 2022 
 
Details of the amendment above can be found in Appendix 10. 
 
 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
QSC207031 Clinical Protocol
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Study Contacts 
Principal Investigator: 
Nand Singh BSc, MD, DPM, MFPM 
Quotient Sciences 
Mere Way 
Ruddington Fields 
Ruddington 
Nottingham NG11 6JS, UK 
Tel: +44 (0)115 974 9000 (day) 
Tel: +44 (0)7774 017236 (out of hours emergency) 
Sub-Investigators: 
Sharan Sidhu MBChB, BAO, MRCS, MFPM 
Philip Evans MBChB, MRCS (Ed) 
Stuart Mair MBChB, DRCOG, DCPSA, FFPM 
Somasekhara Menakuru MBBS, MS, MRCS, DPM, 
MFPM 
Litza McKenzie MBChB, BScMedSci (Hons) 
Martina Fieldingova MUDr 
Elizabeth Maria van Niekerk MBChB, DipPalMed 
David Everton BSc, MBBS 
Anisha Sharma, MBBS, MRCGP 
Courtney Krstic BMedSci, BMBS (Hons) 
Lena Chen BSc (Hons), MBBS, MRCGP 
Nicholas Akam BMedSci, BMBS, MRCGP 
Quotient Sciences 
Tel: +44 (0)115 974 9000 (day) 
Tel: +44 (0)7774 017236 (out of hours emergency) 
Project Manager: 
Peter Green 
Quotient Sciences 
Tel: +44 (0)115 974 9000 
Study Monitor: 
Mat Dawson 
Stoneygate Clinical Research 
260 Kimberley Road, Leicester 
LE2 1LJ, UK 
Tel: +44 (0)77 7551 1802 
 
Medical Monitor: 
Annick Janin MD 
AKJ Consulting 
659 Rue de la Combe de l’eau 01220 Divonne-les-Bains, 
France 
Tel: +33 (0) 6 29 54 71 90 
Email: janina-consultants@mmv.org   
Sponsor’s Medical 
Director/Contact: 
Dr Stephan Chalon MD PhD 
Tel: +41 79 962 9244 (Mobile) (24 h contact) 
Email: chalons@mmv.org 
 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
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Sponsor’s Clinical 
Lead/Contact: 
Dr Myriam El Gaaloul PhD 
Tel: +41 76 442 65 02 (Mobile) 
Email: elgaaloulm@mmv.org 
Pharmacovigilance 
Provider: 
Oliver Abschütz 
Prime Vigilance 
The Surrey Research Park, 
1 Occam Court, Occam Road, 
Guildford, Surrey, GU2 7HJ, UK 
Email: oliver.abschuetz @primevigilance.com 
Tel: +49 (0)1578 3053780 
Tel (Head Office): +44 1483 307920 
 
 
Central Laboratory: 
The Doctors Laboratory 
The Halo Building 
1 Mabledon Place 
London WC1H 9AX, UK 
Tel: + 44 (0)207 3077 404 
Bioanalytical 
Laboratory: 
Swiss BioQuant (SBQ) 
Kägenstrasse 18 
4153 Reinach, Switzerland 
Tel: +41(0) 617 1698 12 
ECG Analysis: 
Banook  
84 Avenue du Xxème Corps 
54000 Nancy, France 
+33 (0) 3 83 39 10 10  
 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
QSC207031 Clinical Protocol
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 08 SEP 2022 
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1 Table of Contents 
1 
Table of Contents ............................................................................................ 5 
2 
List of Tables and Figures ............................................................................... 9 
2.1 
Table of In-Text Tables ...................................................................... 9 
2.2 
Table of In-Text Figures ..................................................................... 9 
3 
Synopsis ....................................................................................................... 10 
4 
List of Abbreviations ...................................................................................... 17 
5 
Background Information ................................................................................ 19 
5.1 
Introduction ...................................................................................... 19 
5.2 
Investigational Medicinal Product .................................................... 19 
5.3 
Previous Study Findings .................................................................. 20 
5.3.1 
Non-clinical Findings ....................................................................... 20 
5.3.2 
Clinical Findings .............................................................................. 22 
6 
Rationale ....................................................................................................... 22 
6.1 
Study Rationale ............................................................................... 22 
6.2 
Dose Rationale ................................................................................ 24 
6.3 
Population Rationale ....................................................................... 27 
6.4 
Risks and Benefits ........................................................................... 28 
6.4.1 
Risks Associated with MMV367 Administration ............................... 28 
6.4.2 
COVID-19 Related Risks and Risk Mitigation Measures .................. 28 
6.4.3 
General Risks and Overall Risk-Benefit Assessment ....................... 29 
7 
Objectives and Endpoints .............................................................................. 30 
8 
Study Design ................................................................................................. 30 
8.1 
Study Plan ....................................................................................... 30 
8.1.1 
Study Plan: Part 1 – Single Ascending Dose Cohorts ...................... 30 
8.1.2 
Study Plan: Part 2 – Food Effect Cohort .......................................... 32 
8.1.3 
Study Plan: Part 3 – Multiple Dose Cohort(s) ................................... 33 
8.2 
Criteria for In-Study Decisions ......................................................... 35 
8.2.1 
Decision Points ................................................................................ 35 
8.2.2 
Criteria for Dose Decision ................................................................ 35 
8.3 
Participant Withdrawal ..................................................................... 37 
8.4 
Participant Replacement .................................................................. 38 
8.5 
Stopping Criteria .............................................................................. 38 
8.6 
Study Termination ........................................................................... 39 
8.7 
Lost to Follow-up ............................................................................. 39 
8.8 
Treatment Assignment and Randomisation ..................................... 40 
8.8.1 
Participant Numbers ........................................................................ 40 
8.8.2 
Blinding ........................................................................................... 41 
9 
Selection of Participants ................................................................................ 42 
9.1 
Informed Consent ............................................................................ 42 
9.2 
Inclusion Criteria .............................................................................. 42 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
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9.3 
Exclusion Criteria ............................................................................. 43 
9.4 
Contraception and Restrictions ........................................................ 45 
9.4.1 
Sperm Donation............................................................................... 46 
9.4.2 
Egg Donation ................................................................................... 46 
9.5 
Pregnancy ....................................................................................... 46 
9.6 
Additional Study Restrictions ........................................................... 47 
10 
Study Procedures .......................................................................................... 47 
10.1 
Screening ........................................................................................ 47 
10.1.1 
Participant Re-Screening ................................................................. 47 
10.2 
Admission and Pre-dose Procedures ............................................... 47 
10.3 
Study Day Procedures ..................................................................... 48 
10.3.1 
Blood Volume .................................................................................. 48 
10.3.2 
Timing of Procedures ...................................................................... 48 
10.3.3 
Discharge from the Clinical Unit ....................................................... 49 
10.3.4 
Return Visits .................................................................................... 49 
10.3.5 
End of Study Visits .......................................................................... 49 
10.3.6 
Medical Supervision ........................................................................ 49 
10.3.7 
Follow-up ......................................................................................... 50 
11 
Dosing of Participants ................................................................................... 50 
11.1 
Food and Fluid Intake ...................................................................... 50 
11.2 
Administration of Test Preparations ................................................. 51 
11.3 
Dosing Compliance ......................................................................... 52 
11.4 
Prior and Concomitant Medications ................................................. 52 
12 
Assessment of Efficacy ................................................................................. 52 
13 
Assessment of Pharmacokinetics, Metabolite Identification and 
Pharmacodynamics ....................................................................................... 52 
13.1 
Assessment 
of 
Pharmacokinetics 
and 
Metabolite 
Identification .................................................................................... 52 
13.1.1 
Blood Sampling for Pharmacokinetics and Metabolite 
Identification .................................................................................... 52 
13.1.2 
Urine Sampling for Pharmacokinetics and Metabolite 
Identification .................................................................................... 53 
13.2 
Assessment of Pharmacodynamics ................................................. 54 
13.3 
Taste/Palatability Evaluation ............................................................ 54 
14 
Assessment of Safety ................................................................................... 54 
14.1 
Definition and Classification of Adverse Events ............................... 54 
14.2 
Assessment of Assessment of Causality ......................................... 54 
14.3 
Recording Adverse Events .............................................................. 55 
14.4 
Serious Adverse Events .................................................................. 56 
14.4.1 
Definition of Serious Adverse Events ............................................... 56 
14.4.2 
Definition of Suspected Unexpected Serious Adverse 
Reactions ........................................................................................ 56 
14.4.3 
Expectedness (Reference Safety Information) ................................. 56 
14.5 
Laboratory Measurements ............................................................... 56 
14.5.1 
Haematology, Clinical Chemistry and Coagulation .......................... 57 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
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14.5.2 
Urinalysis ......................................................................................... 57 
14.5.3 
Pregnancy Test ............................................................................... 57 
14.5.4 
Follicle-Stimulating Hormone Test ................................................... 58 
14.5.5 
Drug Screen .................................................................................... 58 
14.5.6 
Alcohol Breath Test ......................................................................... 58 
14.5.7 
Carbon Monoxide Breath Test ......................................................... 58 
14.5.8 
SARS-CoV-2 Tests .......................................................................... 58 
14.5.9 
Genetic Samples ............................................................................. 58 
14.5.10 Abnormal Laboratory Findings ......................................................... 59 
14.6 
Vital Signs Measurements ............................................................... 59 
14.7 
ECG Measurements ........................................................................ 60 
14.8 
Holter (continuous ECG) Monitoring ................................................ 60 
14.9 
Telemetry (Continuous ECG)........................................................... 61 
14.10 
Body Weight, Height and BMI .......................................................... 61 
14.11 
Physical Examination ...................................................................... 61 
14.12 
Beck Depression Inventory (BDI-II) Questionnaire ........................... 62 
14.13 
Additional Safety Procedures........................................................... 62 
15 
Statistics and Data Analysis .......................................................................... 62 
15.1 
Sample Size Justification ................................................................. 62 
15.2 
Data Management ........................................................................... 63 
15.3 
Pharmacokinetic Data Analysis ....................................................... 63 
15.4 
Metabolite Profiling and Identification Assessment .......................... 65 
15.5 
Statistical Data Analysis .................................................................. 65 
15.6 
Interim Analysis ............................................................................... 66 
16 
Safety Reporting to Regulatory Authorities and Ethics Committees............... 67 
16.1 
Events Requiring Expedited Reporting ............................................ 67 
16.2 
Urgent Safety Measures .................................................................. 67 
16.3 
Reporting ......................................................................................... 68 
16.3.1 
Reporting Serious Adverse Events .................................................. 68 
16.3.2 
Reporting of Suspected Unexpected Serious Adverse 
Reactions ........................................................................................ 68 
16.3.3 
Expedited Reporting of Events ........................................................ 68 
16.3.4 
Reporting of Urgent Safety Measures .............................................. 68 
16.3.5 
Reporting of COVID-19 Vaccine-Related Adverse Events ............... 69 
16.4 
Serious Breaches ............................................................................ 69 
17 
Protocol Amendments and Deviations ........................................................... 69 
17.1 
Amendments ................................................................................... 69 
17.2 
Protocol Deviations .......................................................................... 69 
18 
Regulatory ..................................................................................................... 69 
18.1 
Compliance ..................................................................................... 69 
18.2 
MHRA and Ethical Approval ............................................................ 70 
18.3 
Source Data .................................................................................... 70 
18.4 
Declaration of the End of the Study ................................................. 70 
18.5 
Document Storage and Archiving .................................................... 70 
18.6 
Protection of Personal Data and Confidentiality ............................... 71 
18.7 
Data Security Breach ....................................................................... 72 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
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19 
Quality Control and Quality Assurance .......................................................... 72 
19.1 
Monitoring........................................................................................ 72 
20 
Finance and Insurance .................................................................................. 72 
21 
Publication .................................................................................................... 72 
22 
References .................................................................................................... 73 
Appendix 1 
Clinical Laboratory Parameters ........................................................ 75 
Appendix 2 
Schedule of Assessments: Part 1 (Cohorts 1A to 1E) ...................... 76 
Appendix 3 
Schedule of Assessments: Part 2 .................................................... 78 
Appendix 4 
Schedule of Assessments: Part 3 (Cohorts 3A to 3C) ...................... 80 
Appendix 5 
Part 1 (All Cohorts) Safety and Pharmacokinetic Assessment 
Time Points (Days 1 to 7) .............................................................................. 82 
Appendix 6 
Part 2 Safety and Pharmacokinetic Assessment Time Points 
(Days 1 to 14) ............................................................................................... 83 
Appendix 7 
Part 3 Safety and Pharmacokinetic Assessment Time Points 
(Days 1 to 9) ................................................................................................. 85 
Appendix 8 
Breakfast Content (Part 2 only) ........................................................ 87 
Appendix 9 
Example Taste/Palatability Questionnaire ....................................... 88 
Appendix 10 
Protocol Amendment Summary of Changes .................................... 90 
 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
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2 List of Tables and Figures  
2.1 
Table of In-Text Tables 
Table 1 
Investigational Medicinal Product .............................................................. 19 
Table 2 
Margins between the Clinical Doses Predicted Plasma AUC(0-inf) 
and Cmax, and the Exposure at NOAEL in the Most Sensitive 
Species (Dog) ........................................................................................... 27 
Table 3 
Description of Regimens: Part 1 ............................................................... 31 
Table 4 
Description of Regimens: Part 2 ............................................................... 33 
Table 5 
Description of Regimens: Part 3 ............................................................... 34 
Table 6 
Participant Numbers ................................................................................. 41 
Table 7 
Plasma Pharmacokinetic Parameters: Part 1 and 2 .................................. 63 
Table 8 
Plasma Pharmacokinetic Parameters: Part 3 ............................................ 64 
Table 9 
Urine Pharmacokinetic Parameters: Part 1, Cohorts 1C and 1D only
 ................................................................................................................. 64 
Table 10 
QTcF Categorical Analysis ....................................................................... 66 
 
2.2 
Table of In-Text Figures 
Figure 1 
Study Sequence: Part 1 (Cohorts 1A to 1E) .............................................. 31 
Figure 2 
Study Sequence: Part 2 ............................................................................ 33 
Figure 3 
Study Sequence: Part 3 (Cohorts 3A to 3C) ............................................. 34 
 
 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
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3 Synopsis 
Sponsor:  
Medicines for Malaria 
Venture 
Drug Substance: 
MMV367 
EudraCT No.: 
2022-000918-33 
Title of Study: 
A First-in-Human, Single-Centre, Single Ascending Dose, Multiple Dose and Pilot Food 
Effect Study to Assess the Safety, Tolerability, and Pharmacokinetics of MMV367 in 
Healthy Participants 
Principal Investigator: 
Nand Singh BSc, MD, DPM, MFPM 
Study Centre: 
Quotient Sciences, Mere Way, Ruddington Fields, Ruddington, Nottingham, NG11 6JS, 
UK 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of single and 
multiple oral doses of MMV367 in healthy 
participants 
 
 
Incidence of adverse events (AEs), physical 
examination findings, and change from baseline 
for vital signs, electrocardiograms (ECGs) and 
laboratory safety tests. 
Secondary 
To assess the pharmacokinetics (PK) of single 
and multiple doses of MMV367 in plasma 
(Parts 1, 2 and 3) 
 
 
PK parameters such as AUC, Tmax, Cmax, CL/F, 
Vz/F, T1/2 and AR, when applicable 
To assess the effect of a high-fat meal on the PK 
of a single dose of MMV367 in healthy 
participants (Part 2 only) 
 
PK parameters such as AUC, Tmax, Cmax and 
Frel, as appropriate, under fed and fasted 
conditions 
Exploratory  
To assess the PK of single dose of MMV367 in 
urine (Part 1 only) of healthy participants 
(optional)a 
 
 
Urine PK parameters such as Ae, and derived 
plasma PK parameters such as CLr, when 
applicable 
To assess exposure response relationship for 
potential effects of MMV367 on ECG intervals 
(QT, QTcF, QTcB, PR, QRS)b 
 
 
ECG intervals, MMV367 plasma concentrations 
(time-matched) 
To investigate metabolite(s) of MMV367 in healthy 
participantsa 
 
