Conditions: Malaria
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 64
Healthy volunteers: yes

Brief summary:
The First in Human (FIH) study is separated into two parts:

* The first part is a Single Ascending Dose (SAD), double-blinded, randomized and placebo-controlled, including 8 cohorts of 8 subjects (2 placebo and 6 on active drug).
* The second part is a food effect cohort with an open-labelled, randomized fed/fasted cross-over design.

The main objectives of the study are to confirm safety, tolerability and Pharmacokinetics (PK) of P218 in healthy volunteers.

Detailed description:
The study is divided into two parts:

Part A

This is a double-blind randomised, placebo-controlled, parallel group, ascending dose study and will comprise up to eight fasted cohorts (8 volunteers in each) that will receive a single ascending dose (SAD) of P218 to assess its safety, tolerability and pharmacokinetic profile. Each subject will participate in only one dose group and will receive only one dose of study drug. In each cohort, 2 and 6 subjects will be randomized to placebo and P218, respectively. The data obtained from each cohort will undergo a formal review by the Safety Review Team (SRT). SRT will confirm that it is safe to proceed with the next dose/cohort.

Part B

This is the pilot food effect evaluation. Once predicted human efficacious concentrations of P218 and a safe exposure window (at least 3-fold above the targeted therapeutic exposure in order to account for a possible increase in exposure with food) has been achieved in Part A, a new cohort of 8 subjects (all receiving active drug) will be evaluated for food effect in an open-label, randomized fed/fasted crossover design. Subjects participating in this food effect cohort will be randomized to two single dose sessions (fed/fasted). The second dose will be administered after a washout period of at least 5x observed human half-life (T1/2), to be confirmed once PK data are available from the relevant doses from Part A.

Primary objectives:

* To investigate the safety and tolerability of single escalating oral doses of P218 when administered to healthy volunteers (men and Women of Non Child Bearing Potential (WNCBP)) under fasted conditions.

Secondary objectives:

* To describe the pharmacokinetics of P218 and its major glucuronide metabolite (P218 acyl glucuronide) in healthy volunteers (men and WNCBP) after administration of single escalating oral doses
* To investigate the effect of a high fat meal on the pharmacokinetics and safety/tolerability of P218.

This study incorporates the use of an adaptive design. All anticipated dosing levels can be adjusted in accordance with PK, safety and tolerability data collected up to the decision making time-point.

Arms:
arm 1: Oral administration of P218 capsules 10 mg arm 2: Oral administration of P218 capsules 30 mg arm 3: Oral administration of P218 capsules 100 mg arm 4: Oral administration of P218 capsules 250 mg arm 5: Oral administration of P218 capsules 500 mg arm 6: Oral administration of P218 capsules 750 mg arm 7: Oral administration of P218 capsules 1000 mg arm 8: Oral administration of P218 matching placebo arm 9: Oral administration of P218 capsules 250 mg Under fed then fasted conditions. arm 10: Oral administration of P218 capsules 250 mg Under fasted then fed conditions.

Interventions: intervention 1: Oral administration of P218 capsules intervention 2: Oral administration of P218 matching placebo
Intervention descriptions: intervention 1: Oral administration of P218 capsules. The number of capsules is determined by the dose level of the cohort. intervention 2: Oral administration of P218 matching placebo. The number of capsules is identical to the corresponding number of P218 capsules administered to the volunteers on the investigational drug.

Protocol document:
Prot_000.pdf: 
 
 
 
CLINICAL STUDY PROTOCOL 
Sponsor’s Reference Number: MMV_P218_15_01 
Richmond Pharmacology Study Number: C16009 
EudraCT Number: 2016-001933-29 
 
TITLE: 
A Phase I study to investigate the safety, tolerability and 
pharmacokinetic profile and food effect of P218 in healthy adult 
volunteers 
PHASE: 
Phase 1 
DRUG: 
P218 
SPONSOR: 
Medicines for Malaria Venture 
PRINCIPAL 
INVESTIGATOR: 
Dr Ulrike Lorch, MD FRCA FFPM  
Richmond Pharmacology Ltd. 
St George’s University of London 
Cranmer Terrace, Tooting 
London SW17 0RE, UK 
Telephone: 
+44 (0)20 7042 5800 Fax: 
+44 (0)20 7378 9135 
STUDY SITE: 
Richmond Pharmacology Ltd. 
1A Newcomen Street, London Bridge, London, SE1 1YR, UK 
Croydon University Hospital, Thornton Wing, 530 London Road, 
Croydon, CR7 7YE, UK  
Protocol Version 
and Date: 
Version 4.0 
31 Oct 2017 
Information in this protocol is confidential and should not be disclosed, other than to 
those directly involved in the execution or the ethical/regulatory review of the study, 
without written authorisation from MMV or its affiliates. 


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1. 
PROTOCOL APPROVAL SIGNATURES 
Version 4.0 dated 31 Oct 2017 
Sponsor’s Approval 
This protocol has been approved by MMV. 
Sponsor’s Signatory:  
 
Name:  
Signature: 
Dr Emilie Rossignol 
 
 
Date: 
 
 
 
 
Name:  
Signature: 
Dr Stephan Chalon 
 
Date: 
 
 
 
 
Name:  
Signature: 
Dr Stephan Duparc 
 
Date: 
 
 
 
 
 
 
 
 
 
 
 




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2. 
STUDY PERSONNEL 
 
Sponsor’s Representative 
 
Dr Jörg Täubel MD FFPM 
Richmond Pharmacology Ltd. 
 
Sponsor’s Main Contact 
 
Dr Emilie Rossignol, Project Director 
Medicines for Malaria Venture 
ICC – Block G, 3rd floor 
20, Route de Pré-bois  
PO Box 1826 
1215 Geneva 15 
Switzerland 
Phone:           +41 22 555 0335 
Mobile:           +41 79 934 4083  
Fax:               +41 22 555 0369 
e-mail: rossignole@mmv.org 
 
Sponsor’s Medical Director  
Dr. Stephan Chalon 
Medicines for Malaria Venture 
Phone:           +41 22 555 0379 
Mobile:          .+41 79 962 9244 
Fax:                +41 22 555 0369 