Metabolite characterisation for MMV367 in 
plasma and urine, when applicable 
To evaluate the taste attributes (smell, sweetness, 
bitterness, flavour, mouthfeel/texture, grittiness 
and aftertaste) and overall acceptability of the IMP 
(Part 1 only) 
Taste questionnaire score, based on a 9-point 
Likert scale assessing the acceptability for each 
taste attribute (smell, sweetness, bitterness, 
flavour, mouthfeel/texture, grittiness, and 
aftertaste) and overall acceptability for each dose 
level of MMV367 
a Depending on availability of the data, these objectives may be reported in an addendum to the final study 
Clinical Study Report (CSR) or in a separate report. 
b This objective will be reported in a separate cardiac safety report and will not be part of the final study CSR 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
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Methodology: 
Part 1: Single Ascending Dose Cohorts 
Part 1 will be a double-blinded, randomised, placebo-controlled, single ascending dose 
(SAD) study, which will comprise up to 5 fasted cohorts (Cohorts 1A to 1E; Cohort 1E 
will be optional), with 8 participants in each cohort. Participants will be randomly 
assigned to receive a single oral dose of either active IMP (6 participants) or placebo 
(2 participants) to assess its safety, tolerability and PK profile. Each participant will take 
part in one cohort and will receive one of the following regimens according to the 
randomisation schedule: 
SAD Cohort 
Regimen 
IMP 
Dose 
Route of 
Administration 
1A 
1 
MMV367 or 
placebo 
100 mg 
Oral, Fasted 
1B 
2 
MMV367 or 
placebo 
300 mga 
Oral, Fasted 
1C 
3 
MMV367 or 
placebo 
750 mga 
Oral, Fasted 
1D 
4 
MMV367 or 
placebo 
1500 mga 
Oral, Fasted 
1E 
Optional 
5 
MMV367 or 
placebo 
2000 mga 
Oral, Fasted 
a Predicted dose. There will be a blinded interim review of the safety, tolerability and PK data after each 
cohort prior to the dose decision for subsequent cohorts.  
The data obtained from each cohort (safety and PK) will undergo a formal review by the 
safety advisory committee (SAC). The SAC will determine if it is safe to proceed with the 
next dose/cohort. Following review of the emerging PK data from each preceding cohort, 
if results suggest that the exposure plateau has been reached, the next planned cohort 
will not be conducted. Similarly, if PK predictions suggest that this exposure plateau 
would be exceeded at the next cohort/dose level, a lower dose than originally anticipated 
will be proposed. 
Part 2: Food Effect Cohort 
Part 2 will be an open-label, randomised, balanced two-period crossover, food effect 
evaluation. The effect of food on the PK of MMV367 will be explored in Part 2 by 
administering a single dose of MMV367 after a high-fat breakfast, as per FDA guidance 
(Appendix 8), and a single dose of MMV367 in the fasted state.  
Each participant will receive 2 single doses of MMV367. In Period 1, participants will be 
randomised 
to 
1 
of 
2 
treatment 
sequences 
(Regimen 
6/Regimen 
7 
or 
Regimen 7/Regimen 6). If a participant is randomised to receive MMV367 in the fasted 
state (Regimen 6) in Period 1, they will receive MMV367 in the fed state (Regimen 7) in 
Period 2 and vice versa. 
The following regimens will be administered according to the randomisation schedule: 
Food Effect 
Cohort 
Period 
Regimen 
IMP 
Dosea 
Route of 
Administration 
2A 
1 and 2 
(randomised) 
6 
MMV367 
XX mg 
Oral, Fasted 
7 
MMV367 
XX mg 
Oral, Fed 
a The dose administered in Part 2 will be determined once predicted human therapeutic concentrations of 
MMV367 and a safe exposure window has been established in Part 1. The dose for Regimens 6 and 7 will 
be the same. 
Part 3: Multiple Dose Cohort(s) 
Part 3 will be a double-blinded, randomised, placebo-controlled, multiple-dose study. A 
total of 8 participants per cohort will receive once-daily doses of MMV367 (6 participants) 
or placebo (2 participants) for 3 days, in the fasted state, to assess safety, tolerability 
and PK profile of multiple dosing. 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
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The following regimen(s) will be administered according to the randomisation schedule: 
Multiple Dose 
Cohort 
Regimen 
IMP 
Dosea 
Route of 
Administration 
3A 
8 
MMV367 or 
placebo 
XX mg for 3 days 
Oral, Fasted 
3B 
Optional 
9 
MMV367 or 
placebo 
XX mg for 3 days 
Oral, Fasted 
3C 
Optional 
10 
MMV367 or 
placebo 
XX mg for 3 days 
Oral, Fasted 
a The dose(s) administered in Part 3 will be determined after review of the data from Part 1. 
Parts 2 and 3 may be conducted before completion of Part 1 provided that this is justified 
by PK and safety data obtained from completed cohorts in Part 1. The total amount of 
active IMP administered as multiple doses in Part 3 will be no greater than the maximum 
safe and well tolerated dose in Part 1, dosed at a single dose level. Parts 2 and 3 may 
be conducted in parallel. 
The data obtained (safety and PK) from the multiple dose administration will undergo a 
formal review by the SAC after all 8 participants have completed the study. 
Consequently, Part 3 may be extended to evaluate a second and/or third dose level in a 
3-day once daily regimen. 
Study Design: 
The study is divided into Parts 1, 2 and 3. For each of the three parts, participants will be 
screened within 28 days prior to first admission to the clinical unit on the morning of 
Day -1.  
Part 1: Single Ascending Dose Cohorts 
In each cohort, participants will be dosed on Day 1 and will remain resident in the clinical 
unit until discharge on Day 5. They will attend the clinical unit for a return visit on Day 7 
and again on Day 15 (± 1 day) for end of study assessments. Blood samples will be 
collected at regular intervals for PK analysis and safety from Day 1 to discharge from the 
study on Day 15 (± 1 day). Each cohort will follow the same study design. 
Participants will also complete a written taste/palatability questionnaire individually and 
privately following administration of the IMP. 
Part 2: Food Effect Cohort 
Participants will be dosed on Day 1 (Period 1 dose) and on Day 8 (Period 2 dose) and 
will remain resident in the clinical unit until discharge on Day 12. They will attend the 
clinical unit on Day 14 (± 1 day) for end of study assessments. Based on emerging PK 
data from Part 1, the washout period between the Period 1 and Period 2 doses may be 
extended. Blood samples will be collected at regular intervals for PK analysis and safety 
from Day 1 to discharge from the study on Day 14 (± 1 day). 
Part 3: Multiple Dose Cohort(s) 
Participants will receive a single dose on Days 1, 2 and 3 and will remain resident in the 
clinical unit until discharge on Day 7. They will attend the clinical unit for a return visit on 
Day 9 and again on Day 17 (± 1 day) for end of study assessments. Blood samples will 
be collected at regular intervals for PK analysis and safety from Day 1 to discharge from 
the study on Day 17 (± 1 day). Each cohort will follow the same study design. 
Parts 1 and 3 will follow a sentinel dosing design. On the first day of dosing in each cohort 
in Part 1 and in Part 3, only 2 (sentinel) participants will be dosed. The randomisation 
schedule will be constructed such that 1 of the participants dosed on the first day will 
receive MMV367 and 1 will receive placebo. After review of the safety data up to 96 h 
post-dose for SAD cohorts in Part 1 and up to 96 h post-final dose in Part 3, the 
investigator, or medically qualified designee who is familiar with the study protocol and 
Investigator’s Brochure, and medical monitor or delegate (with approval from the 
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sponsor’s medical director or delegate) will decide whether to proceed with dosing the 
remaining participants in the cohort. 
Number of Participants Planned: 
In Part 1, it is planned to enrol 8 healthy male and female participants per cohort to 
ensure data in a minimum of 4 participants (per cohort) on active investigational 
medicinal product (IMP). 
In Part 2, it is planned to enrol 8 healthy male and female participants to ensure data in 
a minimum of 6 participants. 
In Part 3, it is planned to enrol 8 healthy male and female participants per cohort (if 
optional cohorts are utilised) to ensure data in a minimum of 4 participants (per cohort) 
on active IMP. 
Participants withdrawn due to an IMP-related adverse event (AE) will not be replaced. 
Participants who are withdrawn for other reasons may be replaced as required by 
agreement between the investigator and the sponsor to ensure sufficient evaluable 
participants.  
In Part 1, up to 2 replacement participants may be used per cohort. The maximum 
number of participants that may be dosed is 50 (8+2 per cohort). 
In Part 2, up to 4 replacement participants may be enrolled into the study. The maximum 
number of participants that may be dosed in Part 2 is 12 (8+4). 
In Part 3, up to 2 replacement participants per cohort (if optional cohorts are utilised) may 
be enrolled into the study. The maximum number of participants that may be dosed is 
30 (8+2 per cohort). 
Duration of Study: 
The estimated time from screening until the end of study visit is approximately 6 weeks 
for Parts 1, 2 and 3. 
Main Inclusion Criteria: 
Healthy males and healthy females aged 18 to 55 years inclusive at the time of signing 
informed consent. 
Body mass index (BMI) of 18.0 to 32.0 kg/m2 as measured at screening. 
Investigational Medicinal Product, Dose and Mode of Administration: 
The following IMP will be used in this clinical study. 
IMP Name 
Dose  
Route of Administration 
MMV367 Dispersible Granules, 
250 mg/g (25% w/w) 
Starting dose 100 mga 
Oral, Fasted (Parts 1, 2 and 
3) or Oral, Fed (Part 2) 
Placebo for MMV367 Dispersible 
Granules, 250 mg/g (25% w/w) 
N/A 
Oral, Fasted (Parts 1 and 3) 
a Doses are not predicted to exceed the AUCcap set at 376 µg.h/mL, which is based on linear PK projections 
for a putative dose of 2000 mg or Cmaxcap set at 23.8 µg/mL, which is based on mean Cmax at the NOAEL 
in dog 
The IMP will be dispersed in sterile water. Immediately after administration of the oral 
solution, the dosing vessel will be rinsed with water and participants will consume the 
rinse solution. During dosing, participants will consume up to a maximum total volume of 
500 mL (including the dosing volume and volume of water used to rinse the dosing 
vessel) depending on the dose level. If required, additional water in 50 mL aliquots may 
be given with the test product. 
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Pharmacokinetic Assessments: 
Blood samples for PK analysis will be collected at regular time intervals. The plasma 
concentration-time data for MMV367 will be analysed by Quotient Sciences using 
industry standard software (WinNonlin v8.3 or a more recent version, Certara USA, Inc., 
USA) and appropriate non-compartmental techniques to obtain estimates of the following 
parameters, where possible and appropriate: 
Plasma Pharmacokinetic Parameters: Part 1 and 2 
Parameter 
Definition 
Tmax 
Time of maximum observed concentration 
Cmax 
Maximum observed concentration 
AUC(0-24) 
Area under the curve from time 0 to 24 h post-dose 
AUC(0-48) 
Area under the curve from time 0 to 48 h post-dose 
AUC(0-last) 
Area under the curve from time 0 to the time of last measurable concentration 
AUC(0-inf) 
Area under the curve from time 0 extrapolated to infinity 
T1/2  
Terminal elimination half-life 
CL/F 
Total body clearance calculated after a single extravascular administration where 
F (fraction of dose bioavailable) is unknown 
Vz/F 
Apparent volume of distribution based on the terminal phase calculated using 
AUC(0-inf) after a single extravascular administration where F (fraction of dose 
bioavailable) is unknown 
Frel Cmax 
Relative bioavailability based on Cmax (Part 2 fed dosing only) 
Frel AUC(0-last) 
Relative bioavailability based on AUC(0-last) (Part 2 fed dosing only) 
Frel AUC(0-inf) 
Relative bioavailability based on AUC(0-inf) (Part 2 fed dosing only) 
Plasma Pharmacokinetic Parameters: Part 3 
Parameter 
Definition 
Tmax 
Time of maximum observed concentration 
Cmax 
Maximum observed concentration 
AUC(0-tau) 
Area under the curve for the defined interval between doses (tau) 
T1/2  
Terminal elimination half-life (Day 3 only) 
CL/Ftau 
Total body clearance calculated using AUC(0-tau) after repeated extravascular 
administration where F (fraction of dose bioavailable) is unknown (Day 3 only) 
Vz/Ftau 
Apparent volume of distribution based on the terminal phase calculated using 
AUC(0-tau) after repeated extravascular administration where F (fraction of dose 
bioavailable) is unknown (Day 3 only) 
AR Cmax 
Accumulation ratio based on Cmax repeated dose/Cmax single dose (Day 3 only) 
AR AUC 
Accumulation ratio based on AUC(0-tau) repeated dose/AUC(0-tau) single dose 
(Day 3 only)  
Analysis of drug related QT/QTc interval changes relative to plasma PK concentrations 
will be conducted. This analysis will be performed on the analysis set for intensive cardiac 
assessment. Concentration/QTc modelling may be performed after completion of the 
CSR and will be reported separately. 
In Part 1 Cohorts 1C and 1D, urine samples will be collected at regular time intervals 
provided a future bioanalytical method is available. Urine concentration data for MMV367 
will be analysed by Quotient Sciences and reported in an addendum to the CSR or in a 
separate report. Estimates of the parameters of the following parameters in urine will be 
obtained where possible and appropriate: 
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Urine Pharmacokinetic Parameters: Part 1, Cohorts 1C and 1D only 
Parameter 
Definition 
CLr 
Renal clearance calculated using plasma AUC 
Ae 
Amount excreted 
CumAe 
Cumulative amount excreted 
%Ae 
Percentage of dose excreted 
Cum%Ae 
Cumulative percentage of dose excreted  
Metabolite Profiling and Identification Assessment:  
Metabolite profiling of MMV367 in plasma and urine will be performed using existing PK 
samples (pooled residual samples) collected in Part 1. Potential metabolites will be 
identified using liquid chromatography-mass spectrometry analysis. If results suggest 
that a major metabolite is present in plasma (e.g. greater than 10% of circulating 
MMV367 in plasma based on peak AUCs), metabolite quantification and PK analysis in 
plasma will be performed provided a future bioanalytical method is available. These 
results may be reported in an addendum to the CSR or in a separate report. 
Taste/Palatability Questionnaire  
Taste/palatability will be assessed in Part 1 using a questionnaire. The questionnaire will 
ask participants to rate the overall acceptability of palatability, with additional questions 
asked on specific palatability attributes (smell, sweetness, bitterness, flavour, mouth 
feel/texture, grittiness and aftertaste). 
Safety Assessments: 
The safety assessments to be conducted are: 
• 
AE monitoring 
• 
12-lead ECGs 
• 
Holter ECG monitoring 
• 
Telemetry 
• 
Vital signs 
• 
Clinical laboratory tests (clinical chemistry, haematology, coagulation and urinalysis) 
• 
Physical examinations 
Statistical Methodology: 
Assessment of Dose Proportionality  
For Part 1, dose proportionality will be assessed using a power model approach using 
log-transformed Cmax, AUC(0-last) and AUC(0-inf) values, including data from up to 
5 different dose levels, i.e. general linear model including log dose as a fixed effect and 
log PK parameter as the dependent variable. The estimate obtained for β together with 
its 90% confidence interval (CI) will be presented along with the number of participants 
and the geometric means. The resulting estimate slope (β) and 90% CI is a measure of 
dose proportionality; the relationship is considered dose proportional when β = 1. 
Assessment of Taste Questionnaire Data  
In Part 1, formal statistical analysis will be performed on the scores of each taste attribute 
and overall acceptability, in the comparison of each dose level of MMV367 to the pooled 
placebos, using non-parametric methods. Hodges-Lehmann estimation methods will be 
used to estimate the median difference between each dose level and the pooled 
placebos. The associated 95% CI will be calculated for the estimate. The p-value will be 
calculated from the Wilcoxon Rank Sum Test (Mann-Whitney-Wilcoxon Test) for the test 
of the null hypothesis that the difference between the medians of each dose level and 
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the pooled placebos is equal to zero, with the alternative hypothesis being that the 
difference is not equal to zero.  
The number of participants and the median score for each treatment will be presented 
together with the Hodges-Lehmann estimate of the median difference and associated 
90% CI. In addition, the p-value from the Wilcoxon Rank Sum Test will also be presented. 
Assessment of Food Effect 
In addition, for Part 2, formal statistical analysis will be performed, at a minimum, on the 
following PK parameters: Cmax, AUC(0-last) and AUC(0-inf) to assess for the effects of 
food. The PK parameters will undergo a natural logarithmic transformation and will be 
analysed using a mixed effect model with terms for fed/fasted status and period fitted as 
fixed effects and participant fitted as a random effect. The adjusted mean difference 
between the fed and fasted states, and the associated 90% CI obtained from the model 
are back transformed on the log scale to obtain the adjusted geometric mean ratio and 
90% CI of the ratio. These will be presented together with the p-value from the fed/fasted 
comparison.  
Sample Size and Power: 
For Parts 1 and 3, the primary objective is an initial assessment of safety and each 
treatment group is therefore limited to 6 participants receiving active IMP. Administration 
of MMV367 to 6 participants at each dose level provides a 47%, 62%, 74%, or 82% 
probability of observing at least 1 occurrence of any AE, with a true incidence rate for a 
given dose group of 10%, 15%, 20%, or 25%, respectively. 
Furthermore, it is assumed that pooling the data for the 2 participants who receive 
placebo in each cohort will provide an adequately sized control group to assess a 
possible drug effect on safety laboratory tests, vitals and ECG parameters. 
Part 2 is a pilot evaluation designed to determine whether MMV367 PK is impacted by 
high-fat food. Historically, 8 participants have proven sufficient to characterise the 
preliminary effects of food on safety and PK of a new chemical entity in healthy 
participants. Therefore, a sample size of 8 is considered adequate at this stage of drug 
development. 
In Parts 1 and 3, a participant will be considered evaluable if they have received study 
drug and completed safety and PK assessments up to 96 h post-dose (Part 1)/post-final 
dose (Part 3). In Part 2, a participant will be considered evaluable if they have received 
study drug and completed safety and PK assessments up to 96 h post-dose in both 
periods. 
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4 List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
BDI-II 
Beck Depression Inventory 
BMI 
body mass index 
CI 
confidence interval 
CLcr 
creatinine clearance 
COVID-19 
Coronavirus Disease 2019 
CSPM 
Clinical Sample Processing Manual 
CV% 
coefficient of variation 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DMP 
data management plan 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form  
FIH 
first-in-human 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
GLP 
good laboratory practice 
HBsAg 
hepatitis B surface antigen 
HCV Ab 
hepatitis C virus antibody 
HED 
human equivalent dose 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IMP 
investigational medicinal product 
ISF 
Investigator Site File 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NOAEL 
No-Observed-Adverse-Effect Level 
PBPK 
physiological-based pharmacokinetic 
PIS 
Participant Information Sheet 
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PK 
pharmacokinetic(s) 
QA 
quality assurance 
QD 
once daily 
QTcB 
Corrected QT interval by Bazett’s formula 
QTcF 
Corrected QT interval by Fridericia’s formula 
RAP 
Reporting and Analysis Plan 
SAC 
safety advisory committee 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAR 
serious adverse reaction 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SBP 
systolic blood pressure 
SoC 
standard of care 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
WOCBP 
woman of childbearing potential 
 
The pharmacokinetic definitions used in this study are presented in Section 15.3. 
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5 Background Information 
5.1 
Introduction  
MMV367 is a first in class, fast acting, orally bioavailable blood stage inhibitor of 
Plasmodium falciparum. It is highly active against different Plasmodium falciparum 
mutants and field panels exhibiting various resistance profiles, thus demonstrating 
absence of cross resistance to other antimalarial drugs. MMV367 is being developed 
primarily for the curative treatment of acute uncomplicated malaria, due to Plasmodium 
falciparum in adults and children, as a single dose regimen (best case) or up to a 3-day 
treatment, in a fixed-dose combination with another active and safe non-artemisinin 
antimalarial drug. 
Malaria is a major infectious disease caused by Plasmodium parasites and transmitted 
by infected female Anopheles mosquitoes. Despite the fact that five different species can 
cause malaria in humans (falciparum, vivax, malariae, ovale and knowlesi), Plasmodium 
falciparum is by far the deadliest species and is responsible for the high mortality. In 
2020, there were an estimated 241 million cases of malaria, an increase of approximately 
14 million cases compared to 2019. Deaths reached 627000 compared to 558000 in the 
previous year. Most of the deaths occurred in the African region (94%) [1]. 
Historically, antimalarials have been designed to kill the intraerythrocytic stages of the 
parasite lifecycle that are directly responsible for the symptoms of the disease. Based on 
a high-throughput whole cell phenotypic screen, a new pyrrolidinamide class of 
antimalarials was selected for further research [2]. Within this novel antimalarial 
pyrrolidinamide series, MMV367 was identified as the most balanced compound; it is a 
compound able to kill parasite asexual blood stages.  
None of the current clinical antimalarials share a similar mode of action and/or 
mechanism of resistance. It is anticipated that MMV367 exerts a novel antimalarial 
mechanism. 
The clinical development programme will aim to evaluate the safety and efficacy of 
MMV367 in the treatment of acute uncomplicated malaria in adults and children. In this 
first-in-human (FIH) study, the safety, tolerability and pharmacokinetics (PK) of MMV367 
will be assessed in healthy adult participants. 
5.2 
Investigational Medicinal Product 
The investigational medicinal product (IMP) that will be used in this clinical study is 
presented in Table 1. 
Table 1 
Investigational Medicinal Product 
IMP Name 
Dose 
Route of Administration 
MMV367 Dispersible Granules, 
250 mg/g (25% w/w) 
Starting dose 100 mga 
Oral, Fasted (Parts 1, 2 and 
3) or Oral, Fed (Part 2) 
Placebo for MMV367 Dispersible 
Granules, 250 mg/g (25% w/w) 
N/A 
Oral, Fasted (Parts 1 and 3) 
a Doses are not predicted to exceed the AUCcap set at 376 µg.h/mL, which is based on linear PK projections 
for a putative dose of 2000 mg or Cmaxcap set at 23.8 µg/mL, which is based on mean Cmax at the NOAEL 
in dog 
The IMP is an un-licensed medicinal product for use only in the proposed clinical trial.  
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Only participants enrolled in the study may receive study treatment and only authorised 
site staff may supply or administer study treatment. All study treatments will be stored in 
a secure, environmentally-controlled, and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the investigator 
and authorised site staff. 
Where Quotient Sciences (hereafter referred to as Quotient) is manufacturing the IMP(s), 
suitability of the manufacturing process will be documented in a Pharmaceutical 
Development and Control Strategy Report. 
IMPs will be reconciled and destroyed in accordance with the study-specific quality 
agreement and technical addendum. 
5.3 
Previous Study Findings 
Full details of previous non-clinical study findings can be found in the Investigator’s 
Brochure (IB) [3]. A summary of the non-clinical findings is provided below. No clinical 
studies have been conducted with MMV367. 
5.3.1 Non-clinical Findings 
5.3.1.1 Primary Pharmacology 
MMV367 exhibited potent in vitro activity against asexual stages of both sensitive and 
multi-drug resistant Plasmodium falciparum strains including fresh clinical isolates. 
Furthermore, MMV367 was active against other Plasmodium species (knowlesi and 
vivax) although with reduced potency compared to falciparum. The in vitro and in vivo 
parasite killing rates were high and comparable to artemisinins. The in vitro frequency of 
spontaneous resistance measured for MMV367 was low. In vivo, the compound 
demonstrated good oral efficacy in a Plasmodium falciparum murine model, with a 
potency comparable to or greater than marketed antimalarial drugs. 
Preliminary target identification efforts conducted in order to characterise the mode of 
action of MMV367 suggest the involvement of the acyl CoA synthetase (ACS) pathway. 
This putative new mode of action could offer differentiation against all other antimalarials 
in clinical use or currently in development, which is of paramount importance in the 
development of de novo combination treatments, thereby ultimately avoiding the 
emergence of resistance. Model simulations predicted that a single human dose of 
440 mg of MMV367 can potentially decrease 12 logs parasitaemia burden in acute 
uncomplicated malaria, generally parasite burden in acute uncomplicated malaria is 
lower than 12 logs and, therefore, predicted reduction by 12 logs indicates robust and 
potent antimalarial activity. The same efficacy can potentially be obtained with a dose of 
100 mg once daily (QD) for two consecutive days or 30 mg QD for three consecutive 
days. 
Results from activity measurements of MMV367 against parasite sexual stages 
suggested that MMV367 inhibits parasite development in the mosquito, but without 
affecting the functionality of mature gametocytes, thereby indicating lack of activity of 
MMV367 against mature gametocytes. 
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Activity against Plasmodium falciparum liver stages 
The potential of MMV367 to inhibit intrahepatocytic parasite development was assessed 
in an infected primary human hepatocyte assay. Salivary gland sporozoites, isolated 
from mosquitoes infected with NF175 Plasmodium falciparum were used to infect 
cultured human hepatocytes. The percentage of infected hepatocytes was determined 
by immunofluorescence staining and automated high content imaging. MMV367 was 
tested in nine dilutions; 10 μM to 1 nM or 1 μM to 0.1 nM. MMV367 was found to inhibit 
liver stage parasites at relatively low concentrations (half maximal inhibitory 
concentration = 1.7 to 29.3 nM). 
5.3.1.2 Pharmacokinetics 
High oral bioavailability was observed in rats, and moderate oral bioavailability for mice 
and dogs. Minipigs showed a low bioavailability. Based on a physiological-based 
pharmacokinetic (PBPK) model, it has been predicted that MMV367 shows a high oral 
bioavailability, moderate volume of distribution and low blood clearance in humans, with 
a predicted human half-life of 19 h. Results from in vitro studies with human hepatocytes 
suggested that MMV367 is metabolised slowly in humans (predicted liver elimination of 
1.60 mL/min/Kg). MMV367 has a low potential for drug-drug interactions based on in 
vitro findings. Results from a PK study in dogs suggested that concomitant food intake 
may increase systemic exposure to MMV367. Toxicokinetic data indicated that at high 
doses, elimination of MMV367 is limited by the solubility resulting in a prolonged 
apparent half-life. 
Following intravenous administration of MMV367 to mice, rats dogs and minipigs, 
clearance values were low in mice and rats but high for dogs and minipigs. Associated 
mean terminal half-lives ranged between 0.6 h (dogs) and 2.1 h (mice). 
5.3.1.3 Safety Pharmacology and Toxicology 
In line with ICH M3 (R2) [11] and a previous FIH conducted with another malaria drug 
candidate in the US [4], standard safety pharmacology studies and 7-day oral toxicity 
studies in rats and dogs were conducted to support a short treatment course from single 
dose to 3 days against acute uncomplicated malaria. These studies demonstrated that 
MMV367 has a low oral toxicity. In rats, 100, 300 and 1000 mg/kg/day doses were 
administered. In male rats, 300 mg/kg/day was well tolerated and was the No-Observed-
Adverse-Effect-Level (NOAEL); the NOAEL was 100 mg/kg/day in female rats. In dogs, 
100, 300 and 1000 mg/kg/day doses were administered, and the NOAEL was assessed 
at 300 mg/kg/day in males and females.  
Microscopic findings in the adrenal glands (cortical hypertrophy with vacuolation) and 
thymus (atrophy) have been observed in the 7-day toxicology study in rats. Overall, these 
observations, which were not detected in dogs, are compatible with a transient and 
reversible stress-induced cortical hypertrophy and changes in lipid composition. While 
no signal for the human targets interfering with lipid metabolism were observed with 
MMV367, positive staining for adipophilin and negative staining for LAMP-2 were 
observed in the rat adrenal glands, suggesting the vacuoles were likely to be neutral fat, 
which is supportive of a transient and reversible effect. 
MMV367 was not mutagenic in the Ames test, showed no clastogenic potential in the in 
vivo rat model and no DNA damage potential in the in vivo Comet test. Standard 
reproductive toxicity studies have not been conducted. In an in vitro study using the rat 
whole embryo culture assay, MMV367 showed no teratogenic potential. 
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The effect of MMV367 on central nervous system function was assessed in rats in a 
GLP-study. Rats (N=6/group) were given single oral doses (gavage) of MMV367 at 0 
(vehicle control), 100, 300 and 1000 mg/kg. MMV367 did not induce signs of CNS toxicity 
in the primary observation test over a 24-h recording period. 
The effect of MMV367 on cardiovascular function was assessed in a GLP-study of 
beagle dogs. Each dog received single oral administrations (gavage) of 0 (vehicle), 100, 
300 and 1000 mg/kg of MMV367 in a randomised crossover fashion. The washout period 
between treatments was at least 48 h. Telemetry recordings lasted for 24 h after each 
administration. 
MMV367 caused a slight and transient increase in arterial blood pressure at 1000 mg/kg. 
The effect reached its maximum at 2 h post-dose (125 ± 2 mmHg for mean arterial blood 
pressure vs. 108 ± 5 mm Hg with vehicle, i.e. +16% from controls, p <0.01). At 
1000 mg/kg MMV367, a slight but prolonged increased mean heart rate was observed. 
The effect was observed from 2 to 20 h post-dose but reached statistical significance at 
12 h (94 ± 3 vs. 69 ± 5 bpm with vehicle, i.e. +36% from controls, p <0.01). Lower doses 
had no effect on arterial blood pressure or heart rate. 
Irrespective of the dose level, MMV367 had no statistically significant effects on core 
temperature, QT and QTc intervals, no substantial effects on the QA interval, pulse 
pressure, and rate pressure product, and no effects on the PR and the QRS interval 
duration. No arrhythmia or other changes in the morphology of the electrocardiograms 
(ECGs) that could be attributed to MMV367 were observed over the test period in any of 
the dogs. 
The effect of MMV367 on respiratory function was evaluated in rats in a GLP-study. The 
rats received single oral administrations (gavage) of 0 (vehicle), 100, 300 and 
1000 mg/kg of MMV367. Measurements took place over 24 h following administration of 
MMV367 or vehicle. At the highest dose (1000 mg/kg), MMV367 decreased peak 
inspiratory (-48%) and expiratory flows (-48%), tidal volume (-36%) and minute volume 
(-40% at 12 h and -60% at 24 h) from 6 h post-dose. The effects reached statistical 
significance at 12 and 24 h for minute volume and at 24 h for the other parameters. Lower 
doses had no substantial effects effect on respiratory function over the 24-hour test 
period. 
5.3.2 Clinical Findings 
MMV367 has not been administered to humans previously. This study will be the first 
time MMV367 will be administered in humans (FIH). 
6 Rationale 
6.1 
Study Rationale 
The main purpose of this FIH study with MMV367 is to generate safety, tolerability and 
PK data when MMV367 is first administered to healthy men and women as escalating 
single ascending doses (Part 1) under fasted conditions. In addition, the potential effect 
of food consumption (high-fat meal) on the PK and safety at the selected dose level will 
be assessed (Part 2) and 3-day multiple doses (Part 3) will be investigated.  
The rationale for taking MMV367 into further development is the expectation that this 
compound could be effective for the treatment of acute uncomplicated Plasmodium 
falciparum malaria with a therapeutic regimen that would ideally be given in a fixed dose 
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combination as a single dose regimen (single dose-single cure treatment) but could also 
be used in a standard fixed dose combination regimen of up to 3 days treatment (QD 
administration). Prior to initial testing in malaria patients, the safety and the PK 
characteristics of the drug in healthy participants must be investigated in order to provide 
sufficient data to proceed with the proof-of-concept study in the patient population. 
Preliminary information regarding the impact of food will also support further 
recommendations for the clinical development programme. 
Parts 1 and 3 of this study will be placebo-controlled to establish the frequency and 
magnitude of changes in safety endpoints that may occur in the absence of active 
treatment. As Part 2 of this study will administer single doses of a single formulation in a 
crossover design to evaluate food effect, Part 2 will be open-label. 
Randomisation will be used in all three study parts to minimise bias in the assignment of 
participants to treatment groups, to increase the likelihood that known and unknown 
participant attributes (e.g. demographic and baseline characteristics) are evenly 
balanced across treatment groups, and to enhance the validity of comparisons across 
dose groups. Blinded treatment will be used in Parts 1 and 3 to reduce potential bias 
during data collection and evaluation of clinical endpoints. 
In Parts 1 and 3, to protect the safety of participants enrolled, a sentinel dosing design 
will be followed for all cohorts: 1 participant will receive active IMP and 1 participant will 
receive matching placebo initially. The remaining 6 participants (5 active, 1 placebo) will 
be dosed approximately 96 h post-dose (Part 1)/post-final dose (Part 3); the decision to 
dose the remaining participants will be made based on the available safety data. After 
review of the safety data up to 96 h post-dose (Part 1)/post-final dose (Part 3), the 
investigator, or medically qualified designees who are familiar with the study protocol 
and IB, and medical monitor or delegate (with approval from the sponsor’s medical 
director or delegate) will decide whether to proceed with dosing the remaining 
participants in the cohort (main group). 
All approved standard of care treatments for acute uncomplicated malaria are 
administered for a maximum of 3 days duration. Therefore, in this study, MMV367 will 
be administered QD (morning dose) for a maximum of 3 days in Part 3. Considering its 
anticipated half-life of approximately 19 h, steady-state concentrations will not be 
achieved with a 3-day regimen. Although the pharmacological profile and PK properties 
of MMV367 are both expected to provide a single dose cure for acute uncomplicated 
malaria, the evaluation of a 3-day regimen will allow the assessment of tolerability and 
safety for an alternative therapeutic strategy in the target population. The assessment of 
up to a 3-day treatment regimen may be useful if a disconnect is observed in the 
predicted efficacy of the malaria human challenge model or malaria patients, such that 
MMV367 needs to be administered over 2 or 3 days to ensure a cure. Additionally, 
MMV367 will ultimately be administered/deployed in a fixed dose-combination regimen 
with an existing or novel antimalarial drug and dosing frequency will have to take the 
pharmacology of any proposed partner drug into account. 
This study may also identify the genetic factors that affect the PK of MMV367 in humans 
through exploratory pharmacogenetic sampling. Such analysis will be triggered after 
study completion if specific safety and/or PK observations suggest that a genetic 
polymorphism could potentially account for variability in the study. 
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6.2 
Dose Rationale 
The recommendations of the following guidelines have been considered when setting 
the starting dose and escalation rules for this trial:  
• 
Guideline on strategies to identify and mitigate risks for first-in-human and early 
clinical trials with investigational medicinal products (EMEA/CHMP/SWP/28367/07 
Rev. 1), 20 July 2017 [5]  
• 
Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical 
Trials for Therapeutics in Adult Healthy Volunteers. U.S. Department of Health and 
Human Services Food and Drug Administration Center for Drug Evaluation and 
Research. July 2005 [6] 
Part 1 
The maximum recommended safe starting dose (MRSD) of 100 mg was calculated 
based on results from two GLP toxicology studies in rats (male/females) and dogs 
(male/females) supporting Phase I and in accordance with the 2005 FDA [6] and the 
2017 [5] EMEA Guidances. The female rat was identified as the most sensitive species 
to set the starting dose according to the 2005 FDA guidance, whereas the dog was 
identified to be the most sensitive species with regards to the drug exposure, i.e. lower 
exposure at NOAEL, and was therefore selected to set the highest achievable human 
exposure. 
To set the starting dose, the NOAEL of the most sensitive species was selected from the 
7-day rat GLP toxicology study (NOAEL observed in female rats) and was 
100 mg/kg/day. On the basis of body surface area, the corresponding extrapolated 
human equivalent dose (HED) for a human body weight of 60 kg was 960 mg. Applying 
a safety factor of 10, a starting dose of 100 mg can be supported from a toxicology 
perspective. This proposed starting dose is approximately 4 times below the predicted 
human efficacious single dose (440 mg) for treatment of acute uncomplicated malaria 
and is expected to be devoid of pharmacological activity in healthy participants. 
Based on human PK predictions and assuming human bioavailability of approximately 
90%, the proposed starting dose of 100 mg is associated with a safety margin of 
approximately 60-fold for AUC (i.e. compared with cumulative AUC(0-168) at the dog 
NOAEL) and 30-fold for Cmax. 
Part 2 
Since MMV367 is a lipophilic molecule and considering the median bioavailability range 
of 13% to 94% in pre-clinical species, there is potential for increase in its bioavailability 
in the presence of high-fat food. In addition, a PK study in dogs showed that food 
consumption increases MMV367 exposure. The maximum exposure for a dose of 
400 mg when administered with food (assuming close to 100% bioavailability) is 
expected to be less than a 750 mg single dose administered fasted considering predicted 
human bioavailability; therefore, Part 2 is planned to run after completion of safety and 
PK analysis of Cohort 1C data, in which a 750 mg dose is predicted for administration.  
Part 3 
The final selection of multiple doses to be administered in Part 3 will be confirmed based 
on preliminary PK results and safety data from the single ascending dose (SAD) cohorts 
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(Part 1). The predicted exposure (AUC(0-inf)) of the cumulative dose after a 3-day 
treatment will not exceed that of a single dose evaluated in Part 1. It is proposed to 
administer a cumulative dose of 600 mg to participants in Part 3 (200 mg every 24 h for 
3 days), but this will be confirmed on review of data from Part 1. 
Estimated Human Minimal Efficacious Dose 
Pre-clinical studies using a validated pre-clinical model for malaria (SCID mice inoculated 
with Plasmodium falciparum-infected red blood cells) were used to establish the minimal 
parasiticidal concentration (MPC) and the minimal inhibitory concentration (MIC) of 
MMV367. A human dose that could maintain blood concentrations above Minimal 
Parasiticidal Concentration (MPC) for 100 h (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 PBPK 
modelling for predicting human PK profile and a typical human body weight of 60 kg, the 
predicted efficacious human dose of MMV367 after single-dose administration was 
estimated to be 440 mg. This dose is projected to maintain blood concentrations above 
the MPC90 in humans for at least 4.5 days and to be sufficient to reduce parasitaemia 
by 12-log in 50% of the population, while 100 and 30 mg would have similar efficacy for 
a two- and three-day QD treatment respectively. The parasite rate reduction was 
measured at ≥8 and 5 within the in vitro and ex vivo assays, respectively, and therefore, 
the value of 5 was retained to estimate the killing rate Emax (0.26 h-1). This is sufficient 
to reduce parasitaemia by 12-log in 4.5 days. 
The 3-day regimen is proposed as it is in-line with the duration of treatment for the current 
standard of care (SoC) for uncomplicated malaria. Although a single dose cure for 
uncomplicated malaria is the ideal product profile, a QD regimen that is taken for 2 to 3 
days would offer significant benefits over SoC in terms of efficacy and adherence if it 
overcomes the existing resistance to the current SoC (which has to be given multiple 
times a day). Furthermore, extended exposures will allow the assessment of tolerability 
and safety in the case of extended exposure in the patient population due to drug-drug 
interactions or co-morbidities, which is especially important due to the fact that the 
malaria burden disproportionately affect regions with fragile health systems where 
aftermarket drug monitoring may be less robust. 
Rationale for Highest Proposed Dose 
The rational for the highest proposed dose in Part 1 is based on:  
1. The predicted human efficacious exposure (AUC(0-inf) = 80 µg.h/mL) for a single 
dose/single cure of acute uncomplicated malaria, which is anticipated to be 
achieved with a dose of approximately 440 mg 
2. The need to document safety and tolerability of MMV367 at supratherapeutic 
exposures in humans in order to account for PK variability (intrinsic and extrinsic 
factors) in the target population 
3. The toxicity profile of MMV367 observed in preclinical species, which showed 
monitorable toxicity and an absence of life-threatening events  
4. The NOAEL in the two GLP species (rat and dog):  
− The cumulative exposure at NOAEL (100 mg/kg/day) in female rats was 
4270 µg.h/mL 
− The cumulative exposure at NOAEL (300 mg/kg/day) in male rats was 
3511 µg.h/mL 
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− The gender averaged cumulative exposure at NOAEL (300 mg/kg/day) in 
dogs was 1250 µg.h/mL (respectively, 1155 µg.h/mL in females and 
1344 µg.h/mL in males) 
Therefore, the exposure at NOAEL of the most sensitive species was identified from the 
7-day GLP toxicology study in dogs as the highest acceptable human exposure. The 
corresponding exposure of 1250 µg.h/mL is the cumulative AUC(0-168) of the parent 
drug MMV367 observed in the 7-day GLP dog study (Average cumulative AUC(0-168) 
calculated as follows: (AUC on Day 1 [AUCD1] + AUC on Day 7 [AUCD7]) / 2*7)). This 
would correspond to a theoretical HED of 6500 mg, assuming a linear PK from 100 to 
2000 mg.  
Based on the predicted human efficacious exposure, the need to document a safety 
window above that exposure and the anticipated human dose levels, the human AUCcap 
identified for this FIH study (376 µg.h/mL) was calculated as the predicted exposure 
(AUC(0-inf), assuming dose linearity from 100 to 2000 mg) for a theoretical dose of 
2000 mg. This proposed AUCcap is therefore 3-fold below the cumulative AUC identified 
at dog NOAEL (1250 ng.h/mL). Of note, based on the PBPK model, which suggests a 
less than dose-proportional increase in exposure, the highest dose of 2000 mg would 
result in a lower AUC(0-inf) of 208 µg.h/mL.  
For the multiple-dose part (Part 3), a dose of 200 mg every 24 h for 3 days would result 
in an AUC(0-inf) of 114 µg.h/mL and a safety factor of 3 to the AUCcap and a margin of 
11 to the cumulative AUC for the NOAEL from the dog study. 
The simulated exposure in human along with exposure multiples compared to NOAEL 
exposure in the most sensitive species are presented in Table 2. Exposure multiples for 
AUC are presented using two different methods. The standard method compares 
AUCtau(24h),ss in animal to AUC(0-inf) in human. Given the current goal of developing 
a single dose combination regimen (single dose-single cure treatment) and/or a 
combination regimen of up to 3 days treatment (QD administration) and the fact that the 
steady-state will never be reached, the cumulative method comparing AUC(0-168) in 
animal to AUC(0-inf) was considered more relevant in this case. Therefore, the exposure 
multiple at the top dose of 2000 mg is at least 6 for AUC (using a cumulative method). 
Additionally, the findings in animal toxicological species were non-adverse, monitorable 
and reversible [3]. Therefore, these increments are considered safe. Nevertheless, 
available PK data will be reviewed after each cohort to confirm that the observed AUC is 
comparable to the AUC simulated using the PBPK model and dose adjustments will be 
made, if required, before proceeding to the next cohort to ensure that the mean group 
exposure of the subsequent cohort will not exceed the highest achievable human 
exposure (AUCcap) of 376 µg.h/mL and/or the Cmaxcap of 23.8 µg/mL. 
Selecting mean group values for human AUC(0-inf)cap and Cmaxcap in this FIH is 
considered acceptable due to the nature of the preclinical observations (GI toxicity, 
increased blood pressure/heart rate and decreased respiratory function) in the two GLP 
toxicology and safety pharmacology studies. These toxicities are not associated with 
steep dose-response relationship and are monitorable in humans. 
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Table 2 
Margins between the Clinical Doses Predicted Plasma AUC(0-inf) and 
Cmax, and the Exposure at NOAEL in the Most Sensitive Species (Dog) 
Proposed 
Dose 
(mg) 
Prediction in Human 
based on PBPK model 
Exposure multiple in dogs 
(NOAEL dose 300 mg/kg QD for 7 days) 
Cmax 
(µg/mL) 
AUC(0-inf) 
(µg.h/mL) 
Cmax  
(23.8 µg/mL)a 
AUC(0-168)  
(1250 
µg.h/mL) 
Cumulative 
methodb,c 
AUCtau(24h)-ss  
(192 µg.h/mL) 
Standard 
methodd 
Single dose 
100 mg 
0.7 
18.8 
34.0 
66.5 
10.2 
300 mg 
2.2 
55.5 
10.8 
22.5 
3.5 
750 mg 
5.0 
127 
4.8 
9.8 
1.5 
1500 mg 
7.7 
193 
3.1 
6.5 
1.0 
2000 mg 
8.2 
208 
2.9 
6.0 
0.9c 
Multiple dose 
200 mg 
QD × 3 
2.2 
112 
10.8 
11.2 
1.7 
a Cmax after last dose in dogs 
b Cumulative exposure method, AUC(0-168) / predicted AUC(0-inf) in humans. The average cumulative 
AUC(0-168) is calculated as follows: (AUCD1 + AUCD7) / 2*7. 
c The approach calculating safety margin based on the cumulative method is considered more relevant in 
our setting because the steady-state will never be reached due to the maximum 3-day QD treatment duration 
with a 19 h half-life.   
d Standard method: AUCtau(24h)-ss / predicted AUC(0-inf) in humans  
Note: AUCcap = 376 µg.h/mL, calculated exposure at 2000 mg assuming dose linearity from 100 to 2000 mg. 
6.3 
Population Rationale 
As this is a Phase I study assessing the PK, relative bioavailability and safety of 
MMV367, the most relevant population is healthy volunteers. Participants who are 
non-smokers without a history of alcohol or drug abuse or regular co-medication (except 
hormonal contraception and hormone replacement therapy [HRT]) are proposed to avoid 
interaction on drug metabolism and to avoid non-compliance.  
Due to the target population in endemic areas with a substantial proportion of young 
women suffering from acute uncomplicated malaria, efforts will be made to enrol women 
of childbearing potential (WOCBP) in Phase I studies. In accordance with ICH M3 at this 
early stage of development, reproductive and developmental toxicity studies have not 
yet been conducted and, therefore, the risk of teratogenicity with MMV367 is currently 
unknown. Embryofoetal development studies will be completed before initiation of 
Phase II trials in African patients. Given the current lack of standard reproductive toxicity 
studies, WOCBP enrolled in Phase I studies with MMV367 must have a negative 
pregnancy test at screening and admission and are required to use a double method of 
contraception as described in Section 9.4. 
As it is unknown whether MMV367 is found in semen and considering the current lack of 
fertility studies in animals, male study participants are also required to use highly 
effective contraception with their partner, if their partner is a WOCBP. Contraception 
requirements are detailed in Section 9.4. 
Based on the above considerations and target population, healthy non-pregnant and 
non-lactating female participants and healthy male participants, aged 18 to 55 years are 
considered suitable for this study. In order to reflect the majority patient population, 
efforts will be made to ensure a gender balance and to recruit participants of 
Sub-Saharan origins (i.e. both parents are black and are of sub-Saharan African origin). 
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6.4 
Risks and Benefits 
6.4.1 Risks Associated with MMV367 Administration 
There is currently no clinical experience with MMV367. Potential risks will be closely 
monitored as part of systematic safety evaluations being performed in this FIH study. 
Based on pre-clinical observations at toxicological doses in rats and dogs, potential risks 
associated with MMV367 administration are all monitorable in humans and consist of:  
• 
Gastrointestinal toxicity with symptoms such as nausea and vomiting 
• 
Cardiovascular effects with transient increased heart rate and blood pressure 
• 
Decreased respiratory function 
Gastrointestinal adverse reactions may manifest as epigastric/abdominal pain, 
nausea/vomiting, diarrhoea or constipation. 
Heart rate and blood pressure will be closely monitored in this study and will also include 
orthostatic evaluations. 
Effects on respiratory function may result in an increased resting respiratory rate. 
Measures to minimise the risks to healthy participants will include: 
• 
Selection of a starting dose below a dose level for which pharmacological effects are 
expected. 
• 
Sentinel dosing in the SAD cohorts (Part 1) and the multiple dose cohort(s) (Part 3); 
one participant on IMP and one participant on placebo. If safety and tolerability is 
acceptable, the remaining participants in each cohort can be dosed with a minimum 
interval of 96 h post-dose (Part 1) or 96 h post-final dose (Part 3) in the sentinel 
participants. 
• 
Progression to consecutive study parts or higher exposure dosing regimens only after 
evaluation of data from previous parts/cohorts and following approval from the safety 
advisory committee (SAC). 
• 
Close and regular clinical, laboratory and ECG monitoring of study participants. 
• 
Telemetry (Day 1 in Part 1 and Days 1 and Day 8 in Part 2) and Holter monitoring 
(up to 24 h post-dose on Day 1 in Part 1, up to 24 h post-dose on Days 1 and 8 in 
Part 2, and up to 24 h post-dose on Days 1 and 3 in Part 3) of each cohort/study part. 
• 
Pre-defined stopping rules based on emerging human safety and PK data. 
6.4.2 COVID-19 Related Risks and Risk Mitigation Measures 
The following risks and risk mitigating measures apply to parts of the study in which the 
study is conducted during the Coronavirus Disease 2019 (COVID-19) pandemic.  
6.4.2.1 IMP Related Risk 
Against the background of the COVID-19 pandemic, the potential risk of a participant 
developing COVID-19 has been considered in terms of the risk-benefit evaluation. The 
mode of action of the IMP – as an inhibitor of acyl CoA synthetase in Plasmodium – has 
been considered alongside available pre-clinical and clinical data (including class 
effects) and it is considered that a participant would not be at increased risk of either 
becoming infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; 
the virus that causes COVID-19) or experiencing a more severe illness. That is, the IMP 
has no known immunomodulatory effect that would confer an increased risk to healthy 
participants enrolled in the study. 
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6.4.2.2 General COVID-19 Related Risk Mitigation Measures 
General risk mitigation against COVID-19 will be implemented in accordance with 
Quotient’s monitoring and prevention control measures. 
COVID-19 testing may be performed based on current infection rates and availability of 
tests. If required, it is planned that testing will comprise an antigen test performed at 
screening and on Day -1. Testing time points may be changed and additional time points 
may be added throughout the study as required. The decision on COVID-19 testing and 
the definition of the testing time points are subject to change based on the current risk 
mitigation in place and will be agreed by the study team and documented in the 
Investigator Site File (ISF) via the Clinical Kick-Off Meeting minutes. 
The risk mitigation measures, where applicable, will be amended based on emerging 
government guidance. 
6.4.2.3 COVID-19 Vaccine-Related Risk 
Approved (including health authority conditional marketing authorisation) COVID-19 
vaccines e.g. killed, inactivated, peptide, DNA and RNA vaccines will not be permitted 
during the study.  
Based on the mechanism of action of the IMP, as an inhibitor of acyl CoA synthetase in 
Plasmodium, there is no perceived impact on the safety of the study participants or on 
the study objectives for participants who may receive these vaccines. It is also very 
unlikely that administration of the IMP would interfere with COVID-19 vaccination 
response; however, no specific pre-clinical or clinical investigations have been 
conducted at this point with MMV367.  
The emerging safety and efficacy data from millions of vaccinated people indicate that 
these vaccines have an excellent safety and efficacy record. In the broader interests of 
society and to limit the extent of the global pandemic, it is important that participants 
should receive a vaccine when it is offered to them. 
6.4.3 General Risks and Overall Risk-Benefit Assessment 
Collecting a blood sample from a vein may cause pain, swelling, bruising, 
light-headedness, fainting, and very rarely, clot formation, nerve damage and/or infection 
at the site of the needle stick. 
During cannulation, more than one attempt may be needed to insert the cannula in a 
vein of a participant and it is possible that bruising and/or inflammation may be 
experienced at the site of cannulation.  
Electrocardiogram (ECG) and Holter stickers, and telemetry electrodes on the 
participants' chests and limbs may cause some local irritation and may be uncomfortable 
to remove but participants will be closely monitored to ensure any local irritation does not 
persist. 
There is no benefit to the participants from taking part in this study. The development of 
a product to treat malaria or improve the treatment of malaria will be of benefit to patients 
with malaria. 
The overall risk benefit balance is therefore considered to be acceptable. 
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7 Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of single and 
multiple oral doses of MMV367 in healthy 
participants 
 
 
Incidence of adverse events (AEs), physical 
examination findings, and change from baseline 
for vital signs, electrocardiograms (ECGs) and 
laboratory safety tests. 
Secondary 
To assess the pharmacokinetics (PK) of single 
and multiple doses of MMV367 in plasma 
(Parts 1, 2 and 3) 
 
 
PK parameters such as AUC, Tmax, Cmax, CL/F, 
Vz/F, T1/2 and AR, when applicable 
To assess the effect of a high-fat meal on the PK 
of a single dose of MMV367 in healthy 
participants (Part 2 only) 
 
PK parameters such as AUC, Tmax, Cmax and 
Frel, as appropriate, under fed and fasted 
conditions 
Exploratory  
To assess the PK of single dose of MMV367 in 
urine (Part 1 only) of healthy participants 
(optional)a 
 
 
Urine PK parameters such as Ae, and derived 
plasma PK parameters such as CLr, when 
applicable 
To assess exposure response relationship for 
potential effects of MMV367 on ECG intervals 
(QT, QTcF, QTcB, PR, QRS)b 
 
 
ECG intervals, MMV367 plasma concentrations 
(time-matched) 
To investigate metabolite(s) of MMV367 in healthy 
participantsa 
 
Metabolite characterisation for MMV367 in 
plasma and urine, when applicable 
To evaluate the taste attributes (smell, sweetness, 
bitterness, flavour, mouthfeel/texture, grittiness 
and aftertaste) and overall acceptability of the IMP 
(Part 1 only) 
Taste questionnaire score, based on a 9-point 
Likert scale assessing the acceptability for each 
taste attribute (smell, sweetness, bitterness, 
flavour, mouthfeel/texture, grittiness, and 
aftertaste) and overall acceptability for each dose 
level of MMV367 
a Depending on availability of the data, these objectives may be reported in an addendum to the final study 
Clinical Study Report (CSR) or in a separate report. 
b This objective will be reported in a separate cardiac safety report and will not be part of the final study CSR 
8 Study Design 
The study is divided into Parts 1, 2 and 3. For each of the three parts, participants will be 
screened within 28 days prior to first admission to the clinical unit on the morning of 
Day -1. Each participant will receive verbal and written information followed by signing 
of the informed consent form (ICF) prior to any screening procedures taking place. 
8.1 
Study Plan 
8.1.1 Study Plan: Part 1 – Single Ascending Dose Cohorts 
Part 1 will be a double-blinded, randomised, placebo-controlled, SAD study, which will 
comprise up to 5 fasted cohorts (Cohorts 1A to 1E; Cohort 1E will be optional), with 
8 participants in each cohort. Participants will be randomly assigned to receive a single 
oral dose of either active IMP (6 participants) or placebo (2 participants) to assess its 
safety, tolerability and PK profile. Each participant will take part in one cohort. The data 
obtained from each cohort (safety and PK) will undergo a formal review by the SAC (see 
Section 8.2). The SAC will determine if it is safe to proceed with the next dose/cohort. 
Following review of the emerging PK data from each preceding cohort, if results suggest 
that the exposure plateau has been reached, the next planned cohort will not be 
conducted. Similarly, if PK predictions suggest that this exposure plateau would be 
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exceeded at the next cohort/dose level, a lower dose than originally anticipated will be 
proposed. 
It is planned to enrol 8 healthy male and female participants per cohort to ensure data in 
a minimum of 4 participants (per cohort) on active IMP. A participant will be considered 
evaluable if they have received study drug and completed safety and PK assessments 
up to 96 h post-dose. 
In each cohort, participants will be dosed on Day 1 and will remain resident in the clinical 
unit until discharge on Day 5. They will attend the clinical unit for a return visit on Day 7 
and again on Day 15 (± 1 day) for end of study assessments. Blood samples will be 
collected at regular intervals for PK analysis and safety from Day 1 to discharge from the 
study on Day 15 (± 1 day), as detailed in Appendix 2. Each cohort will follow the same 
study design (Figure 1). 
Figure 1 
Study Sequence: Part 1 (Cohorts 1A to 1E) 
Screening 
Day -28 to Day -2 
 
Admission 
Day -1 
 
Dose 
Day 1 
 
Discharge 
Day 5  
 
Return Visit  
Day 7 
 
End of Study Visit 
Day 15 (± 1 day) 
Each participant will take part in one cohort and will receive one of the regimens 
presented in Table 3, according to the randomisation schedule. 
Table 3 
Description of Regimens: Part 1 
SAD Cohort 
Regimen 
IMP 
Dose 
Route of 
Administration 
1A 
1 
MMV367 or 
placebo 
100 mg 
Oral, Fasted 
1B 
2 
MMV367 or 
placebo 
300 mga 
Oral, Fasted 
1C 
3 
MMV367 or 
placebo 
750 mga 
Oral, Fasted 
1D 
4 
MMV367 or 
placebo 
1500 mga 
Oral, Fasted 
1E 
Optional 
5 
MMV367 or 
placebo 
2000 mga 
Oral, Fasted 
a Predicted dose 
Details of the IMPs are provided in Section 5.2.  
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There will be a blinded interim review of the safety, tolerability and PK data after each 
cohort prior to the dose decision for subsequent cohorts. Full details of the interim data 
reviews are provided in Section 8.2. 
Participants will also complete a written taste/palatability questionnaire individually and 
privately following administration of the IMP (see Section 13.3). In the evening of Day -1, 
participants will be trained to respond to a sample questionnaire using a suitable example 
fluid (e.g. orange juice/squash). On the morning of Day 1, participants will brush their 
teeth using tap water (toothpaste not permitted). In order to evaluate taste, participants 
will hold the IMP in their mouth and swirl it around for 10 to 15 sec before swallowing. 
Immediately after swallowing, they will complete a taste questionnaire individually and 
privately. 
8.1.2 Study Plan: Part 2 – Food Effect Cohort 
Part 2 will be an open-label, randomised, balanced two-period crossover, food effect 
evaluation. The effect of food on the PK of MMV367 will be explored in Part 2 by 
administering a single dose of MMV367 after a high-fat breakfast, as per FDA guidance 
(Appendix 8), and a single dose of MMV367 in the fasted state. 
Each participant will receive 2 single doses of MMV367. In Period 1, participants will be 
randomised 
to 
1 
of 
2 
treatment 
sequences 
(Regimen 
6/Regimen 
7 
or 
Regimen 7/Regimen 6). If a participant is randomised to receive MMV367 in the fasted 
state (Regimen 6) in Period 1, they will receive MMV367 in the fed state (Regimen 7) in 
Period 2 and vice versa. 
It is planned to enrol 8 healthy male and female participants to ensure data in a minimum 
of 6 participants. A participant will be considered evaluable if they have received study 
drug and completed safety and PK assessments up to 96 h post-dose in both periods.  
Participants will be dosed on Day 1 (Period 1 dose) and on Day 8 (Period 2 dose) and 
will remain resident in the clinical unit until discharge on Day 12. They will attend the 
clinical unit on Day 14 (± 1 day) for end of study assessments. Based on emerging PK 
data from Part 1, the washout period between the Period 1 and Period 2 doses may be 
extended. Blood samples will be collected at regular intervals for PK analysis and safety 
from Day 1 to the end of study visit on Day 14 (± 1 day), as detailed in Appendix 3. 
The study design for Part 2 is presented in Figure 2. 
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Figure 2 
Study Sequence: Part 2 
Screening 
Day -28 to Day -2 
 
Admission 
Day -1 
 
Period 1 Dose 
Day 1 
 
Period 2 Dose 
Day 8 
 
Discharge 
Day 12 
 
End of Study Visit 
Day 14 (± 1 day) 
Each participant will receive Regimens 6 and 7, presented in Table 4, according to the 
randomisation schedule. 
Table 4 
Description of Regimens: Part 2 
Food Effect 
Cohort 
Period 
Regimen 
IMP 
Dosea 
Route of 
Administration 
2A 
1 and 2 
(randomised) 
6 
MMV367 
XX mg 
Oral, Fasted 
7 
MMV367 
XX mg 
Oral, Fed 
Details of the IMPs are provided in Section 5.2.  
a The dose administered in Part 2 will be determined once predicted human therapeutic concentrations of 
MMV367 and a safe exposure window has been established in Part 1. The dose for Regimens 6 and 7 will 
be the same. 
8.1.3 Study Plan: Part 3 – Multiple Dose Cohort(s) 
Part 3 will be a double-blinded, randomised, placebo-controlled, multiple-dose study. A 
total of 8 participants per cohort will receive once-daily doses of MMV367 (6 participants) 
or placebo (2 participants) for 3 days, in the fasted state, to assess safety, tolerability 
and PK profile of multiple dosing.  
It is planned to enrol 8 healthy male and female participants to ensure data in a minimum 
of 4 participants on active IMP. A participant will be considered evaluable if they have 
received study drug and completed safety and PK assessments up to 96 h post-final 
dose. 
Participants will receive a single dose on Days 1, 2 and 3 and will remain resident in the 
clinical unit until discharge on Day 7. They will attend the clinical unit for a return visit on 
Day 9 and again on Day 17 (± 1 day) for end of study assessments. Blood samples will 
be collected at regular intervals for PK analysis and safety from Day 1 to discharge from 
the study on Day 17 (± 1 day), as detailed in Appendix 4. Each cohort will follow the 
same study design (Figure 3). 
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Figure 3 
Study Sequence: Part 3 (Cohorts 3A to 3C) 
Screening 
Day -28 to Day -2 
 
Admission 
Day -1 
 
Dose 
Days 1, 2 and 3 
 
Discharge 
Day 7  
 
Return Visit  
Day 9 
 
End of Study Visit 
Day 17 (± 1 day) 
Each participant will receive one of the regimen(s) presented in Table 5 according to the 
randomisation schedule. 
Table 5 
Description of Regimens: Part 3 
Multiple Dose 
Cohort 
Regimen 
IMP 
Dosea 
Route of 
Administration 
3A 
8 
MMV367 or 
placebo 
XX mg for 3 days 
Oral, Fasted 
3B 
Optional 
9 
MMV367 or 
placebo 
XX mg for 3 days 
Oral, Fasted 
3C 
Optional 
10 
MMV367 or 
placebo 
XX mg for 3 days 
Oral, Fasted 
Details of the IMPs are provided in Section 5.2. 
a The dose(s) administered in Part 3 will be determined after review of the data from Part 1. 
Parts 2 and 3 may be conducted before completion of Part 1 provided that this is justified 
by PK and safety data obtained from completed cohorts in Part 1. The total amount of 
active IMP administered as multiple doses (i.e. cumulative 3-day dose) in Part 3 will be 
no greater than the maximum safe and well tolerated dose in Part 1, dosed at a single 
dose level. Parts 2 and 3 may be conducted in parallel. 
The data obtained (safety and PK) from the multiple dose administration will undergo a 
formal review by the SAC after all 8 participants have completed the study. 
Consequently, Part 3 may be extended to evaluate a second and/or third dose level in a 
3-day QD regimen. 
Parts 1 and 3 will follow a sentinel dosing design. On the first day of dosing in each cohort 
in Part 1 and in Part 3, only 2 (sentinel) participants will be dosed. The randomisation 
schedule will be constructed such that 1 of the participants dosed on the first day will 
receive MMV367 and 1 will receive placebo. After review of the safety data up to 96 h 
post-dose for SAD cohorts in Part 1 and up to 96 h post-final dose in Part 3, the 
investigator, or medically qualified designee who is familiar with the study protocol and 
IB, and medical monitor or delegate (with approval from the sponsor’s medical director 
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or delegate) will decide whether to proceed with dosing the remaining participants in the 
cohort. 
8.2 
Criteria for In-Study Decisions 
In-study decisions will be made by the safety advisory committee (SAC), which will 
always comprise the investigator, the medical monitor, the sponsor’s medical director, 
and a PK expert where appropriate. 
8.2.1 Decision Points  
The following in-study decisions will be made during this study: 
• 
Dose selection for Cohorts 1B to 1E in Part 1 
• 
Progression from Cohort 1D to 1E in Part 1 
• 
Washout period duration between periods in Part 2 
• 
Dose selection for Parts 2 and 3 
• 
Changes to safety and/or PK time points, if there is reason to believe that the change 
might improve the quality of the data as a consequence of review of emerging data 
• 
Progression from Cohort 3A to further multiple dose levels in Part 3  
8.2.2 Criteria for Dose Decision 
Part 1: Single Ascending Dose Cohorts 1A to 1E 
Progression to the next dose cohort will be permitted after review of safety, tolerability 
and PK data suggests that it is safe to do so. Quotient will provide data to the SAC in 
accordance with Quotient’s standard operating procedure (SOP) on interim dose 
decision making and dose escalation. The decision will be documented and signed by 
the investigator as per Quotient’s current SOP. Evidence of the decision will be retained 
in the ISF and Trial Master File. 
For dose escalation to proceed, data must be available from a minimum of 6 participants 
who have completed the planned safety assessments up to 7 days after dosing and 
planned PK assessments up to 144 h after dosing to ensure at least 4 participants had 
received active IMP. Dose increases will only be made after a complete review of all data 
collected from the previous dose group by the SAC.  
It is planned that the dose will be escalated for each subsequent cohort; however, the 
SAC may also agree to enrol additional participants for an intermediate dose level if 
warranted or may agree to reduce the dose with no limit on the possible extent of 
reduction. Any decision to investigate an intermediate or reduced dose level will be fully 
documented. 
The decision to proceed to the next dose level will be based on safety, tolerability and 
available PK data. The following data are required: 
• 
AEs 
• 
Vital signs 
• 
Safety laboratory results 
• 
ECGs 
• 
Physical examination findings 
• 
Plasma concentrations of MMV367 
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• 
Interim PK parameter estimations (Tmax, Cmax, AUC(0-24), AUC(0-48), 
AUC(0-last), AUC(0-inf), T1/2, where possible and appropriate) 
Rules for dose decision are as follows: 
• 
Dose increments between SAD cohorts will be a maximum of 3-fold and dose 
escalation may be halted in the SAD cohorts if an exposure plateau appears to have 
been reached 
• 
Dose increments between multiple dose optional cohorts will be no more than 3-fold 
• 
No dose selected for SAD or MAD will be expected to result in a mean group 
exposure at the next dose level (based on predicted human PK and assuming 
dose-linearity) greater than AUC(0-inf) 376 µg.h/mL, and Cmax 23.8 µg/mL based 
on the NOAEL in dogs and the corresponding human therapeutic exposure 
• 
The predicted exposure (AUC(0-inf)) of the cumulative dose after a 3-day treatment 
will not exceed that of a single dose evaluated in Part 1 
• 
The study will be halted (see Section 8.5) and thus a further dose decision will not 
be made if: 
− One or more participants experience an IMP-related serious adverse event 
(SAE) 
− Two or more participants experience an IMP-related severe or clinically 
significant non-serious AE at the same dose level/same cohort 
If, following review by the SAC it is deemed acceptable to continue dose escalation 
above the defined maximal dose or exposure limit, a substantial amendment with 
relevant data will be submitted for approval to the Medicines and Healthcare products 
Regulatory Agency (MHRA) and ethics committee (EC). 
Progression from Part 1 (SAD) to Part 2 (Food Effect).  
For the dose level decision to be made for Part 2, data must be available from a minimum 
of 6 participants who have completed the planned safety assessments up to 7 days after 
dosing and planned PK assessments up to 144 h after dosing (to ensure at least 
4 participants had received active IMP), at a relevant dose level in Part 1. A “relevant 
dose level” is defined as a dose that demonstrated acceptable safety/tolerability 
(i.e. exposure levels at which no study specific criteria stopping dose progression and/or 
escalation were met) at a mean exposure that is not anticipated to be exceeded by the 
dosing regimen in Part 2, taking into account a potential bioavailability increase to 100% 
after a high-fat breakfast. 
Progression from Part 1 (SAD) to Part 3 (Multiple Dose).  
For the dose level decision to be made for Part 3, data must be available from a minimum 
of 6 participants who have completed the planned safety assessments up to 7 days after 
dosing and planned PK assessments up to 144 h after the final dose (to ensure at least 
4 participants had received active IMP), at a relevant dose level in Part 1. The total dose 
in Part 3 (3 × QD dose) will not exceed a dose of MMV367 administered and evaluated 
as a single dose in Part 1, and the predicted exposure will not exceed an exposure 
observed and determined to be safe in Part 1. If a less than dose-proportional increase 
in exposure is observed in Part 1 (SAD), the proposed dose(s) for Part 3 may be adjusted 
to ensure the equivalent exposures between SAD and MAD. 
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8.2.1 Criteria for Sentinel Dosing Decisions 
For all cohorts following a sentinel design (Parts 1 and 3) the decision to proceed with 
the main group will be made by the investigator, based on safety data until 96 h post-dose 
(Part 1) or 96 h post-final dose (Part 3) in the sentinel participants. The investigator or 
medically qualified designee who is familiar with the study protocol and IB, and medical 
monitor or delegate (with approval from the sponsor’s medical director or delegate) will 
decide whether to proceed with dosing the remaining participants in the cohort.  
8.3 
Participant Withdrawal 
If a participant wishes to leave the study at any time, they will be permitted to do so. 
Every 
reasonable 
effort 
will 
be 
made 
by 
Quotient 
to 
complete 
final 
assessments/discharge procedures. Quotient will advise the sponsor of the withdrawal 
of any participant from the study. 
Early withdrawal is defined as the date of the decision to withdraw the participant from 
the study. Participant completion is defined as the date of the last procedure conducted 
or last contact (e.g. discharge from the study or unscheduled visit) for that participant. 
If a participant requests to leave the clinical unit earlier than the planned discharge time 
e.g. due to unforeseen personal circumstances, but aims to return to the clinical unit to 
complete the study, this will be documented as a participant self-discharge and a protocol 
deviation. The participant must complete the planned assessments/discharge 
procedures before discharge from the clinical unit, and may return for the next study 
period/assessments, as planned following agreement between the sponsor and the 
investigator.  
Participants in Part 1 will receive a single dose in the study; therefore, after an individual 
participant has received a dose of IMP, withdrawal of that participant from further dosing 
is not possible. Participants will be monitored for the criteria listed below, which may 
require their withdrawal from some or all study procedures if continuation is not in their 
best interests, except when the withdrawal is a result of withdrawal of consent.  
Participants in Parts 2 and 3 will be withdrawn from the study drug for the following 
reasons: 
• 
Experiencing a serious or severe AE including but not limited to: 
− corrected QT interval by Fridericia’s formula (QTcF) of >500 msec or 
increase in QTcF of >60 msec from baseline (confirmed following a repeat 
ECG) 
− alanine aminotransferase (ALT) concentration >3 × the upper limit of the 
reference range (confirmed following a repeat ALT blood test) 
• 
Pregnancy (see Section 9.5) 
• 
Termination of the study 
• 
Upon the participant’s request (withdrawal of consent) 
• 
Significant deviation from the protocol 
• 
Concurrent illness that would adversely affect participant safety or data integrity or 
requirement for prohibited medication 
• 
At the discretion of the investigator 
For the purpose of withdrawal criteria, baseline will be considered as the last available 
assessment prior to first dose. 
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For a participant who withdraws because of an IMP-related AE, every effort will be made 
to ensure the participant completes discharge procedures.  
Early withdrawal for safety reasons will be distinguished from withdrawal of consent by 
the participant to participate in any further activities. 
8.4 
Participant Replacement 
In Part 1, up to 2 replacement participants may be used per cohort. The maximum 
number of participants that may be dosed is 50 (8+2 per cohort). 
In Part 2, up to 4 replacement participants may be enrolled into the study. The maximum 
number of participants that may be dosed in Part 2 is 12 (8+4). 
In Part 3, up to 2 replacement participants per cohort (if optional cohorts are utilised) may 
be enrolled into the study. The maximum number of participants that may be dosed is 
30 (8+2 per cohort). 
Any participant withdrawn due to an IMP-related AE will not be replaced. 
Participants withdrawing for other reasons may be replaced as required by agreement 
between the investigator and sponsor to ensure sufficient evaluable participants. 
8.5 
Stopping Criteria 
Cohort stopping rules 
Dose escalation, as well as continued dosing within any given cohort, will be paused and 
may be halted based on full review of all available clinical safety data if any of the 
following occur: 
• 
Two or more participants in the same cohort experience an AE assessed as severe 
• 
Two or more participants with QTcF >500 msec and/or an increase in QTcF 
>60 msec considered related to IMP administration 
• 
At least 2 participants in the same cohort with demonstrated recurrent or persistent 
post-dose orthostatic hypotension (i.e., either a drop of systolic blood pressure [SBP] 
≥20mmHg or diastolic blood pressure [DBP] ≥10mmHg after 3 min standing) and/or 
symptomatic hypotension (lightheadedness, weakness, blurry vision, dizziness or 
fainting upon standing) requiring medical intervention 
Overall study stopping rules 
Enrolment into the study will be placed on hold and dosing will be halted if any of the 
following occur cumulatively across all of the cohorts 
• 
At least one IMP-related SAE 
• 
Two severe non-serious adverse reactions considered as, at least, possibly related 
to the IMP administration in two subjects in the same cohort, independent of within 
or not within the same system-organ-class are observed. 
• 
The investigator and/or the study sponsor considers that the number and/or severity 
of AEs, abnormal safety monitoring test, or abnormal laboratory findings justify 
putting the study on hold. 
Relatedness to IMP will be determined by the investigator.  
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If the study is halted, a temporary halt will be submitted to the MHRA and EC in the form 
of a substantial amendment. The study may be resumed or terminated; however, it will 
not be resumed until a further substantial amendment to resume the study is submitted 
and approved by MHRA and EC. 
8.6 
Study Termination 
After the start of protocol activities but prior to the commencement of dosing, the study 
may be terminated by the sponsor and investigator without consultation with the 
Medicines and Healthcare products Regulatory Agency (MHRA) and EC. Notification of 
early termination must be provided to the MHRA and EC immediately and at the latest 
within 15 days after the study is terminated, clearly explaining the reasons. A description 
of follow-up measures taken for safety reasons, if applicable, will also be provided. 
If the study is abandoned prior to commencement of any protocol activities, the 
investigator or sponsor must notify the EC and MHRA by letter outlining the reasons for 
abandonment of the trial. 
Once exposure to dosing has begun, the study will be completed as planned unless the 
following criteria are satisfied that require a temporary halt or early termination of the 
study:  
• 
The occurrence of serious or severe AE(s), as defined in Section 8.5, if considered 
to be related to the IMP, as defined in Section 14.2. 
• 
New information regarding the safety of the IMP that indicates a change in the 
risk/benefit profile for the compound, such that the risk/benefit is no longer acceptable 
for participants participating in the study. 
• 
Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary study objectives or compromises participant safety. 
If any of the above occurs, the study will be terminated if careful review of the overall 
risk/benefit analysis described in Section 6.4 demonstrates that the assumptions have 
changed and that the overall balance is no longer acceptable. In these circumstances 
termination can only take place with the agreement of the investigator and sponsor. The 
MHRA and EC will be informed of study termination. 
If it becomes necessary to consider termination of the study after dosing has begun, 
dosing may be suspended pending discussion between the investigator and sponsor. 
Dosing will be stopped immediately on safety grounds. 
The study may be terminated or suspended at the request of the MHRA or EC. 
8.7 
Lost to Follow-up 
A participant will be considered lost to follow-up if they fail to return for scheduled visits 
and cannot be contacted by the clinical unit.  
If a participant fails to return to the clinical unit for a required study visit: 
• 
The clinical unit must attempt to contact the participant and reschedule the missed 
visit as soon as possible. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (e.g. three telephone calls on 
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three separate occasions and, if necessary, an email or letter to the participant’s last 
known email/postal address). These contact attempts should be documented in the 
participant’s source. 
• 
If the participant cannot be contacted, they will be considered lost to follow-up.  
8.8 
Treatment Assignment and Randomisation 
Parts 1 and 3 will be randomised (IMP/placebo) and double-blinded. Part 2 will be 
randomised (fed/fasted) and open-label. A randomisation schedule will be produced for 
each study part. 
Instructions to dispense and dose will be produced prior to dosing using the 
randomisation schedule and will be retained in the ISF. 
For Part 2, the original randomisation schedule and proof of quality control procedures will 
be held by the Data Sciences department at Quotient until the study is archived, at which 
time the randomisation materials will be retained in the ISF. 
Using computer-generated randomisation schedules, participant numbers will be 
allocated to treatment regimens in a 6:2 ratio (MMV367:placebo) in each cohort (Part 1) 
or part (Part 3). In Part 2, the allocation will be balanced with 8 participants assigned to 
receive MMV367 in both the fed and fasted states. Participants will be randomised to 
1 of 2 treatment sequences (Regimen 6/Regimen 7 or Regimen 7/Regimen 6) on Day 1 
prior to dosing in the first period. 
For participants in Parts 1 and 3, a sentinel group of 2 participants will be dosed ahead 
of the remaining participants in each cohort. For each cohort, using a 
computer‑generated randomisation schedule, the first 2 participant numbers will be 
allocated to active or placebo in a 1:1 ratio (i.e. 1 participant will be randomly assigned 
to receive MMV367 and 1 participant will be randomly assigned to receive placebo). The 
remaining 6 participant numbers will be allocated to active or placebo in a 5:1 ratio 
(i.e. 5 participants will be randomly assigned to receive MMV367 and 1 participant will 
be randomly assigned to receive placebo). 
Participants will be randomised immediately before administration of the first dose. 
8.8.1 Participant Numbers 
Participant numbers will be allocated on the morning of dosing according to the code 101 
to 140 in Part 1, 201 to 208 in Part 2, and 301 to 324 in Part 3 using the lowest number 
available. Replacement participants will be allocated participant numbers 901 to 940 in 
Part 1, 801 to 808 in Part 2 and 701 to 724 in Part 3, where the last two digits are the 
same as those of the original participant (e.g. if Participant 105 withdraws, the 
replacement will have Participant Number 905 and will receive the same regimen as 
Participant 105).  
Participant numbering by study part and cohort is provided in Table 6. 
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Table 6 
Participant Numbers 
Study Part 
Cohort 
Participant Numbers 
1 
1A 
101–108 
1B 
109–116 
1C 
117–124 
1D 
125–132 
1E (optional) 
133–140 
2 
2A 
201–208 
3 
3A 
3B (optional) 
3C (optional) 
301–308 
309–316 
317–324 
8.8.2 Blinding  
Parts 1 and 3 of the study are double-blinded. Treatment assignment will not be known 
to the participants, the sponsor or the staff who are involved in the clinical evaluation of 
the participants and the analysis of data. If appearance matching of the placebo is not 
possible then masking and/or unblinded dosing teams will be used to preserve the study 
blind. Further details of these steps will be contained in the study specific blinding plan, 
which will be approved prior to dosing. The randomisation schedules and disclosure 
envelopes will be generated by an unblinded statistician at Quotient according to 
Quotient’s SOPs. The unblinded statistician will not be involved in any decisions relating 
to populations for analysis prior to unblinding. Prior to database lock and unblinding, all 
original randomisation materials, including the original final signed and dated 
randomisation schedule, will be held by the Quality Assurance (QA) department at 
Quotient. The Data Sciences department will not have access to the randomisation 
schedule before database lock and unblinding.  
Interim PK parameter estimations will be performed using bioanalytical data applied with 
participant aliases in order to maintain the study blind.  
There may be instances where interim PK data have the potential to be treatment 
revealing e.g. missed blood sampling occasions. In these cases, every effort will be 
made by the pharmacokineticist to maintain the study blind by appropriate presentation 
of data to the study team. Data demonstrating extremes of exposure will always be 
presented, regardless of the potential to reveal the study blind. To permit selection of the 
dose level, individual data may be made available in full if judged necessary by the 
investigator or sponsor regardless of the potential to reveal study blind. 
The unblinded Qualified Person or designee at the clinical site will receive a copy of the 
final randomisation schedule for preparation of the study drug and preparation of the 
instructions to dispense and dose. A copy of the randomisation schedule will also be 
made available to the laboratory performing the bioanalysis to allow selective analysis of 
drug concentrations (for Parts 1 and 3) and to the pharmacovigilance provider for 
analysis of pharmacovigilance. 
Two sets of disclosure envelopes (i.e. sealed envelopes containing individual participant 
randomisation details) will be provided. One set will be held in the clinical area and the 
other retained in the ISF. These may be used in the event of an emergency by the 
investigator or delegate. Any request for information on the randomisation schedule after 
initial issue must be made using a randomisation disclosure form, except in the case of 
emergency unblinding, which must be recorded on the emergency unblinding form. 
Access to study drug assignment will be immediately available if the investigator deems 
it necessary to break the study blind in the interest of a participant’s medical safety, in 
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case of a medical emergency, or if warranted during scheduled safety reviews. The 
medical monitor must be contacted within 24 h following disclosure of study drug 
assignment.  
Details of any disclosure of the randomisation schedule will be documented and retained 
in the ISF. The sponsor will be notified if the study blind is broken. 
The study blind will be broken after the study database has been locked and the safety 
population has been defined. Any subsequent request for issue of the randomisation 
schedule prior to unblinding must be made using a randomisation disclosure form. 
Part 2 of the study is open-label and therefore blinding is not required. 
9 Selection of Participants 
Participants will be recruited from the Quotient panel or by direct advertising to the public.  
Before participants are admitted to the clinical unit, The Over Volunteering Prevention 
System will be checked to ensure that each participant has not been dosed in a study 
within 90 days of the planned first dosing date of this study. 
9.1 
Informed Consent 
Participants will be provided with a written explanation of the study at least the day before 
the screening visit. A physician or nurse will explain to each participant the nature of the 
study, its purpose, expected duration and the benefits and risks involved in study 
participation. Participants will be informed that, for safety reasons, brief details of their 
involvement in the study may be revealed to other units and companies that carry out 
clinical studies nationally. Participants will then be given the opportunity to ask questions 
and will be informed of their right to withdraw from the study without prejudice. After this 
explanation and before entering the study, the participant will voluntarily sign an ICF. 
Until written consent has been obtained from the participant no study specific procedure 
or investigation will be performed. If an amendment is made to the participant information 
sheet (PIS), participants will be re-consented to the most current version of the ICF(s) 
where appropriate. 
9.2 
Inclusion Criteria 
Informed Consent and Compliance 
1. Must provide written informed consent 
2. Must be willing and able to communicate and participate in the whole study 
Demographics and Contraception 
3. Aged 18 to 55 years inclusive at the time of signing informed consent 
4. Must agree to adhere to the contraception requirements defined in Section 9.4 
Baseline characteristics  
5. Healthy males or non-pregnant, non-lactating healthy females. 
6. Body mass index (BMI) of 18.0 to 32.0 kg/m2 as measured at screening  
7. Weight ≥50 kg at screening 
Inclusion criterion 5 from the list above will be re-assessed at admission/pre-dose on 
Day 1.  
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9.3 
Exclusion Criteria 
Medical/Surgical History and Mental Health 
1. Serious adverse reaction or serious hypersensitivity to any drug or the formulation 
excipients 
2. Presence or history of clinically significant allergy requiring treatment, as judged 
by the investigator. Hay fever is allowed unless it is active 
3. History of clinically significant cardiovascular, renal, hepatic, dermatological, 
chronic respiratory or gastrointestinal disease, neurological or psychiatric 
disorder, as judged by the investigator 
4. Blood pressure (supine) at screening or admission outside the range of 90 to 
140 mmHg systolic or 50 to 90 mmHg diastolic; and pulse rate outside the range 
of 45 to 100 bpm, unless deemed not clinically significant by the investigator 
5. A decrease of SBP ≥20 mmHg after 3 min standing and/or a decrease of DBP 
≥10 mmHg after 3 min standing, at screening (applies to Part 1 and Part 3 only) 
6. History or presence of known structural cardiac abnormalities, family history of 
long QT syndrome, cardiac syncope or recurrent, idiopathic syncope, exercise 
related clinically significant cardiac events. Any clinically significant abnormalities 
in rhythm, conduction or morphology of resting ECG or clinically important 
abnormalities that may interfere with the interpretation of QT interval changes  
7. Presence of sinus node dysfunction, clinically significant PR interval prolongation 
(>210 msec), intermittent second- or third-degree atrioventricular block, complete 
bundle branch block, sustained cardiac arrhythmias including (but not limited to) 
atrial fibrillation or supraventricular tachycardia; any symptomatic arrhythmia with 
the exception of isolated extra systoles, abnormal T wave morphology which may 
impact on the QT/QTc assessment, or QTcF >450 msec. Participants with 
borderline abnormalities may be included if the deviations do not pose a safety 
risk, and if agreed between the sponsor’s medical monitor and the investigator 
8. Participants with a history of cholecystectomy or gall stones 
9. Participants with conditions that affect their ability to smell or taste (Part 1 only) 
including, but not limited to mouth ulcers, gum disease, nasal surgery and smell 
and/or taste disorders (e.g. dysosmia, dysgeusia, respiratory and/or sinus 
infection or cold)  
Physical Examination 
10. Participants 
who 
do 
not 
have 
suitable 
veins 
for 
multiple 
venepunctures/cannulation as assessed by the investigator or delegate at 
screening 
Diagnostic assessments 
11. Evidence of current SARS-CoV-2 infection 
12. Clinically significant abnormal clinical chemistry, haematology, coagulation or 
urinalysis as judged by the investigator (laboratory parameters are listed in 
Appendix 1). Participants with Gilbert’s Syndrome are not allowed.  
13. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) 
or human immunodeficiency virus (HIV) 1 and 2 antibody results 
14. Females who are pregnant or lactating (all female participants must have a 
negative highly sensitive serum pregnancy test at screening and a negative urine 
pregnancy test at admission) 
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Prior Study Participation 
15. Participants who have received any IMP in a clinical research study within the 
90 days prior to Day 1, or less than 5 elimination half-lives prior to Day 1, 
whichever is longer 
16. Participants who have previously been administered IMP in this study. 
Participants who have taken part in Part 1 are not permitted to take part in Parts 2 
and 3 and participants who have taken part in Part 2 are not permitted to take part 
in Part 3 
17. Donation of blood or plasma within the previous 3 months or loss of greater than 
400 mL of blood 
Prior and Concomitant Medication 
18. Participants who are taking, or have taken, any prescribed or over-the-counter 
drug or herbal remedies (other than up to 4 g of paracetamol per day, hormonal 
contraception or HRT) in the 14 days before first IMP administration (see 
Section 11.4) 
19. Participants who have received a COVID-19 vaccine within 7 days before first IMP 
administration 
Lifestyle Characteristics 
20. History of any drug or alcohol abuse in the past 2 years 
21. Regular alcohol consumption in males >21 units per week and females >14 units 
per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units = 
125 mL glass of wine, depending on type) 
22. A confirmed positive alcohol breath test at screening or admission 
23. Current smokers and those who have smoked within the last 12 months. A 
confirmed breath carbon monoxide reading of greater than 10 ppm at screening 
or admission 
24. Current users of e-cigarettes and nicotine replacement products and those who 
have used these products within the last 12 months 
25. Confirmed positive drugs of abuse test result (drugs of abuse tests are listed in 
Appendix 1) 
26. Participant with a vegan or vegetarian diet (Part 2 only)  
Other 
27. Male participants with pregnant or lactating partners 
28. A score of 20 or more on the Beck Depression Inventory (BDI-II), and/or a 
response of 1, 2 or 3 for item 9 of this inventory (related to suicidal ideation) [7]. 
Note, individuals with a BDI-II score of 17-19 may be enrolled, at the discretion of 
the investigator, if they do not have a medical history of psychiatric conditions 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 
29. Participants who are, or are immediate family members of, a study site or sponsor 
employee 
30. Failure to satisfy the investigator of fitness to participate for any other reason 
Exclusion criteria 2, 4, 6, 7, 11, 12, 14, 15, 16, 18, 19, 22, 23, 25, 27, 28 and 30 from the 
list above will be re-assessed at admission/pre-dose on Day 1.  
Healthy participants who do not meet the inclusion/exclusion criteria for the study will not 
be enrolled. 
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9.4 
Contraception and Restrictions 
Male Participants with Partners of Childbearing Potential 
Male participants who are sexually active with a partner of childbearing potential must 
use, with their partner, a condom plus an approved method of highly effective 
contraception from the time of informed consent until 94 days after the last IMP 
administration. This has been calculated based on 90 days (one cycle of 
spermatogenesis) plus 5 half-lives of the IMP. Five half-lives (based on predicted human 
half-life of 19 h) has been calculated as 4 days. 
The following methods are acceptable: 
• 
Partner’s use of combined (oestrogen and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation:  
− oral  
− intravaginal  
− transdermal  
• 
Partner’s use of progestogen-only hormonal contraception associated with inhibition 
of ovulation:  
− oral  
− injectable/implantable 
− intrauterine hormone-releasing system  
• 
Partner’s use of intrauterine device  
• 
Vasectomised 
• 
Partner’s bilateral tubal occlusion 
These contraception requirements are considered to be more conservative than the 
guidance issued by the Heads of Medicines Agency: Clinical Trials Facilitation Group [8]. 
Males with Partners of Non-childbearing Potential 
There is a significant risk of drug exposure through the ejaculate (which also applies to 
vasectomised males) that might be harmful to sexual partners. Therefore, even if a male 
is sexually active with a partner of non-childbearing potential, they will be required to use 
a condom from first administration of IMP until after the end of study visit from the study. 
Female Participants of Childbearing Potential 
Female participants who are sexually active and of childbearing potential must use, with 
their partner, a double method of contraception, consisting of a highly effective method 
of birth control combined with a barrier contraceptive (condom) from the time of informed 
consent until 34 days after last IMP administration. This has been calculated based on 
30 days (one female menstrual cycle) plus 5 half-lives of the IMP. Five half-lives has 
been calculated as 4 days. 
The following highly effective methods are acceptable: 
• 
Combined (oestrogen and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation:  
− oral  
− intravaginal  
− transdermal  
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
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− oral  
− injectable/implantable 
− intrauterine hormone-releasing system  
• 
Intrauterine device  
• 
Vasectomised partner 
• 
Bilateral tubal occlusion 
Female Participants are not required to use any of the above contraceptive methods if 
their sexual partner is female. 
These contraception requirements are considered to be more conservative than the 
guidance issued by the Heads of Medicines Agency: Clinical Trials Facilitation Group [7]. 
All Participants (Male and Female Participants of Childbearing Potential) 
Alternatively, sexual abstinence is considered a highly effective method only if defined 
as refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the 
participant. 
Females of Non-Childbearing Potential  
Female participants who are not of childbearing potential do not need to use any 
methods of contraception. A woman is considered of childbearing potential unless 
postmenopausal or permanently sterile. Permanent sterilisation methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A post-menopausal 
state is defined as no menses for 12 months without an alternative medical cause and 
confirmed by a follicle-stimulating hormone (FSH) result of ≥40 IU/L. 
9.4.1 Sperm Donation 
Male participants should not donate sperm for the duration of the study and for 94 days 
after last IMP administration.  
9.4.2 Egg Donation 
Female participants should not participate in egg donation from dosing, for the duration 
of the study and for at least 34 days after last IMP administration.  
9.5 
Pregnancy 
Participants will be instructed that if they/their partner becomes pregnant during the study 
or up to 3 months after final dose, this should be reported to the investigator. The 
investigator should also be notified of pregnancy occurring during the study but 
confirmed after completion of the study. In the event that a participant/participant’s 
partner is subsequently found to be pregnant after the participant is included in the study, 
then consent will be sought from the participant/partner and, if granted, any pregnancy 
will be followed and the status of mother and/or child(ren) will be reported to the sponsor 
after delivery. Any participant reporting a pregnancy during the study will be discontinued 
from the study treatment and every reasonable effort will be made by Quotient to follow 
up the pregnancy until delivery. 
A pregnancy notification form and follow-up will be completed. 
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9.6 
Additional Study Restrictions 
The following additional restrictions will be in place for the duration of the study: 
1. Participants must abstain from alcohol during the 24 h prior to screening and the 
24 h prior to admission until after the end of study visit  
2. Participants must not drink liquids or eat food containing grapefruit, cranberry, 
caffeine or other xanthines from 24 h prior to admission until after the end of study 
visit 
3. Participants should refrain from eating food containing poppy seeds for 48 h prior 
to screening and for 48 h prior to admission until after the end of study visit 
4. Participants must not take part in any unaccustomed strenuous exercise from the 
72 h before the screening visit and then from 72 h prior to admission until after the 
end of study visit 
5. Must not donate blood or plasma (outside of this study), from clinical unit 
admission, throughout the study duration, and for at least 90 days following last 
dose of study medication 
The additional restrictions above are not exclusion criteria; if non-compliance occurs, a 
protocol deviation will be completed.  
10 Study Procedures 
Study procedures will be performed as detailed in the study schedule of assessments in 
Appendix 2, Appendix 3 and Appendix 4, Appendix 5, Appendix 6 and Appendix 7, and 
in accordance with Quotient’s SOPs unless otherwise stated in this protocol. 
10.1 Screening 
Within the 28 days preceding first dose, all participants will be required to undergo a 
screening visit. Screening procedures will be carried out in accordance with the schedule 
of assessments in Appendix 2, Appendix 3 and Appendix 4. 
If the start of the study is delayed for any reason so that the interval between screening 
and first dose exceeds 28 days, all or part of the screening procedures will be repeated 
at the discretion of the investigator. 
Screening safety procedures such as safety bloods, ECGs, vital signs, carbon monoxide 
breath tests, alcohol breath tests and urinalysis can be repeated as clinically indicated 
under the discretion of the investigator or sub-investigator if there is a concern regarding 
a participant’s safety or eligibility to participate in the trial. 
10.1.1 Participant Re-Screening 
This study permits the re-screening of a participant who has discontinued the study as a 
pre-treatment failure (i.e. participant has not been randomised); the reason for failure 
must be temporary and expected to resolve. If re-screened, the participant must be 
re-consented. 
10.2 Admission and Pre-dose Procedures 
The identity of the participants will be confirmed at admission and pre-dose.  
In addition, the ongoing eligibility of participants will be re-assessed at 
admission/pre-dose, as described in Sections 9.2 and 9.3.  
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Admission/pre-dose safety procedures such as safety bloods, ECGs, vital signs, 
urinalysis, pregnancy and drugs of abuse tests can be repeated as clinically indicated 
under the discretion of investigator or sub-investigator if there is a concern regarding a 
participant’s safety or eligibility to participate in the clinical trial. 
Reserve participants for the first dose occasion, in any group, will not require admission 
procedures to be repeated, if dosing is within 2 days.  
If dosing is delayed, participants who have completed admission procedures do not need 
admission procedures to be repeated if dosing is within 2 days and the participants have 
remained resident in the clinical unit. 
The participants will be admitted to the clinical unit on the morning before dosing 
(Day -1).  
In addition, participants may be required to visit the clinical unit on Day -1 prior to 
admission to the clinical unit for SARS-CoV-2 antigen tests (if required; see 
Sections 6.4.2.2 and 14.5.8). Test results must be available prior to dosing. 
The admission and pre-dose procedures are presented in Appendix 2, Appendix 3 and 
Appendix 4. 
10.3 Study Day Procedures 
10.3.1 Blood Volume 
The number and timing of samples may be amended following any interim PK parameter 
estimations. However, in this case, the total blood volume for each participant will not 
exceed 550 mL in a 4-week period.  
The first 0.5 mL of blood withdrawn via cannula will be discarded. 
10.3.2 Timing of Procedures 
There are times where the protocol requires more than one procedure to be completed 
at the same time point. In these instances, the following will apply to post-dose time 
points: 
• 
PK samples should take priority (i.e. taken at the nominal time point) over other 
procedures scheduled at the same time point 
• 
Resting periods will be completed prior to ECGs and no other procedures will be 
performed within this time window 
• 
ECGs should be taken prior to vital signs when both measurements are scheduled 
at the same time point  
• 
Other assessments, e.g. physical examinations, will be performed within the required 
time windows 
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As guidance, where Holter resting periods coincide with other procedures i.e. vital signs 
and ECGs the order of procedures will be: 
Resting 
period 
 
ECGs 
 
Holter 
Extraction or 
ECG Machine 
 
Vitals  
 
PK blood 
sampling 
(nominal 
time) 
 
Other 
assessments 
e.g. physical 
examinations 
 
The Holter recording will be initiated before IMP dosing to allow for extraction of baseline 
ECGs. Then, before each PK time point, a rest period of approximately 15 min will be 
applied to ensure reasonable heart rate stability to allow extraction from the Holter 
recording or triplicate machine ECGs. 
All safety assessments will be timed and performed relative to the start of dosing. 
10.3.3 Discharge from the Clinical Unit 
A participant will be allowed to leave the premises without additional investigator or 
sub-investigator review, following completion of study-specific procedures at 96 h 
post-dose (Part 1)/post-final dose (Parts 2 and 3), providing that: 
• 
No AEs have been reported during the study visit  
• 
The participant responds in the affirmative when asked if they are feeling well 
If any of these conditions are not met, then the participant will only be allowed to leave 
the clinical unit with the authorisation of the investigator or sub-investigator. 
There will be no continued provision of the study intervention or treatment for participants 
as this study involves healthy volunteers only. 
10.3.4 Return Visits 
Participants will be required to return to the clinical unit on Day 7 in Part 1 for the 
assessments described in Appendix 2 and on Day 9 in Part 3 for the assessments 
described in Appendix 4. The acceptable deviations for the return visit PK, vital signs 
and ECG assessments are described in Sections 13.1.1, 14.6 and 14.7, respectively. 
10.3.5 End of Study Visits 
Participants will be required to return to the clinical unit for end of study assessments on 
Day 15 (± 1 day) in Part 1 (as described in Appendix 2), on Day 14 (± 1 day) in Part 2 
(as described in Appendix 3), and on Day 17 (± 1 day) in Part 3 (as described in 
Appendix 4). The acceptable deviations for the end of study visit PK, vital signs and ECG 
assessments are described in Sections 13.1.1, 14.6 and 14.7, respectively. 
10.3.6 Medical Supervision 
A physician will be responsible for the clinical aspects of the study and will be available 
at all times during the study. In accordance with the current Association of the British 
Pharmaceutical Industry guidelines [9], each participant will receive a card stating the 
telephone number of the investigator and the 24/7 contact details of the Quotient’s on-call 
physician. 
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10.3.7 Follow-up 
If a participant reports an SAE in the 30 days after the end of study visit, they may be 
required to attend the clinical unit for a further follow-up assessment (as an unscheduled 
visit). Completion of the last discharge assessment or unscheduled follow-up visit will be 
considered the end of the study. 
11 Dosing of Participants 
11.1 Food and Fluid Intake 
Participants will be allowed water up to 1 h before the scheduled dosing time and will be 
provided with 240 mL of water at 1 h post-dose (to ensure adequate hydration), and 
thereafter, water will be allowed ad libitum. Decaffeinated fluids will be allowed ad libitum 
from lunch time on the day of dosing. 
If, for technical reasons, dosing is delayed for more than 2 h beyond the expected dosing 
time, participants will receive 200 mL of an electrolyte drink (e.g. Lucozade Sport) at the 
originally scheduled dosing time, or earlier if possible. 
Fed Dosing: Part 2, Fed Period 
The calorie/fat content of breakfast will be controlled on the fed dosing day (refer to 
Appendix 8 for breakfast content). Participants will be provided with a standardised menu 
for all other meals.  
For the fed regimen, a standard high-fat breakfast will be given 30 min before dosing. 
Participants will be provided with a light snack the evening prior to dosing and will fast 
from all food and drink (except water) until the following morning, when they will be 
provided with a standard high-fat breakfast.  
The breakfast should be consumed over a maximum period of 25 min, with dosing 
occurring 30 min after the start of breakfast. Participants should be encouraged to eat 
their meal evenly over the 25 min period. It is acknowledged that some participants will 
take less time to eat, but dosing should still occur 30 min after the start of breakfast. 
Participants must consume at least 90% of the pre-dose breakfast in order to eligible for 
dosing. The start and stop time and percentage of the breakfast consumed must be 
recorded in the source.  
The acceptable deviation for the pre-dose meal from the nominal time point is: 
• 
Pre-dose meal will be provided within ± 5 min of the nominal time point  
Lunch will be provided at approximately 4 h post-dose, an evening meal at approximately 
10 h post-dose and an evening snack at approximately 14 h post-dose. On subsequent 
days, meals will be provided at appropriate times. 
Fasted Dosing (Parts 1 and 3 and Part 2, Fasted Period) 
The calorie/fat content of meals are not required to be controlled. Participants will be 
provided with a standardised menu.  
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Participants will be provided with a light snack the evening prior to dosing and then fast 
from all food and drink (except water) for a minimum of 8 h on the day prior to dosing 
until approximately 4 h post-dose, at which time lunch will be provided. An evening meal 
will be provided at approximately 10 h post-dose and an evening snack at approximately 
14 h post-dose. 
On subsequent non-dosing days, meals will be provided at appropriate times. 
11.2 Administration of Test Preparations 
Specific details of the IMP, and doses to be administered are provided in Section 5.2 and 
Section 8.1, respectively. In Parts 1 and 2, participants will be dosed on the morning of 
Day 1 of each study period, as applicable. In Part 3, participants will be dosed on the 
morning of Days 1, 2 and 3.  
The exact time of dosing will be decided based on logistics and will be documented in 
the source. If appearance matching of the placebo is not possible then masking and/or 
unblinded dosing teams will be used to preserve the study blind. Further details of these 
steps will be contained in the study specific blinding plan, which will be approved prior to 
dosing (see also Section 8.8.2). 
For Part 3, the acceptable deviation for dose administrations from the nominal time point 
is: 
• 
Days 2 and 3 dose will be administered within ± 30 min of the nominal dosing 
time point, relative to the dosing time on Day 1 
It is planned that each dose level (Parts 1 and 3) will be administered in a staggered 
‘sentinel’ dose design. All groups will be split into two subcohorts; in Cohort Xa, one 
participant will receive active IMP and one participant will receive placebo; in Cohort Xb, 
five participants will receive active IMP, and one participant will receive placebo, where 
X indicates the number of the cohort. 
Participants in Part 1 will receive a single dose of MMV367 or matching placebo. 
Participants in Part 2 will receive a single dose of MMV367 on 2 separate occasions: 1 in 
the fed state and 1 in the fasted state, in a crossover design. Participants in Part 3 will 
receive three doses of MMV367 or matching placebo QD over 3 consecutive days.  
The IMP will be dispersed in sterile water. Immediately after administration of the oral 
solution, the dosing vessel will be rinsed with water and participants will consume the 
rinse solution. During dosing, participants will consume up to a maximum total volume of 
500 mL (including the dosing volume and volume of water used to rinse the dosing 
vessel) depending on the dose level. If required, additional water may be given with the 
IMP in 50 mL aliquots and will be recorded in the source but will not be classed as a 
protocol deviation. 
In Part 1 only, each participant will test the taste and palatability of the IMP (single dose 
on Day 1). The IMP will be held in the mouth and swirled for 10 to 15 sec before 
swallowing. The participant will subsequently complete a written palatability 
questionnaire individually and privately. Participants will receive training on admission 
(see Section 8.1.1) before the palatability test/dosing. Participants will be allowed to 
cleanse their palates using tap water (administered freely in 50 to 100 mL aliquots) 
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before tasting the IMP. During the taste test, participants will be observed by study staff 
to assure compliance.   
11.3 Dosing Compliance 
During all clinical phases of the study, participants will be observed by study staff to 
assure compliance to all study procedures, including dose administration.  
Mouth checks will be conducted after dosing to ensure the solution has been swallowed. 
The date and time that each participant is dosed will be recorded in the participant’s 
source data. Any violation of compliance will require evaluation by the investigator and 
sponsor to determine if the participant can continue in the study. 
11.4 Prior and Concomitant Medications 
No prescribed, over-the-counter medication or herbal remedies will be permitted from 
14 days before IMP administration until after the end of study visit, except up to 4 g of 
paracetamol per day, hormonal contraception and HRT and those deemed necessary 
by the investigator to treat AEs (see also Section 9.3). Any medications used will be 
recorded in the source. 
COVID-19 vaccines are not accepted concomitant medications. Participants will be 
excluded if they have received the vaccine within 7 days prior to first administration of 
IMP so that by the time of dosing any effects of the vaccine (e.g. pyrexia, fatigue, 
pain/stiffness at site of injection) are likely to have abated, and vaccines will be prohibited 
until discharge from the study. 
Emergency equipment and drugs will be available within the clinical unit as per current 
standard procedures. In the unlikely event that they are required, their use will be 
documented. 
12 Assessment of Efficacy 
Not applicable for this Phase I study.  
13 Assessment of Pharmacokinetics, Metabolite Identification 
and Pharmacodynamics 
13.1 Assessment of Pharmacokinetics and Metabolite Identification 
13.1.1 Blood Sampling for Pharmacokinetics and Metabolite Identification 
Venous blood samples will be collected from the participants by a trained member of the 
clinical team. Consent will be collected from the participants for use of these samples for 
the purposes of the proposed study. Samples will be processed to isolate plasma and 
PK analysis and metabolite identification, where appropriate, will be carried out on 
plasma samples. 
Plasma samples will be sent for laboratory testing in linked anonymised form (participant 
number only). This information is able to be linked directly to the volunteer by the 
Quotient research team and study monitor, however not by the laboratory staff or 
sponsor. 
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Venous blood samples will be withdrawn via an indwelling cannula or by venepuncture 
according to the time schedules presented in Appendix 5, Appendix 6 and Appendix 7. 
All PK windows will be timed relative to the start of dosing and actual sampling times will 
be recorded. 
The acceptable deviations from the nominal blood sampling times are as follows: 
• 
Day 1 in all parts and Day 8 in Part 2: The pre-dose samples will be taken ≤15 min 
before dosing 
• 
On Days 2 and 3 (Part 3 only): The 24 h time point will coincide with the pre-dose 
sample; samples will be taken ≤10 min of the nominal time point 
• 
0 to 1 h post-dose samples will be taken within ± 2 min of the nominal post-dose 
sampling time  
• 
2 to 12 h post-dose samples will be taken within ± 10 min of the nominal post-dose 
sampling time 
• 
24 to 96 h post-dose samples will be taken within ± 30 min of the nominal post-dose 
sampling time if participants are resident in the clinical unit 
• 
≥144 h post-dose samples will be taken within ± 2 h of the nominal post-dose 
sampling time if participants are attending a return visit 
• 
On Day 14 (Part 2 only): The End of Study sample will be taken within ± 1 day of the 
nominal post-dose sampling time point 
The timing and number of the samples may be amended following any interim PK 
parameter estimations, including collection over a longer duration. Any changes to blood 
sampling time points would be documented in the interim dose decision report and 
retained in the ISF. 
Samples will be collected into appropriate tubes as specified by the bioanalytical 
laboratory. Details of sample tubes and processing will be contained in the 
Clinical Sample Processing Manual (CSPM). 
Samples will be shipped to Swiss BioQuant for the analysis of MMV367 and, where 
appropriate, metabolite(s). 
13.1.2 Urine Sampling for Pharmacokinetics and Metabolite Identification 
Urine samples will be collected in Part 1, Cohorts 1C and 1D, according to the time 
schedule presented in Appendix 5, provided a future bioanalytical method will be 
available. 
The pre-dose urine sample will be taken in the 24 h period before dosing. Where a 
sample is not provided, this will not be considered a deviation. All individual urine voids 
will be collected and shipped to the bioanalytical laboratory for analysis, according to 
Quotient’s SOPs, unless indicated otherwise by the sponsor. 
Consent will be collected from the participants for use of these samples for the purposes 
of the proposed study. Samples will be collected into appropriate containers as specified 
by the bioanalytical laboratory. Details of sample containers and processing will be 
contained in the CSPM. 
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Urine samples will be sent for laboratory testing in linked anonymised form (participant 
number). This information is able to be linked directly to the volunteer by the Quotient 
research team and study monitor; however, not by the laboratory staff or sponsor. 
Samples will be shipped to Swiss BioQuant for the analysis of MMV367 and 
metabolite(s). 
13.2 Assessment of Pharmacodynamics 
Not applicable for this Phase I study. 
13.3 Taste/Palatability Evaluation 
Taste/Palatability will be assessed in Part 1 using a questionnaire (example provided in 
Appendix 9) at the time points detailed in Appendix 2. The questionnaire will ask 
participants to rate the overall acceptability of taste/palatability, with additional questions 
asked on specific palatability attributes (smell, sweetness, bitterness, flavour, mouth 
feel/texture, grittiness, and aftertaste), on a 9-point Likert scale. The clinical staff will 
provide definitions and examples of each aspect that is being rated if required. 
Each participant in Part 1 of the study will complete the questionnaire individually and 
privately, within no more than 10 min, following IMP administration. 
14 Assessment of Safety 
14.1 Definition and Classification of Adverse Events 
An AE is any untoward medical occurrence in a participant that occurs either before 
dosing (referred to as a pre-dose AE) or once a medicinal product has been 
administered, including occurrences which are not necessarily caused by or related to 
that product.  
An adverse drug reaction is any AE where a causal relationship with the IMP is at least 
a reasonable possibility (related). 
AEs will be monitored from the time the participant signs the ICF until the end of study 
visit. The severity of AEs should be assessed as follows: 
Mild 
An AE that is easily tolerated by the participant, causes minimal discomfort 
and does not interfere with everyday activities 
Moderate An AE that is sufficiently discomforting to interfere with normal everyday 
activities; intervention may be needed 
Severe 
An AE that prevents normal everyday activities; treatment or other 
intervention usually needed 
14.2 Assessment of Assessment of Causality 
Every effort should be made by the investigator to try to explain each AE and assess its 
relationship, if any, to the IMP. The temporal relationship of the event to IMP 
administration should be considered in the causality assessment (i.e. if the event starts 
soon after IMP administration and resolves when the IMP is stopped). 
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Causality should be assessed using the following categories: 
Unrelated: 
An AE which cannot be reasonably explained by available facts (evidence) or arguments 
that the study drug caused the AE. For example, the occurrence of the AE can be 
explained by other causative factors, such as: 
• 
Event attributed to concomitant medication. 
• 
No reasonably temporal relationship associated with IMP administration  
• 
Event is expected in the study indication and/or target population 
• 
Negative de-challenge and/or negative re-challenge 
• 
Other (must be specified) 
Related: 
An AE for which it can be reasonably explained that the study drug caused the AE by 
available facts (evidence) or arguments. For example, the occurrence of the AE cannot 
be explained by other causative factors, but can be explained by pharmacological effect 
of the study drug such as: 
• 
Temporal relationship to IMP exposure 
• 
Event is known to be associated with the IMP drug class 
• 
Event improved on discontinuation or dose reduction of IMP 
• 
Biological plausibility 
• 
Other (must be specified on the source documents) 
 
The degree of certainty with which an AE is attributed to IMP administration (or 
alternative causes, e.g. natural history of the underlying disease, concomitant therapy) 
will be determined by how well the experience can be understood in terms of one or more 
of the following: 
• 
Known pharmacology of the IMP 
• 
Reactions of a similar nature have been previously observed with the IMP or this 
class of drug 
• 
The experience being related by time to IMP administration, terminating with IMP 
withdrawal or recurring on re-challenge 
• 
Alternative cause 
14.3 Recording Adverse Events 
AEs (including SAEs) will be recorded from the time of providing written informed consent 
until the end of study visit or unscheduled follow-up visit. During each study visit the 
participant will be questioned directly regarding the occurrence of any adverse medical 
event according to the schedule in the source. All AEs, whether ascribed to study 
procedures or not, will be documented immediately in the participant’s source. This will 
include the date and time of onset, a description of the AE, severity, seriousness, 
duration, actions taken, outcome and an investigator’s current opinion on the relationship 
between the study drug and the event. A diagnosis and final opinion on the relationship 
between the study drug and the event will be provided at the end of the study by the 
investigator.  
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Any participant who withdraws from the study due to an AE will be followed up until the 
outcome is determined and written reports are provided by the investigator. 
14.4 Serious Adverse Events 
14.4.1 Definition of Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at 
any dose:  
• 
Results in death 
• 
Is life-threatening 
• 
Requires hospitalisation or prolongation of existing hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Consists of a congenital anomaly or birth defect 
• 
An important medical event as recognised by the investigator 
SAEs must be immediately reported to the sponsor. 
Spontaneously reported SAEs will be collected until 30 days following the final study 
visit. SAEs experienced after this 30-day period will only be reported if the investigator 
suspects a causal relationship with the study drug. 
14.4.2 Definition of Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are believed 
to be related to an IMP and are both unexpected (i.e. the nature or severity is not 
expected from the information provided in the IB) and serious. SUSARs are subject to 
expedited reporting to the MHRA and EC (see Section 16.3.2 for details on reporting 
SUSARs). 
14.4.3 Expectedness (Reference Safety Information) 
The Reference Safety Information is used for the assessment of the expectedness of all 
‘suspected’ serious adverse reactions (SARs) that occur in clinical trials. The 
expectedness of a SAR is determined by the sponsor. The list of ‘expected SARs’ should 
be based on ‘suspected’ SARs that were previously observed and not on the basis of 
what might be anticipated from the pharmacological properties of a medicinal product or 
the compound class. An ‘expected’ SAR is therefore one that is listed in the Reference 
Safety Information. An adverse reaction, the nature of which is not consistent with the 
applicable reference safety information (in the IB for drugs in clinical development or 
SmPC for marketed drugs) is unexpected. Reports which add significant information on 
the specificity, increase in the occurrence or severity of a known and already 
documented SAR are unexpected events. 
14.5 Laboratory Measurements 
Venous blood and urine samples will be collected from the participants by a trained 
member of the clinical team. Consent will be collected from the participants for use of 
these samples for the purposes of the proposed study. 
Blood and urine samples are sent for laboratory testing in linked anonymised form 
(participant number, gender and date of birth for analytical reasons). This information is 
able to be linked directly to the volunteer by the Quotient research team and study 
monitor; however, not by the laboratory staff or sponsor. 
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Safety laboratory tests and virology will be carried out on blood samples, and drugs of 
abuse tests and urinalysis will be carried out on urine samples. Blood samples will be 
collected for DNA analysis, as detailed in Section 14.5.9. 
Blood and urine samples results will be reviewed by a physician and acted upon before 
the participant is dosed or receives their next dose, or is released from the study, as is 
appropriate. A list of the laboratory parameters measured is presented in Appendix 1. 
14.5.1 Haematology, Clinical Chemistry and Coagulation 
Laboratory tests will be performed by The Doctors Laboratory according to the time 
schedules presented in Appendix 5, Appendix 6 and Appendix 7. Blood samples will be 
collected and processed as detailed in the CSPM. Scheduled blood samples will be 
taken following an 8 h fast. 
The acceptable deviations from the nominal blood sampling time points for laboratory 
assessments are: 
• 
Post-dose/post-first dose blood samples will be taken ± 1 h from the nominal blood 
sampling time 
• 
End of Study blood samples will be taken ± 1 day from the nominal blood sampling 
time 
Creatinine clearance (CLcr) will be calculated at admission by The Doctors Laboratory 
using the Cockcroft-Gault equation [10] and body weight. Results of this assessment will 
be used for PK analysis and PK-PD modelling (reported separately). 
14.5.2 Urinalysis 
Urinalysis will be performed on-site using a dipstick according to the time schedules 
presented in Appendix 2, Appendix 3 and Appendix 4.  
Urine samples will be collected and processed as detailed in the CSPM.  
In Part 1, any urine used for urinalysis will be added back to the full sample for PK and 
metabolite identification analysis. If microscopy is required, a urine sample 
(approximately 20 mL) will be taken from the urine PK and metabolite collection, and 
sent to The Doctor’s Laboratory, after the void has been weighed. 
In Parts 2 and 3, if microscopy is required, a urine sample will be sent to The Doctor’s 
Laboratory. 
The acceptable deviations from the nominal urine sampling time points for urinalysis are: 
• 
On Day 3 (Part 3 only): the pre-dose urine sample will be taken ≤1 h before dosing.  
• 
Post-dose urine samples will be taken ± 2 h from the nominal urine sampling time 
• 
End of Study urine samples will be taken ± 1 day from the nominal urine sampling 
time 
14.5.3 Pregnancy Test 
Serum and urine highly sensitive pregnancy tests will be performed as detailed in 
Appendix 2, Appendix 3 and Appendix 4. The samples will be collected and processed 
as detailed in the CSPM.  
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14.5.4 Follicle-Stimulating Hormone Test 
Serum FSH tests will be performed as detailed in Appendix 2, Appendix 3 and 
Appendix 4. The samples will be collected and processed as detailed in the CSPM. 
14.5.5 Drug Screen 
A urine drug screen will be performed on-site using a point of care testing method 
(e.g. Alere Drug Screen Test Cup) according to the time schedules presented in 
Appendix 2, Appendix 3 and Appendix 4. The sample will be collected and processed as 
detailed in the CSPM. Participants will be screened for the drugs of abuse listed in 
Appendix 1.  
14.5.6 Alcohol Breath Test 
An alcohol breath test will be performed according to the time schedules presented in 
Appendix 2, Appendix 3 and Appendix 4. A positive result will exclude the participant 
from dosing. 
14.5.7 Carbon Monoxide Breath Test 
A carbon monoxide breath test will be performed according to the time schedules 
presented in Appendix 2, Appendix 3 and Appendix 4. A result of greater than 10 ppm 
will exclude the participant from the study. 
14.5.8 SARS-CoV-2 Tests 
Testing for the SARS-CoV-2 virus will be performed at screening and admission and may 
be performed at other time points, if required, based on current infection rates and 
availability of tests. Tests will be performed according to the time schedules presented 
in Appendix 2, Appendix 3 and Appendix 4. The samples will be collected and processed 
as detailed in the Screening Sample Processing Manual and CSPM. 
Testing time points may be changed and additional time points may be added throughout 
the study as required. The decision on COVID-19 testing and the definition of the testing 
time points are subject to change based on the current risk mitigation in place and will 
be agreed by the study team and documented in the ISF via the Clinical Kick-Off Meeting 
minutes. 
14.5.9 Genetic Samples 
In Part 1, Part 2 (Period 1 only) and Part 3, one mandatory blood sample per participant 
will be collected on Day 1 prior to IMP administration (≤2 h before dosing) to investigate 
allelic variants related to drug metabolism cytochrome P450 (CYP) enzymes and drug 
transporters that are potentially involved in the MMV367 absorption, distribution, 
metabolism and excretion. 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 last participant visit. The blood sample and 
extracted DNA will be destroyed either upon completion of analysis or when it is 
confirmed that they will not be required for analysis. 
The sample will be collected and processed as detailed in the CSPM. 
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14.5.10 
Abnormal Laboratory Findings 
In cases where laboratory findings are outside the normal range and the investigator 
believes that the results may be of clinical significance, repeat sampling may be 
requested as clinically indicated. If the abnormal finding is clinically significant, 
appropriate actions will be taken e.g. the participant will not be entered into the study or 
the participant may be withdrawn from the study. The participant will be referred to their 
general practitioner or other appropriate provider for further care if necessary. The same 
will apply if the results of the HBsAg, HCV Ab or HIV test are positive and in addition the 
investigator will ensure that adequate counselling is available if requested. 
Abnormal results at any unscheduled follow-up assessments will also require repeat 
testing if the investigator believes the results may be of clinical significance. 
Any clinically significant abnormality, including changes from baseline, must be reported 
as an AE. 
Additional blood and/or urine samples may be taken for safety tests. Furthermore, 
additional assays outside those specified in the protocol may be performed for safety 
reasons as requested by the investigator or sub-investigator. 
14.6 Vital Signs Measurements 
Blood pressure and heart rate will be measured by an automated recorder after the 
participant has been in a supine position for a minimum of 5 min and oral temperature 
and respiratory rate will be measured according to the time schedules presented in 
Appendix 2Appendix 5, Appendix 6 and Appendix 7.  
Blood pressure and heart rate orthostatic measurements will also be taken according to 
the time schedules presented in Appendix 5, Appendix 6 and Appendix 7. Two 
measurements will be recorded; 1 supine and 1 standing. The first supine measurement 
will be performed after the participant has rested in a supine position for at least 5 min. 
The second blood pressure and heart rate measurements will be performed after the 
participant has been standing for at least 3 min but no more than 5 min. Orthostatic 
hypotension will be defined as either: 
• 
A decrease of SBP ≥ 20 mmHg after 3 min standing, or 
• 
A decrease of DBP ≥ 10 mmHg after 3min standing 
The acceptable deviations from the nominal vital signs measurement time points are: 
• 
Day 1 in all parts and Day 8 in Part 2: The pre-dose vital signs measurements will be 
taken ≤2 h before dosing 
• 
On Days 2 and 3 (Part 3 only): the pre-dose vital signs measurements will be taken 
≤1 h before dosing.  
• 
Post-dose vital signs measurements will be taken ± 15 min from the nominal 
post-dose time point. 
• 
For return visits, vital signs measurements will be taken ± 2 h from the nominal return 
visit time point. 
• 
End of study visit vital signs measurements will be taken ± 1 day from the nominal 
time point. 
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If a participant shows an abnormal assessment at any stage, repeat measurements may 
be made and the abnormality followed to resolution if required. Additional measurements 
may be taken as deemed necessary by the investigator or sub-investigator.  
Any clinically significant abnormality, including changes from baseline, must be reported 
as an AE. 
14.7 ECG Measurements 
Single 12-lead ECGs will be measured after the participant has been in the supine 
position for a minimum of 5 min according to the time schedules presented in Appendix 5, 
Appendix 6 and Appendix 7. 
Triplicate 12-lead ECG measurements will be performed at least 2 min and no longer 
than 4 min apart after the participant has been in the supine position with no external 
stimuli (e.g. music or television) for 15 min prior to the nominal time point where a 
triplicate ECG is scheduled (Appendix 5, Appendix 6 and Appendix 7). No other 
procedures should be performed within the 15 min resting period. 
The acceptable deviations from the nominal ECG measurement time points are: 
• 
Post-dose triplicate ECG resting periods will be ended within ± 15 min of the nominal 
time point 
• 
Day 1 only: The pre-dose ECG measurements will be taken ≤2 h before dosing 
• 
On Days 2 and 3 (Part 3 only): the pre-dose ECG measurements will be taken ≤1 h 
before dosing.  
• 
Post-dose ECG measurements will be taken ± 15 min from the nominal post-dose 
time point. 
• 
For return visits, ECG measurements will be taken ± 2 h from the nominal return visit 
time point.  
• 
End of study ECG measurements will be taken ± 1 day from the nominal time point.  
The ECGs will be collected electronically and over-read by cardiologists at Banook. The 
Banook over-read will be used for cardiac safety evaluations during SAC data review. 
For safety assessments, a mean value for the triplicate ECGs will be reviewed. 
If a participant shows an abnormal assessment at any stage, repeat measurements may 
be made and the abnormality followed to resolution if required. Additional measurements 
may be taken as deemed necessary by the investigator or sub-investigator. 
Any clinically significant abnormality, including changes from baseline, will be reported 
as an AE. 
14.8 Holter (continuous ECG) Monitoring 
All ECGs will be collected electronically using a Mortara H12+ Holter Recorder, and 
analysed by Banook. Specific procedures for ECG Holter recording and extractions will 
be provided to the investigator by Banook.  
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According to the time schedules presented in Appendix 5, Appendix 6 and Appendix 7, 
continuous Holter monitoring will commence at least 1.5 h prior to dosing until at least 
24 h post-dose. Participants will be required to rest in the supine position with no external 
stimuli (e.g. music or television) for 15 min prior to the nominal time point where an ECG 
extraction is scheduled. This extraction will be taken by the third party Holter provider at 
the planned time and therefore no other procedures should be performed within the 
resting period. 
Where one period of ECG rest runs into the rest period for the next ECG extraction, the 
minimum resting period before ECG extraction does not need to be started again except 
in cases where the rest is disturbed (e.g. participants has to get up for a comfort break 
after the preceding rest period).  
Participants may move more freely outside of the primary ECG rest periods. Comfort 
breaks for hygienic purposes will be allowed each morning well in advance of the 
required supine/ECG extraction points. 
Where any scheduled rest times are missed, where there is less than a 10 min rest period 
or where the final 5 min of a rest period is interrupted (for example, by participant 
movement or loss of leads) a protocol deviation will be recorded and the Holter provider 
informed.  
Loss of leads or interruption of the recording outside of the scheduled rest times will not 
be considered a protocol deviation but should be recorded in the source. 
The acceptable deviations for ECG rest periods from the nominal time point are: 
• 
Pre-dose and post-dose ECG resting periods will be ended within ± 15 min of the 
nominal time point 
See Section 10.3.2 for details on timing of Holter rest period/extractions in relation to 
other procedures and Appendix 7 for rest period/extraction time points.  
The ECGs will be collected electronically and over-read by cardiologists at Banook. The 
Banook over-read will be used for cardiac safety evaluations during SAC data review. 
14.9 Telemetry (Continuous ECG) 
On Day 1 of Parts 1 and 2, telemetry (continuous ECG monitoring) will commence at 
least 30 min before dosing until at least 12 h post-dose. As this monitoring is for safety 
purposes alone no data will be recorded in the source, except the start and stop time. If 
cardiac monitoring shows a potentially significant abnormality, a clinical assessment of 
the participant including a 12-lead ECG will be performed and treatment given, if 
appropriate. 
14.10 Body Weight, Height and BMI 
The participant’s body weight and height will be measured and their BMI will be 
calculated according to the time schedules presented in Appendix 2, Appendix 3 and 
Appendix 4. 
14.11 Physical Examination 
Participants will undergo a physical examination according to the time schedules 
presented in Appendix 2, Appendix 3 and Appendix 4. 
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In the targeted (symptom driven) physical examination, a physician will assess the 
participant; if the participant reports feeling unwell or has ongoing AEs, then the 
physician will examine the appropriate body system(s) if required. 
14.12 Beck Depression Inventory (BDI-II) Questionnaire   
Each participant will undergo a BDI-II questionnaire [7], according to the time schedules 
presented in Appendix 2, Appendix 3 and Appendix 4. A participant will be excluded from 
the trial if they have 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). 
Individuals with a BDI-II score of 17-19 may be enrolled, at the discretion of the 
investigator, if they do not have a medical history of psychiatric conditions 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. 
14.13 Additional Safety Procedures 
Additional non-invasive procedures that are already specified in the protocol may be 
performed, if it is believed that an important effect of the IMP(s) is occurring or may occur 
at a time when no measurements are scheduled, or if extra procedures are needed in 
the interests of safety. 
Additional blood samples for safety assessments may be taken if required by the 
investigator or sub-investigator at any point. 
15 Statistics and Data Analysis 
15.1 Sample Size Justification 
For Parts 1 and 3, the primary objective is an initial assessment of safety and each 
treatment group is therefore limited to 6 participants receiving active IMP. Administration 
of MMV367 to 6 participants at each dose level provides a 47%, 62%, 74%, or 82% 
probability of observing at least 1 occurrence of any AE, with a true incidence rate for a 
given dose group of 10%, 15%, 20%, or 25%, respectively. 
Furthermore, it is assumed that pooling the data for the 2 participants who receive 
placebo in each cohort will provide an adequately sized control group to assess a 
possible drug effect on safety laboratory tests, vitals and ECG parameters. 
Part 2 is a pilot evaluation designed to determine whether MMV367 PK is impacted by 
high-fat food. Historically, 8 participants have proven sufficient to characterise the 
preliminary effects of food on safety and PK of a new chemical entity in healthy 
participants. Therefore, a sample size of 8 is considered adequate at this stage of drug 
development. 
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15.2 Data Management 
Data management will be performed by Quotient. 
Study data will be managed using a validated electronic case report form (eCRF) 
database system and will be subjected to data consistency and validation checks. Data 
queries will be raised within the study eCRF database by data management staff and 
resolved with the assistance of clinical staff. 
AEs, medical histories and medications will be coded using the Medical Dictionary for 
Regulatory Activities (version to be specified in the Data Management Plan [DMP]) and 
the World Health Organization Drug Dictionary Global Drug Reference (version to be 
specified in the DPM), respectively. An independent coding review will also be performed 
within the Data Sciences department. 
Clinical chemistry, haematology and coagulation data (and other safety laboratory data) 
will be collected by a central laboratory (The Doctors Laboratory) and stored 
electronically in their clinical pathology system. The data will be transferred electronically 
to Quotient and all demographic details and sample dates will be cross-referenced with 
the corresponding data on the study database. All queries will be resolved with the 
assistance of laboratory staff, or if necessary, clinical staff.  
The database will be closed after all queries have been resolved. The database will be 
locked when all criteria listed in the DMP are met.  
Further details are addressed in the DMP. 
15.3 Pharmacokinetic Data Analysis 
The plasma concentration data for MMV367 provided by Swiss BioQuant will be 
analysed by Quotient, using Phoenix WinNonlin v8.3 or a more recent version (Certara 
USA, Inc., USA). 
PK analysis of the concentration time data obtained will be performed using appropriate 
non-compartmental techniques to obtain estimates of the PK parameters presented in 
Table 7 and Table 8, where possible and appropriate. 
Table 7 
Plasma Pharmacokinetic Parameters: Part 1 and 2 
Parameter 
Definition 
Tmax 
Time of maximum observed concentration 
Cmax 
Maximum observed concentration 
AUC(0-24) 
Area under the curve from time 0 to 24 h post-dose 
AUC(0-48) 
Area under the curve from time 0 to 48 h post-dose 
AUC(0-last) 
Area under the curve from time 0 to the time of last measurable concentration 
AUC(0-inf) 
Area under the curve from time 0 extrapolated to infinity 
T1/2  
Terminal elimination half-life 
CL/F 
Total body clearance calculated after a single extravascular administration where 
F (fraction of dose bioavailable) is unknown 
Vz/F 
Apparent volume of distribution based on the terminal phase calculated using 
AUC(0-inf) after a single extravascular administration where F (fraction of dose 
bioavailable) is unknown 
Frel Cmax 
Relative bioavailability based on Cmax (Part 2 fed dosing only) 
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Parameter 
Definition 
Frel AUC(0-last) 
Relative bioavailability based on AUC(0-last) (Part 2 fed dosing only) 
Frel AUC(0-inf) 
Relative bioavailability based on AUC(0-inf) (Part 2 fed dosing only) 
Table 8 
Plasma Pharmacokinetic Parameters: Part 3 
Parameter 
Definition 
Tmax 
Time of maximum observed concentration 
Cmax 
Maximum observed concentration 
AUC(0-tau) 
Area under the curve for the defined interval between doses (tau) 
T1/2  
Terminal elimination half-life (Day 3 only) 
CL/Ftau 
Total body clearance calculated using AUC(0-tau) after repeated extravascular 
administration where F (fraction of dose bioavailable) is unknown (Day 3 only) 
Vz/Ftau 
Apparent volume of distribution based on the terminal phase calculated using AUC(0-
tau) after repeated extravascular administration where F (fraction of dose 
bioavailable) is unknown (Day 3 only) 
AR Cmax 
Accumulation ratio based on Cmax repeated dose/Cmax single dose (Day 3 only) 
AR AUC 
Accumulation ratio based on AUC(0 tau) repeated dose/AUC(0 tau) single dose 
(Day 3 only)  
Analysis of drug related QT/QTc interval changes relative to plasma PK concentrations 
will be conducted. This analysis will be performed on the analysis set for intensive cardiac 
assessment. Concentration/QTc modelling may be performed after completion of the 
CSR and will be reported separately. 
In Part 1 Cohorts 1C and 1D, provided a future bioanalytical method is available, urine 
concentration data for MMV367, provided by Swiss BioQuant, will be analysed by 
Quotient and reported in an addendum to the CSR or in a separate report. Estimates of 
the parameters presented in Table 9 in urine will be obtained where possible and 
appropriate. 
Table 9 
Urine Pharmacokinetic Parameters: Part 1, Cohorts 1C and 1D only 
Parameter 
Definition 
CLr 
Renal clearance calculated using plasma AUC 
Ae 
Amount excreted 
CumAe 
Cumulative amount excreted 
%Ae 
Percentage of dose excreted  
Cum%Ae 
Cumulative percentage of dose excreted  
Interim PK parameter estimations will be provided as described in Section 8.2. 
Further details of the PK data analysis will be included in the reporting and analysis plan 
(RAP). 
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15.4 Metabolite Profiling and Identification Assessment 
Metabolite profiling of MMV367 in plasma and urine will be performed using existing PK 
samples (pooled residual samples) collected in Part 1. Potential metabolites will be 
identified using liquid chromatography-mass spectrometry analysis. If results suggest 
that a major metabolite is present in plasma (e.g. greater than 10% of circulating 
MMV367 in plasma based on peak AUCs), metabolite quantification and PK analysis in 
plasma will be performed provided a future bioanalytical method is available. These 
results may be reported in an addendum to the CSR or in a separate report. 
15.5 Statistical Data Analysis  
Statistical analysis and production of summary tables, figures and listings for this study 
will be performed by Quotient using the statistical package SAS (v9.4 or more recent 
version).  
In general terms, categorical data (including treatment-emergent AEs) will be presented 
using counts and percentages, while continuous variables will be presented using the 
mean, median, standard deviation, minimum and maximum. Additional statistics will be 
provided for PK-related data including coefficient of variation (CV%), geometric mean 
and geometric CV%.  
Descriptive summaries for all safety data (AEs, vital signs, ECGs and safety laboratory 
assessments) by regimen will be provided (including changes from baseline as required). 
Descriptive summaries for all PK data by regimen will be provided.  
All safety and PK data will be listed. 
Assessment of Dose Proportionality  
For Part 1, dose proportionality will be assessed using a power model approach using 
log-transformed Cmax, AUC(0-last) and AUC(0-inf) values, including data from up to 
5 different dose levels, i.e., general linear model including log dose as a fixed effect and 
log PK parameter as the dependent variable. The estimate obtained for β together with 
its 90% confidence interval (CI) will be presented along with the number of participants 
and the geometric means. The resulting estimate slope (β) and 90% CI is a measure of 
dose proportionality; the relationship is considered dose proportional when β = 1. 
Assessment of Taste Questionnaire Data  
In Part 1, formal statistical analysis will be performed on the scores of each taste attribute 
and overall acceptability, in the comparison of each dose level of MMV367 to the pooled 
placebos, using non-parametric methods. Hodges-Lehmann estimation methods will be 
used to estimate the median difference between each dose level and the pooled 
placebos. The associated 95% CI will be calculated for the estimate. The p-value will be 
calculated from the Wilcoxon Rank Sum Test (Mann-Whitney-Wilcoxon Test) for the test 
of the null hypothesis that the difference between the medians of each dose level and 
the pooled placebos is equal to zero, with the alternative hypothesis being that the 
difference is not equal to zero.  
The number of participants and the median score for each treatment will be presented 
together with the Hodges-Lehmann estimate of the median difference and associated 
90% CI. In addition, the p-value from the Wilcoxon Rank Sum Test will also be presented. 
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Assessment of Food Effect 
In addition, for Part 2, formal statistical analysis will be performed, at a minimum, on the 
following PK parameters: Cmax, AUC(0-last) and AUC(0-inf), to assess for the effects of 
food. The PK parameters will undergo a natural logarithmic transformation and will be 
analysed using a mixed effect model with terms for fed/fasted status and period fitted as 
fixed effects and participant fitted as a random effect. The adjusted mean difference 
between the fed and fasted states, and the associated 90% CI obtained from the model 
are back transformed on the log scale to obtain the adjusted geometric mean ratio and 
90% CI of the ratio. These will be presented together with the p-value from the fed/fasted 
comparison. 
A categorical analysis of QTcF data will be reported (Table 10). 
Table 10 
QTcF Categorical Analysis 
Absolute QTcF prolongation 
• 
QTcF >450 msec 
• 
QTcF >480 msec 
• 
QTcF >500 msec 
Change from baseline in QTcF 
• 
QTcF increases from baseline >30 msec 
• 
QTcF increases from baseline >60 msec 
Populations and analysis sets will be determined for safety, PK and taste data after 
database lock using the criteria defined in the RAP; the RAP will be signed off prior to 
database lock. 
The safety population and safety analysis set will be defined after database lock but prior 
to study unblinding; all other populations and analysis sets will be defined after database 
lock and unblinding when the relevant data are available. 
Further details relating to the statistical analysis will be included in the RAP including the 
following: 
• 
Criteria to be used to define each of the population and analysis sets 
• 
Additional detail covering the analyses and/or description of primary and secondary 
analyses and safety data 
• 
Handling of missing data, unused or spurious data 
• 
Handling of data from withdrawn participants 
• 
Unblinding procedures and maintaining the blind 
15.6 Interim Analysis 
No formal interim analyses are planned for this study. Interim Data Reviews will be 
performed as detailed in Section 8.2. 
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16 Safety Reporting to Regulatory Authorities and Ethics 
Committees 
16.1 Events Requiring Expedited Reporting 
SUSARs (Section 14.4.2) are subject to expedited reporting to the appropriate regulatory 
authority and EC. 
In addition to SUSARs, other safety issues may qualify for expedited reporting where 
they might materially alter the current benefit-risk assessment of an IMP or that would 
be sufficient to consider changes in the IMPs’ administration or in the overall conduct of 
the study, for instance: 
• 
An increase in the rate of occurrence or a qualitative change of an expected serious 
adverse reaction, which is judged to be clinically important 
• 
SAEs that occur after the participant has completed the clinical study where the 
sponsor considers them to be a SUSAR 
• 
New events related to the conduct of the study or the development of the IMPs and 
likely to affect the safety of the participants, such as: 
− An SAE which could be associated with the study procedures and which 
could modify the conduct of the study 
− A major safety finding from a newly completed animal study (such as 
carcinogenicity) 
− Any anticipated end or temporary halt of a study for safety reasons and 
conducted with the same IMPs in another country by the same sponsor 
16.2 Urgent Safety Measures 
If Quotient or any of its staff or contractors becomes aware of an actual or potential 
urgent safety issue, then the sponsor must be immediately contacted so that appropriate 
urgent safety measures can be agreed. An urgent safety issue is defined as:  
• 
An immediate hazard to the health or safety of participants participating in a clinical 
study 
• 
A serious risk to human health or potentially a serious risk to human health 
An urgent safety issue may include issues with an investigational drug or comparators, 
study procedures, inter-current illness (including pandemic infections), concomitant 
medications, concurrent medical conditions or any other issues related to the safe 
conduct of the study or that pose a risk to study participants. 
In exceptional circumstances of imminent hazard and in order to safeguard the health or 
safety of individuals, Quotient may take urgent safety measures before informing the 
sponsor, but the sponsor must be informed immediately after the hazard has resolved.  
The sponsor is responsible for informing the appropriate regulatory authorities, and the 
EC; the task of reporting urgent safety measures will be delegated to Quotient. 
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16.3 Reporting 
16.3.1 Reporting Serious Adverse Events 
The investigator is required to notify the study sponsor and pharmacovigilance provider 
within 24 h of becoming aware of the occurrence of an SAE or serious adverse reaction. 
A copy of the written report of the event should promptly be sent to the study sponsor for 
information purposes, in accordance with ICH guidelines for GCP [11]. 
16.3.2 Reporting of Suspected Unexpected Serious Adverse Reactions 
It is the responsibility of the sponsor to determine whether a reported SAE fits the 
classification of a SUSAR and to notify the investigator of their decision as soon as 
possible. 
16.3.3 Expedited Reporting of Events 
It is the responsibility of the sponsor to determine whether an event requires expedited 
reporting and to notify the investigator of their decision as soon as possible. 
Where expedited reporting is required, the following procedures should be followed. 
Fatal or life-threatening SUSARs 
It is the responsibility of the sponsor to report fatal or life-threatening SUSARs to the 
MHRA as soon as possible, but no later than 7 calendar days after they first became 
aware of the reaction. Any additional relevant information should be sent within 8 days 
of the report. The task of reporting fatal or life-threatening SUSARs may be delegated to 
the pharmacovigilance provider.  
The sponsor is required to notify the EC of any fatal or life-threatening SUSAR as soon 
as possible, but no later than 7 calendar days after they first became aware of the 
reaction. Any additional relevant information should be sent within 8 days of the report. 
The task of reporting fatal or life-threatening SUSARs may be delegated to the 
investigator. 
Other SUSARs 
It is the responsibility of the sponsor to report other SUSARs to the MHRA as soon as 
possible, but no later than 15 calendar days after they first became aware of the reaction. 
The task of reporting other SUSARs may be delegated to the pharmacovigilance 
provider. 
The sponsor is required to notify the EC of other SUSARs as soon as possible, but no 
later than 15 calendar days after they first became aware of the reaction. The task of 
reporting other SUSARs may be delegated to the investigator. 
16.3.4 Reporting of Urgent Safety Measures 
Quotient is required to notify the MHRA and the EC of an urgent safety measure 
immediately by telephone and follow-up in writing within 3 calendar days from the date 
the measures are taken. 
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16.3.5 Reporting of COVID-19 Vaccine-Related Adverse Events 
AEs considered by the investigator to be related to COVID-19 vaccines will be reported 
to the MHRA via the Yellow Card system. 
16.4 Serious Breaches 
It is the responsibility of the sponsor to notify the MHRA of any serious breach, which is 
likely to affect, to a significant degree, the safety or mental integrity of the participants of 
the study or the scientific value of the study.  
All serious breaches will be notified to the MHRA within 7 days. The reporting will be 
performed by the party who suspects the serious breach. 
17 Protocol Amendments and Deviations 
17.1 Amendments 
After the protocol has been submitted to the MHRA and EC, any amendment must be 
agreed by the investigator after discussion with the sponsor and will be formally 
documented. 
All substantial amendments will be submitted to the MHRA and/or EC for an opinion as 
required by current regulations. 
If the PIS and ICF are updated as a result of the substantial amendment, the new 
approved versions will be used to re-consent currently enrolled participants and must be 
provided to newly enrolled participants prior to their entry into the study. 
17.2 Protocol Deviations 
The study must be conducted in accordance with the Clinical Protocol. Should a protocol 
deviation occur, it must be promptly assessed in order to decide whether any of these 
non-compliances should be reported to the MHRA as a serious breach of GCP and the 
Clinical Protocol. 
Protocol waivers are not acceptable. 
Deviations from the protocol will be recorded in the source as noted by the clinical staff. 
If necessary, the sponsor will be informed of the deviation. 
Any protocol deviations assessed as major will be discussed with the sponsor in order 
to determine if the withdrawal criteria stated in Section 8.3 have been met. 
18 Regulatory 
18.1 Compliance 
This study will be conducted in accordance with the protocol and with the following 
legislation: 
• 
ICH GCP Guidelines approved by the Committee for Medicinal Products for Human 
Use on 17 Jul 1996, which came into force on 17 Jan 1997, updated Jul 2002, 
Integrated Addendum E6 (R2) dated 09 Nov 2016 [11] 
• 
The Medicines for Human Use (Clinical Trials) Regulations. Statutory Instruments 
2004 No. 1031 [12] 
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• 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. Statutory 
Instruments 2006 No. 1928 [13] 
• 
The Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations. 
Statutory Instruments 2006 No. 2984 [14] 
• 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. Statutory 
Instruments 2008 No. 941 [15] 
• 
The Medicines for Human Use (Clinical Trials) (Amendment) (EU Exit) Regulations. 
Statutory Instruments 2019 No. 744 [16] 
In addition, the study will be performed according to the ethical principles outlined in the 
World Medical Association Declaration of Helsinki and its amendments [17]. 
18.2 MHRA and Ethical Approval 
Prior to the initiation of the study, the clinical trial of an investigational medicinal product 
(CTIMP) application, the protocol and associated documentation must be approved by 
the MHRA and given a favourable opinion by an EC. A copy of this written approval and 
any correspondence with the MHRA and EC will be available at the clinical site and will 
be provided to the sponsor.  
18.3 Source Data 
A study-specific source document identification list will be finalised with the sponsor prior 
to the start of the clinical phase of the study. The document will identify what data should 
be considered source data for this study.  
For this study, electronic data capture will be used where possible and data will be 
automatically recorded into an eCRF. In instances where paper source documents are 
used, data to be transcribed into the eCRF will be identified using a Source Document 
Identification List, as governed by Quotient’s SOPs. 
18.4 Declaration of the End of the Study 
The end of the study is defined as the point at which the sponsor determines that any 
remaining optional groups are not required to meet the objectives of the trial i.e. signed 
dose decision document or the completion of the final end of study visit or unscheduled 
follow-up assessment for the final cohort dosed, whichever occurs later. If all optional 
groups are utilised, completion of the final end of study visit or unscheduled follow-up 
visit will be considered the end of the study. Any changes to this definition will be notified 
as a substantial amendment (see Section 17.1). 
The EC and MHRA should be notified of the conclusion of the study within 90 days of 
the end of the study, or within 15 days if the study is terminated early, clearly explaining 
the reasons for the termination. 
18.5 Document Storage and Archiving 
All documentation and correspondence pertaining to the study (source data, raw data, 
letters etc) will be kept in accordance with the ICH guidelines for Good Clinical Practice 
1996, updated 2002, Integrated Addendum E6 (R2) dated 09 Nov 2016 (ICH GCP 
Section 4.9.5) [11], The Medicines for Human Use (Clinical Trials) Regulations 2004 [12], 
The Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 [13],[14] 
and The Medicines for Human Use (Clinical Trials) (Amendment) (EU Exit) Regulations 
[16]. 
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All study related documents will be retained for a minimum period of 15 years. After this 
time, the sponsor will be contacted to ascertain whether continued storage or destruction 
is required in accordance with current regulations. 
18.6 Protection of Personal Data and Confidentiality 
Personal data are securely stored to prevent unauthorised access, disclosure, 
dissemination, alteration or loss of information and unauthorised personal data 
processing. Access to personal information is restricted so that only personnel who are 
required to access personal data as part of their job role can do so. All personnel who 
access personal information are bound by a duty of confidentiality. 
Technical arrangements surrounding the electronic storage and use of data are as 
follows: 
• 
Computers storing electronic personal data are protected by antivirus software and 
the network on which computers are linked are protected by industry grade firewalls 
• 
Off-site personnel can only access networked computers through a virtual private 
network  
• 
Electronic access of data is limited according to user roles 
• 
All data are stored on password protected computers 
Organisational arrangements are as follows: 
• 
All buildings are secured by key-card access 
• 
Manual files of personal data are stored within locked cabinets/restricted areas of the 
clinical unit that can only be accessed by authorised personnel 
• 
Data security and/or confidentiality provisions are utilised in agreements with third 
parties 
• 
Documented Back-up and disaster recovery procedures are in place 
• 
Internal audit and compliance functions provide regulatory oversight 
The personal data of volunteers will be pseudonymised in that they will only include 
health, initials, date of birth and demographics (gender and ethnicity) and cannot be 
linked back to the individual by the recipient. The sponsor shall be the data controller in 
respect of the personal data of the study participants collected in connection with the 
study, and shall act in accordance with the relevant data protection laws in relation to the 
collection and processing of those personal data. The study participants’ pseudonymised 
personal data shall be collected and processed for the purposes of the study and may 
also be added to research databases and used in the future by the sponsor and its 
affiliates for certain additional clinical research, for product regulation and safety 
reporting purposes and for ensuring compliance with legal requirements. The study 
participants’ pseudonymised personal data may be processed for such purposes by 
other parties including: the sponsor’s affiliates and licensing partners, its business 
partners, regulatory agencies and other health authorities, and ECs. The study 
participants’ authorisation for such use and disclosure shall be obtained by the study 
participants signing the ICF for the study. 
Additionally, Quotient personnel are contractually bound by a duty of confidentiality and 
receive training on this matter. 
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18.7 Data Security Breach 
Quotient has a comprehensive process in place for identifying, assessing, resolving and 
reporting any potential data security breach. All staff are trained in the identification of 
potential data security breaches. Potential breaches are managed by appropriately 
trained QA personnel in accordance with Quotient’s SOPs. After robust assessment of 
data breaches, those deemed serious will be reported to the sponsor and Information 
Commissioner’s Office, as applicable. 
19 Quality Control and Quality Assurance 
Quality control of all data collected from this study will be performed in accordance with 
Quotient’s SOPs. This study (or elements thereof) may be subject to Quotient QA audit, 
in line with current internal auditing procedures. Similarly, the study (or elements thereof) 
may be subject to sponsor QA audit. 
19.1 Monitoring 
GCP requires that studies are adequately monitored. The sponsor should determine the 
appropriate extent and nature of monitoring. A study monitor, independent of Quotient, 
will be appointed to verify that the study is conducted in accordance with current GCP, 
regulatory requirements, the protocol and that the data are authentic, accurate and 
complete.  
The investigator agrees to receive visits from a study monitor and provide assistance to 
verify protocol implementation, source completion and transcription of data into the 
eCRF, document storage and AE reporting. 
Quotient will extend the professional privilege of access to the participants’ clinical 
source documents to the study monitor, EC, regulatory bodies or other authorised 
personnel (e.g. auditor) for the purposes of source data verification. 
Following completion of the study both study related documents and participant data may 
be sent to the sponsor at a location outside of the UK where data protection laws differ. 
In the interests of confidentiality, participants will not be identified on any such documents 
or data, and specific participant consent for such a disposition will be obtained. 
20 Finance and Insurance 
The sponsor (Medicines for Malaria Venture) has co-funded this study, in partnership 
with the pharmaceutical company GlaxoSmithKline. A no-fault clinical trials insurance 
has been obtained by the sponsor. The sponsor insurance will compensate participants 
in accordance with the Association of the British Pharmaceutical Industry Guidelines for 
Phase I Clinical Trials 2018 edition [9]. 
21 Publication 
Please refer to the Master Services Agreement for information on publication.  
Quotient shall have the right to publish the results of the research, subject to the 
sponsor’s prior written consent, which shall not be unreasonably withheld or delayed. 
Following the receipt of such consent, Quotient shall submit a copy of the proposed 
publication to the sponsor who shall have 30 days in which to request amendments 
thereto which, to the extent that such proposed amendments are reasonable, Quotient 
shall be obliged to incorporate prior to such publication. 
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The sponsor undertakes that, prior to publication of any information, article, paper, report 
or other material concerning the research, it will submit a copy of such publication to 
Quotient who shall have 30 days in which to request amendments thereto which, to the 
extent that such proposed amendment are reasonable, the sponsor shall be obliged to 
incorporate prior to such publication. 
22 References 
[1] 
World Health Organization, World Malaria Report, 2021. Available online: 
https://www.who.int/publications/i/item/9789240040496 
[2] 
Gamo FJ, Sanz LM, Vidal J, et al. Thousands of chemical starting points for 
antimalarial lead identification. Nature. 2010; 465 (7296): 305-310. 
[3] 
Medicines for Malaria Venture. Investigator’s Brochure for MMV367. Edition 1.0, 
06 April 2022. 
[4] 
Gaur AH, McCarthy JS, Panetta JC, et al. Safety, tolerability, pharmacokinetics, 
and antimalarial efficacy of a novel Plasmodium falciparum ATP4 inhibitor SJ733: 
a first-in-human and induced blood-stage malaria phase 1a/b trial. Lancet Infect 
Dis. 2020; 20 (8): 964-975. 
[5] 
Guideline of strategies to identify and mitigate risks for first-in-human and early 
clinical trials with investigational medicinal products. Committee for Medicinal 
Products 
for 
Human 
Use 
(CHMP) 
20 
July 
2017 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-
strategies-identify-mitigate-risks-first-human-early-clinical-trials-
investigational_en.pdf 
[6] 
Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers. U.S. Department of 
Health and Human Services Food and Drug Administration Center for Drug 
Evaluation 
and 
Research. 
July 
2005. 
https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/estimating-maximum-safe-starting-
dose-initial-clinical-trials-therapeutics-adult-healthy-volunteers 
[7] 
Beck A, Ward C, Mendelson M, et al. An inventory for measuring depression. 
Archives of General Psychiatry. 1961; 4: 561-571 
[8] 
Heads of Medicines Agency: Clinical Trials Facilitation Group. Recommendations 
related to contraception and pregnancy testing in clinical trials. 21 Sep 2020. 
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_gui
dance_Version_1.1_updated.pdf 
[9] 
Guidelines for Phase I Clinical Trials. Association of the British Pharmaceutical 
Industry Guidelines. London, UK; 2018 Edition (publication date 29 May 2018). 
[10] 
Longmore M, Wilkinson I, Rajagopolan S. Oxford Handbook of Clinical Medicine. 
Sixth Edition (2006): 685. 
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[11] 
International Council for Harmonisation Good Clinical Practice (GCP) Guidelines 
approved by the Committee for Medicinal Products for Human Use (CHMP) on 
17 Jul 1996, which came into force on 17 Jan 1997, updated Jul 2002, Integrated 
Addendum E6 (R2) dated 09 Nov 2016. 
[12] 
The Medicines for Human Use (Clinical Trials) Regulations. Statutory 
Instruments 2004 No. 1031. 
[13] 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. 
Statutory Instruments 2006 No. 1928. 
[14] 
The Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations. 
Statutory Instruments 2006 No. 2984. 
[15] 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. 
Statutory Instruments 2008 No. 941. 
[16] 
The Medicines for Human Use (Clinical Trials) (Amendment) (EU Exit) 
Regulations. Statutory Instruments 2019 No. 744. 
[17] 
World Medical Association, Declaration of Helsinki. Ethical Principles for Medical 
Research Involving Human Participants (and all subsequent amendments). 
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Appendix 1 Clinical Laboratory Parameters 
Haematology 
Clinical Chemistry 
Virology 
Urinalysis 
Drugs of Abuse 
Haemoglobin 
Haematocrit (HCT; packed cell 
volume [PCV]) 
Red blood cell (RBC; erythrocyte) 
count  
Mean corpuscular volume (MCV) 
Mean corpuscular haemoglobin 
(MCH) 
Mean corpuscular haemoglobin 
concentration (MCHC) 
Platelet count 
White blood cell (WBC; leukocytes) 
count 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
 
Coagulation Tests 
Prothrombin time 
International normalised ratio (INR) 
Activated partial thromboplastin time 
(APTT) 
 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Urea 
Creatinine (admission plasma 
creatinine value will be used to 
calculate CLcr) 
Bilirubin (total) 
Bilirubin (direct; only if total is 
elevated) 
Alkaline phosphatase 
Aspartate aminotransferase 
(AST) 
Alanine aminotransferase 
(ALT) 
Creatine kinase (CK) 
Gamma glutamyl transferase 
(GGT) 
Protein (Total) 
Albumin 
Calcium 
Glucose (fasting) 
Glucose 
Follicle stimulating hormone 
(FSH; post-menopausal 
female participants only) 
Human chorionic 
gonadotropin (β-hCG) (in 
serum; all female participants) 
Hepatitis B surface antigen 
Hepatitis C virus antibody 
HIV 1 & 2 antibodies 
 
 
SARS-CoV-2 antigen 
 
 
 
 
Bilirubin 
Urobilinogen 
Ketones 
Glucose 
Protein 
Blood 
Nitrites 
pH 
Specific gravity 
Leukocytes 
 
At discretion of 
investigator based on 
urinalysis results 
Microbiology  
Urine microscopy 
 
Urine Pregnancy 
hCG (all female participants) 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cocaine 
Marijuana/cannabis 
Methadone 
Methamphetamine/ 
ecstasy 
Morphine/opiates 
Phencyclidine 
Tricyclic antidepressants 
 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
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 08 SEP 2022 
Page 76 of 92  
 
Appendix 2 
Schedule of Assessments: Part 1 (Cohorts 1A to 1E) 
Study Day 
Screening Admission 
Resident In-clinic 
Return Visitb End of Study 
Visitb 
-28 to -2 
-1 
1 
2 
3 
4 
5a 
7 
15 
General Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
Xc 
 
 
 
 
 
 
 
Weight, Height and BMI 
X 
Xd 
 
 
 
 
 
Xd 
Xd 
Vein Assessment 
X 
 
 
 
 
 
 
 
 
Carbon Monoxide Breath Test 
X 
X 
 
 
 
 
 
 
 
Drug Screen 
X 
X 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
 
SARS-CoV-2 Antigene 
X 
X 
 
 
 
 
 
 
 
Randomisationf 
 
 
X 
 
 
 
 
 
 
IMP Administrationg 
 
 
X 
 
 
 
 
 
 
Safety Assessments 
BDI-II Questionnaire 
X 
X 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
Targeted (symptom driven) Physical 
Examinationh 
 
 
X 
X 
X 
X 
X 
X 
X 
Safety Labsi 
X 
X 
 
X 
 
 
X 
X 
X 
Urinalysisi 
X 
X 
 
X 
 
 
X 
X 
X 
Follicle-stimulating Hormone (FSH) Testj 
X 
 
 
 
 
 
 
 
 
Serum Pregnancy Testk 
X 
 
 
 
 
 
 
 
 
Urine Pregnancy Testk 
 
X 
 
 
 
 
 
X 
X 
Single 12-Lead ECGsl 
X 
X 
X 
X 
 
 
 
 
X 
Triplicate 12-Lead ECGsl 
 
 
 
 
X 
X 
X 
X 
 
Holter Periodsm 
  
 
X 
X 
 
 
 
 
 
Telemetryn 
 
 
X 
 
 
 
 
 
 
Vital Signso 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Orthostatic Vital Signso 
X 
 
X 
X 
 
 
 
X 
 
Adverse Events 
< ---------------------------------------------------------------------------X--------------------------------------------------------------------------> 
Prior and Concomitant Medication 
< ---------------------------------------------------------------------------X------------------------------------------------------------------------ > 
PK/Metabolite ID/Pharmacogenetic Assessments 
Plasma Samples for MMV367p 
 
 
X 
X 
X 
X 
X 
X 
 
Urine Samples for MMV367pq 
 
 
X 
X 
X 
 
 
 
 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
QSC207031 Clinical Protocol
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 08 SEP 2022 
Page 77 of 92  
 
Study Day 
Screening Admission 
Resident In-clinic 
Return Visitb End of Study 
Visitb 
-28 to -2 
-1 
1 
2 
3 
4 
5a 
7 
15 
Blood Sample for CYP/UGT 
polymorphismr 
 
 
X 
 
 
 
 
 
 
Taste/Palatability Assessments 
Taste/Palatability Questionnaires 
 
 
 
 
 
 
 
 
 
Eligibility will be re-assessed at admission/pre-dose on Day 1. 
a Discharge from clinical unit 
b Participants will return for an outpatient visit on Day 7 and an end of study visit on Day 15 (± 1 day). 
c Update only 
d Weight only 
e It is planned that testing will comprise an antigen test performed at screening and on Day -1 prior to admission to the clinical unit. The definition of the COVID-19 
testing time points are subject to change based on the current risk mitigation in place and will be agreed by the study team and documented in the ISF via the 
Clinical Kick-Off Meeting minutes. 
f Participants will be randomised on the morning of Day 1 prior to dosing 
g Participants will receive a single dose of MMV367 or placebo on Day 1 
h Targeted (symptom driven) physical examination of the relevant body system(s) as clinically indicated, as per the investigator’s judgement 
i Haematology, coagulation and clinical chemistry and urinalysis at each time point, including virology and FSH (post-menopausal female participants only) at 
screening. See Appendix 5 for safety blood sample time points. 
j Post-menopausal female participants only 
k All female participants 
l See Appendix 5 for single and triplicate 12-lead ECG time points. For triplicate ECGs, participants will be required to rest in the supine position with no external 
stimuli (e.g. music or television) for 15 min prior to the nominal time point where a triplicate ECG is scheduled. 
m Continuous Holter monitoring will commence at least 1.5 h prior to dosing until at least 24 h post-dose. Participants will be required to rest in the supine position 
with no external stimuli (e.g. music or television) for 15 min prior to the nominal time point where an ECG extraction is scheduled. See Appendix 5 for Holter 
extraction time points. 
n Telemetry (continuous ECG monitoring) will commence at least 30 min before dosing until at least 12 h post-dose. 
o Blood pressure, heart rate and respiratory rate at all time points. Oral temperature will be measured at screening/admission only. See Appendix 5 for vital signs 
and orthostatic vital signs time points. 
p See Appendix 5 for PK sample time points. Metabolite profiling of MMV367 in plasma and urine will be performed using existing PK samples (pooled residual 
samples). 
q Urine collection in Cohorts 1C and 1D only. 
r Sample will be taken prior to IMP administration (≤2 h before dosing). 
s The taste/palatability questionnaire will be completed immediately after IMP administration, see Appendix 9 for details. 
 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
QSC207031 Clinical Protocol
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 08 SEP 2022 
Page 78 of 92  
 
Appendix 3 
Schedule of Assessments: Part 2 
 
 
 
Resident in Clinic 
End of Study 
Visit 
Study Day 
Screening 
Admi-
ssion 
Period 1 
Period 2 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12a 
14b 
General Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, Height and BMI 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vein Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carbon Monoxide Breath 
Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 Antigene 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisationf 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Administrationg 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Safety Assessments 
BDI-II Questionnaire 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted (symptom driven) 
Physical Examinationh 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Labsi 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
Urinalysisi 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
Follicle-stimulating Hormone 
(FSH) Testj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Testk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Testk 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Single 12-Lead ECGsl 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
X 
Triplicate 12-Lead ECGsl 
 
 
 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
 
Holter Periodsm 
 
 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
Telemetryn 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Vital Signso 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
< --------------------------------------------------------------------------X----------------------------------------------------------------------- > 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
QSC207031 Clinical Protocol
This copy was downloaded by Nia Powell on 09 Sep 2022 at 12:52 GMT+01:00
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 08 SEP 2022 
Page 79 of 92  
 
 
 
 
Resident in Clinic 
End of Study 
Visit 
Study Day 
Screening 
Admi-
ssion 
Period 1 
Period 2 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12a 
14b 
Prior and Concomitant 
Medication 
< --------------------------------------------------------------------------X----------------------------------------------------------------------- > 
PK/Pharmacogenetic Assessments 
Plasma Samples for 
MMV367p 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood Sample for CYP/UGT 
polymorphismq 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility will be re-assessed at admission/pre-dose on Day 1.  
a Discharge from clinical unit 
b Participants will return for an end of study visit on Day 14 (± 1 day). 
c Update only 
d Weight only 
e It is planned that testing will comprise an antigen test performed at screening and on Day -1 prior to admission to the clinical unit. The definition of the COVID-19 
testing time points are subject to change based on the current risk mitigation in place and will be agreed by the study team and documented in the ISF via the 
Clinical Kick-Off Meeting minutes. 
f Participants will be randomised on the morning of Period 1, Day 1 prior to dosing 
g Participants will receive a single dose of MMV367 on Day 1 and Day 8 in the fed or fasted state 
h Targeted (symptom driven) physical examination of the relevant body system(s) as clinically indicated, as per the investigator’s judgement 
i Haematology, coagulation, clinical chemistry and urinalysis at each time point, including virology and FSH (post-menopausal female participants only) at screening. 
j Post-menopausal female participants only 
k All female participants 
l See Appendix 6 for single and triplicate 12-lead ECG time points. For triplicate ECGs, participants will be required to rest in the supine position with no external 
stimuli (e.g. music or television) for 15 min prior to the nominal time point where a triplicate ECG is scheduled. 
m Continuous Holter monitoring will commence at least 1.5 h prior to dosing until at least 24 h post-dose. Participants will be required to rest in the supine position 
with no external stimuli (e.g. music or television) for 15 min prior to the nominal time point where an ECG extraction is scheduled. See Appendix 6 for Holter 
extraction time points. 
n Telemetry (continuous ECG monitoring) will commence at least 30 min before dosing until at least 12 h post-dose. 
o Blood pressure, heart rate and respiratory rate at all time points. Oral temperature will be measured at screening and admission only. See Appendix 6 for vital 
signs time points. 
p See Appendix 6 for PK sample time points. 
q Sample will be taken prior to IMP administration (≤2 h before dosing). 
 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
QSC207031 Clinical Protocol
This copy was downloaded by Nia Powell on 09 Sep 2022 at 12:52 GMT+01:00
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 08 SEP 2022 
Page 80 of 92  
 
Appendix 4 
Schedule of Assessments: Part 3 (Cohorts 3A to 3C) 
Study Day 
Screening Admission 
Resident In-clinic 
Return Visitb End of Study 
Visitb 
 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7a 
9 
17 
General Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xc 
 
 
 
 
 
 
 
 
 
Weight, Height and BMI 
X 
Xd 
 
 
 
 
 
 
 
Xd 
Xd 
Vein Assessment 
X 
 
 
 
 
 
 
 
 
 
 
Carbon Monoxide Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 Antigene 
X 
X 
 
 
 
 
 
 
 
 
 
Randomisationf 
 
 
X 
 
 
 
 
 
 
 
 
IMP Administrationg 
 
 
X 
X 
X 
 
 
 
 
 
 
Safety Assessments 
BDI-II Questionnaire 
X 
X 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
 
Targeted (symptom driven) Physical 
Examinationh 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Labsi 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
Urinalysisi 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
Follicle-stimulating Hormone (FSH) 
Testj 
X 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Testk 
X 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Testk 
 
X 
 
 
 
 
 
 
 
X 
X 
Single 12-Lead ECGsl 
X 
X 
X 
 
X 
X 
 
 
 
 
X 
Triplicate 12-Lead ECGsl 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
Holter Periodsm 
 
 
X 
X 
X 
X 
 
 
 
 
 
Vital Signsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Orthostatic Vital Signsn 
X 
 
X 
X 
X 
X 
 
 
 
X 
 
Adverse Events 
< ------------------------------------------------------------------------X------------------------------------------------------------------ > 
Prior and Concomitant Medication 
< ------------------------------------------------------------------------X------------------------------------------------------------------ > 
PK/Pharmacogenetic Assessments 
Plasma Samples for MMV367o 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
QSC207031 Clinical Protocol
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 08 SEP 2022 
Page 81 of 92  
 
Study Day 
Screening Admission 
Resident In-clinic 
Return Visitb End of Study 
Visitb 
 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7a 
9 
17 
Blood Sample for CYP/UGT 
polymorphismp 
 
 
X 
 
 
 
 
 
 
 
 
Eligibility will be re-assessed at admission/pre-dose on Day 1. 
a Discharge from clinical unit 
b Participants will return for an outpatient visit on Day 9 and an end of study visit on Day 17 (± 1 day). 
c Update only 
d Weight only 
e It is planned that testing will comprise an antigen test performed at screening and on Day -1 prior to admission to the clinical unit. The definition of the COVID-19 
testing time points are subject to change based on the current risk mitigation in place and will be agreed by the study team and documented in the ISF via the 
Clinical Kick-Off Meeting minutes. 
f Participants will be randomised on the morning of Day 1 prior to dosing 
g Participants will receive a dose of MMV367 or placebo in the morning on Days 1, 2 and 3 
h Targeted (symptom driven) physical examination of the relevant body system(s) as clinically indicated, as per the investigator’s judgement 
i Haematology, coagulation, clinical chemistry and urinalysis at each time point, including virology and FSH (post-menopausal female participants only) at screening. 
j Post-menopausal female participants only 
k All female participants 
l See Appendix 6 for single and triplicate 12-lead ECG time points. For triplicate ECGs, participants will be required to rest in the supine position with no external 
stimuli (e.g. music or television) for 15 min prior to the nominal time point where a triplicate ECG is scheduled. 
m Continuous Holter monitoring will commence at least 1.5 h prior to dosing until at least 24 h post-dose. Participants will be required to rest in the supine position 
with no external stimuli (e.g. music or television) for 15 min prior to the nominal time point where an ECG extraction is scheduled. See Appendix 6 for Holter 
extraction time points. 
n Blood pressure, heart rate and respiratory rate at all time points. Oral temperature will be measured at screening and admission only. See Appendix 6 for vital 
signs and orthostatic vital signs time points. 
o See Appendix 6 for PK sample time points. 
p Sample will be taken prior to IMP administration (≤2 h before dosing). 
 
 
 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
QSC207031 Clinical Protocol
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 08 SEP 2022 
Page 82 of 92  
 
Appendix 5 
Part 1 (All Cohorts) Safety and Pharmacokinetic Assessment Time Points 
(Days 1 to 7) 
Study Day 
Time point 
Plasma 
PK 
Urine PKa 
Safety Labs and 
Urinalysis 
Holter Extractions 
Vital 
Signsb 
Orthostatic 
Vital Signs 
Single 
12-lead 
ECGs 
Triplicate 
12-lead 
ECGs 
1 
-1.5 h 
 
 
 
X 
 
 
X 
 
-1 h 
 
 
 
X 
 
 
X 
 
Pre-dose 
(-0.5 h) 
X 
X 
 
X 
X 
X 
X 
 
0 h 
 
0 to 6 h 
 
 
 
 
 
 
0.5 h 
X 
 
X 
X 
 
X 
 
1 h 
X 
 
X 
 
 
X 
 
2 h 
X 
 
X 
X 
X 
X 
 
3 h 
X 
 
X 
 
 
X 
 
4 h 
X 
 
X 
X 
X 
X 
 
5 h 
X 
 
 
 
 
X 
 
6 h 
X 
6 to 12 h 
 
X 
X 
 
X 
 
8 h 
X 
 
X 
X 
 
X 
 
10 h 
 
 
 
X 
 
 
 
12 h 
X 
12 to 24 h 
 
X 
X 
X 
X 
 
2 
24 h 
X 
24 to 48 h 
X 
X 
X 
X 
X 
 
3 
48 h 
X 
48 to 72 h 
 
 
X 
 
 
X 
4 
72 h 
X 
 
 
 
X 
 
 
X 
5 
96 h 
X 
 
X 
 
X 
 
 
X 
7 
144 h 
X 
 
X 
 
X 
X 
 
X 
a Part 1, Cohorts 1C and 1D only. 
b Blood pressure, heart rate and respiratory rate at all time points. 
Allowable windows for PK blood sampling, vital signs assessments and ECGs can be found in: Sections 13.1, 14.6 and 14.7. 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
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Page 83 of 92  
 
Appendix 6 
Part 2 Safety and Pharmacokinetic Assessment Time Points (Days 1 to 14) 
Study Day 
Time point 
Plasma 
PK 
Safety Labs and 
Urinalysis 
Holter Extractions 
Vital Signsa 
Single 
12-lead 
ECGs 
Triplicate 
12-lead 
ECGs 
1 
-1.5 h 
 
 
X 
 
X 
 
-1 h 
 
 
X 
 
X 
 
Pre-dose 
(-0.5 h) 
X 
 
X 
X 
X 
 
0 h 
 
 
 
 
 
 
0.5 h 
X 
 
X 
X 
X 
 
1 h 
X 
 
X 
 
X 
 
2 h 
X 
 
X 
X 
X 
 
3 h 
X 
 
X 
 
X 
 
4 h 
X 
 
X 
X 
X 
 
5 h 
X 
 
 
 
 
 
6 h 
X 
 
X 
X 
X 
 
7 h 
 
 
 
 
 
 
8 h 
X 
 
X 
X 
X 
 
10 h 
 
 
 
X 
 
 
12 h 
X 
 
X 
X 
X 
 
2 
24 h 
X 
X 
X 
X 
X 
 
3 
48 h 
X 
 
 
X 
 
X 
4 
72 h 
X 
 
 
X 
 
X 
5 
96 h 
X 
X 
 
X 
 
X 
7 
144 h 
X 
X 
 
X 
 
X 
8 
-1.5 h 
 
 
X 
 
X 
 
-1 h 
 
 
X 
 
X 
 
Pre-dose 
(-0.5 h) 
X 
 
X 
X 
X 
 
0 h 
 
 
 
 
 
 
0.5 h 
X 
 
X 
X 
X 
 
1 h 
X 
 
X 
 
X 
 
2 h 
X 
 
X 
X 
X 
 
3 h 
X 
 
X 
 
X 
 
4 h 
X 
 
X 
X 
X 
 
5 h 
X 
 
 
 
 
 
6 h 
X 
 
X 
X 
X 
 
7 h 
 
 
 
 
 
 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
QSC207031 Clinical Protocol
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 08 SEP 2022 
Page 84 of 92  
 
Study Day 
Time point 
Plasma 
PK 
Safety Labs and 
Urinalysis 
Holter Extractions 
Vital Signsa 
Single 
12-lead 
ECGs 
Triplicate 
12-lead 
ECGs 
8 h 
X 
 
X 
X 
X 
 
10 h 
 
 
 
X 
 
 
12 h 
X 
 
X 
X 
X 
 
9 
24 h 
X 
 
X 
X 
X 
 
10 
48 h 
X 
X 
 
X 
 
X 
11 
72 h 
X 
 
 
X 
 
X 
12 
96 h 
X 
X 
 
X 
 
X 
14 
144 h 
X 
X 
 
X 
 
X 
a Blood pressure, heart rate and respiratory rate at all time points. 
Allowable windows for PK blood sampling, vital signs assessments and ECGs can be found in: Sections 13.1, 14.6 and 14.7. 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
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Page 85 of 92  
 
Appendix 7 
Part 3 Safety and Pharmacokinetic Assessment Time Points (Days 1 to 9) 
Study 
Day 
Time point 
Plasma PK 
Safety Labs 
and Urinalysis 
Holter Extractions 
Vital Signsa 
Orthostatic 
Vital Signs 
Single 
12-lead 
ECGs 
Triplicate 
12-lead 
ECGs 
1 
-1.5 h 
 
 
X 
 
 
X 
 
-1 h 
 
 
X 
 
 
X 
 
Pre-dose (-0.5 h) 
X 
 
X 
X 
X 
X 
 
0 h 
 
 
 
 
 
 
 
0.5 h 
X 
 
X 
 
 
 
 
1 h 
X 
 
X 
X 
 
X 
 
2 h 
X 
 
X 
X 
X 
X 
 
3 h 
X 
 
X 
X 
 
X 
 
4 h 
X 
 
X 
X 
X 
X 
 
5 h 
X 
 
 
 
 
 
 
6 h 
X 
 
X 
X 
X 
X 
 
8 h 
X 
 
X 
X 
 
X 
 
10 h 
 
 
X 
X 
 
 
 
11 h 
 
 
 
 
 
 
 
12 h 
X 
 
X 
X 
X 
X 
 
2 
-1.5 h 
 
 
 
 
 
 
X 
-1 h 
 
 
 
 
 
 
X 
Pre-dose (-0.5 h)b 
X 
 
X (Day 1, 24 h) 
X 
X (Day 1, 24 h) 
 
X 
0 h 
 
 
 
 
 
 
 
1 h 
 
 
 
 
 
 
 
2 h 
 
 
 
 
 
 
 
3 h 
 
 
 
 
 
 
 
4 h 
X 
 
 
X 
 
 
X 
5 h 
 
 
 
 
 
 
 
6 h 
X 
 
 
X 
 
 
X 
7 h 
 
 
 
 
 
 
 
8 h 
 
 
 
 
 
 
 
9 h 
 
 
 
 
 
 
 
10 h 
 
 
 
X 
 
 
 
11 h 
 
 
 
 
 
 
 
12 h 
X 
 
 
X 
 
 
X 
3 
-1.5 h 
 
 
X 
 
 
X 
 
-1 h 
 
 
X 
 
 
X 
 
Pre-dose (-0.5 h)c 
X 
X (Day 1, 48 h) 
X (Day 1, 48 h) 
X 
X 
X 
 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
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Page 86 of 92  
 
Study 
Day 
Time point 
Plasma PK 
Safety Labs 
and Urinalysis 
Holter Extractions 
Vital Signsa 
Orthostatic 
Vital Signs 
Single 
12-lead 
ECGs 
Triplicate 
12-lead 
ECGs 
0 h 
 
 
 
 
 
 
 
0.5 h 
X 
 
X 
X 
 
X 
 
1 h 
X 
 
X 
X 
 
X 
 
2 h 
X 
 
X 
X 
X 
X 
 
3 h 
X 
 
X 
X 
 
X 
 
4 h 
X 
 
X 
X 
X 
X 
 
5 h 
X 
 
 
 
 
 
 
6 h 
X 
 
X 
X 
X 
X 
 
7 h 
 
 
 
 
 
 
 
8 h 
X 
 
X 
X 
 
X 
 
9 h 
 
 
 
 
 
 
 
10 h 
 
 
X 
X 
 
 
 
11 h 
 
 
X 
 
 
 
 
12 h 
X 
 
X 
X 
X 
X 
 
4 
24 h 
X 
 
X 
X 
X 
X 
 
36 h 
X 
 
 
X 
 
 
X 
5 
48 h 
X 
X 
 
X 
 
 
X 
6 
72 h 
X 
 
 
X 
 
 
X 
7 
96 h 
X 
X 
 
X 
 
 
X 
9 
144 h 
X 
X 
 
X 
X 
 
X 
a Blood pressure, heart rate and respiratory rate at all time points. 
b 24 h post-dose Day 1 sample will be taken pre-dose on Day 2  
c 24 h post-dose Day 2 sample will be taken pre-dose on Day 3  
Allowable windows for PK blood sampling, vital signs assessments and ECGs can be found in: Sections 13.1, 14.6 and 14.7. 
 
 
 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
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Protocol MMV_MMV367_21_01 (QSC207031) Version 3.0 
 08 SEP 2022 
Page 87 of 92  
 
Appendix 8 
Breakfast Content (Part 2 only) 
Meal Description 
Energy from 
Fat (%) 
Composition 
High-Fat Breakfast 
(FDA approved)a 
57.90 
1 (40 g) hash brown, 2 (80 g) smoked rindless streaky bacon, 1 medium (45 g) egg fried in 10 g of butter, 
2 slices (95 g) of white sliced bread with 20 g of butter, 240 mL of full fat milk 
Values/content are approximate. Every effort will be made to include the items described above; however, items may be replaced as long as they contain the 
equivalent nutritional content as the item it has replaced. 
a For FDA high-fat breakfast, if a replacement item is required it will be of comparable volume and viscosity. 
 
 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
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 08 SEP 2022 
Page 88 of 92  
 
Appendix 9 
Example Taste/Palatability Questionnaire  
An example of the taste/palatability questionnaire can be found on the next page. 
 
 
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 08 SEP 2022 
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QSCXXXXXX (Sponsor Study Number) Taste Questionnaire 
 
Study Part:  
 
Test Product:  
 
Participant Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Initials:  
 
 
Start time:  
 
  
 
 
 
 
 
 
 
 
 
 
(to be completed within 10 minutes of tasting) 
 
Date:  
 
  
 
 
  
 
 
 
Question 1 
All aspects considered (smell, sweetness, bitterness, flavour, mouthfeel/texture, grittiness, and aftertaste), how would you rate your overall liking 
of this product:  
NOTE: Tick 1 box below in blue or black pen 
Question 2 
We want to know how much you like certain aspects of the product: smell, sweetness, bitterness, flavour, mouthfeel/texture, grittiness, and 
aftertaste. NOTE: Tick 1 box in the row for each aspect 
 
Dislike 
extremely 
Dislike very 
much 
Dislike 
moderately 
Dislike 
slightly 
Neither like 
nor dislike Like slightly 
Like 
moderately 
Like very 
much 
Like 
extremely 
N/A 
Smell 
 
 
 
 
 
 
 
 
 
 
Sweetness 
 
 
 
 
 
 
 
 
 
 
Bitterness 
 
 
 
 
 
 
 
 
 
 
Flavour 
 
 
 
 
 
 
 
 
 
 
Mouthfeel/texture 
 
 
 
 
 
 
 
 
 
 
Grittiness 
 
 
 
 
 
 
 
 
 
 
Aftertaste 
 
 
 
 
 
 
 
 
 
 
Entered 
into 
eCRF 
by 
(initials): 
 
Date: 
 
QC checked by (initials):  
Date: 
 
Dislike 
extremely 
Dislike very 
much 
Dislike 
moderately 
Dislike slightly 
Neither like nor 
dislike 
Like slightly 
Like 
moderately 
Like very much 
Like extremely 
 
 
 
 
 
 
 
 
 
 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
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Appendix 10 
Protocol Amendment Summary of Changes 
Version 3.0 dated 08 Sep 2022 
Due to logistics within the Quotient screening facility, it would be difficult to ensure 
subjects attend their end of study visit and have all the procedures performed within the 
± 1 h window, and would likely result in protocol deviations. Therefore, it was agreed to 
increase this window from ± 1 h to ± 1 day. 
In addition, clarifications were made throughout the protocol regarding the collection of 
urine for PK assessments, to ensure it is specific to Part 1, Cohorts 1C and 1D. 
Changes were also made to correct previous errors and inconsistencies. These changes 
include: 
• 
The removal of a physical examination and Holter procedure from Part 2 and Part 3 
appendices, respectively; 
• 
The addition of an ECG measurement to the Part 1 appendix; 
• 
The removal of an incorrect sentence from Section 14.7 ECG Measurements and 
14.8 Holter (continuous ECG) Monitoring; 
• 
The specification of which parts exclusion criterion 5 refers to; 
• 
An update to the Sponsor’s Clinical Lead/Contact details in the study contacts and 
sponsor signature page following a change in personnel; 
• 
The shading of blank boxes in the appendices tables to improve readability. 
In addition, minor typographical updates were made throughout. 
As these changes do not significantly affect the scientific value of the trial, the safety or 
physical or mental integrity of the subjects of the trial, this amendment was considered 
to be non-substantial. 
All relevant sections of the protocol were updated accordingly, including: 
• 
Document History Page 
• 
Section 3 Synopsis 
• 
Section 8.1.1 Study Plan: Part 1 – Single Ascending Dose Cohorts 
• 
Section 8.1.2 Study Plan: Part 2 – Food Effect Cohort 
• 
Section 8.1.3 Study Plan: Part 3 – Multiple Dose Cohort(s) 
• 
Section 9.3 Exclusion Criteria 
• 
Section 10.3.5 End of Study Visits 
• 
Section 13.1.1 Blood Sampling for Pharmacokinetics and Metabolite Identification 
• 
Section 14.5.1 Haematology, Clinical Chemistry and Coagulation 
• 
Section 14.5.2 Urinalysis 
• 
Section 14.6 Vital Signs Measurements 
• 
Section 14.7 ECG Measurements 
• 
Section 14.8 Holter (continuous ECG) Monitoring 
• 
Section 15.3 Pharmacokinetic Data Analysis 
• 
Appendix 2 Schedule of Assessments: Part 1 (Cohorts 1A to 1E) 
• 
Appendix 3 Schedule of Assessments: Part 2 
• 
Appendix 4 Schedule of Assessments: Part 3 (Cohorts 3A to 3C) 
• 
Appendix 5 Part 1 (All Cohorts) Safety and Pharmacokinetic Assessment Time Points 
(Days 1 to 7) 
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• 
Appendix 7 Part 3 Safety and Pharmacokinetic Assessments Time Points (Days 1 to 
9) 
• 
Signatures for Sponsor Page 
Version 2.0 dated 01 Jun 2022 
The following revision was made to the protocol in response to a Grounds for 
Non-Acceptance (GNA) request from the MHRA: 
Section 8.5 (Overall Study Stopping Rules): The following stopping criterion, “At least 
three participants experience a similar AE assessed as severe and considered related 
to IMP” has been replaced with: “Two severe non-serious adverse reactions considered 
as, at least, possibly related to the IMP administration in two subjects in the same cohort, 
independent of within or not within the same system-organ-class are observed”. 
 
Signatures for Quotient Sciences 
CONFIDENTIALITY AND GCP COMPLIANCE STATEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
and any other product information provided by the sponsor. I agree to conduct this study 
in accordance with the requirements of this protocol and also protect the rights, safety, 
privacy, and well-being of study participants in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki. 
• 
International 
Council 
for 
Harmonisation 
of 
Technical 
Requirements 
for 
Pharmaceuticals for Human Use E6 (R2) Good Clinical Practice: Consolidated 
Guideline. 
• 
All applicable laws and regulations, including, without limitation, data privacy laws 
and regulations. 
• 
Regulatory requirements for reporting serious adverse events defined in Section 16.3 
of this protocol. 
Information taken from the study protocol may not be disseminated or discussed with a 
third party without the express consent of the sponsor. 
Nand Singh BSc, MD, DPM, MFPM  
See electronic signature at the end of the 
document 
Principal Investigator 
Signature 
Senior Clinical Research Physician 
 
 
Date 
 
 
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
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Signatures for Sponsor
Stephan Chalon, MD, PhD
VP - Head Experimental & Clinical 
Pharmacology
Signature
Date
Myriam El Gaaloul
Director, Clinical Sciences
Signature
Date
September 9th, 2022
9-Sep-2022
ature
p-2022

Document Approvals
Approved Date: 09 Sep 2022
Document Author(s):  Gemma Bell 
Approval Task
Verdict:  Approve
Nand Singh, Medical Director
(Nand.Singh@quotientsciences.com)
Functional / Technical Approval
09-Sep-2022 11:02:12 GMT+0000
Number: DOC-87929               Version: 3.0               Status: Approved    Approved Date: 09 Sep 2022
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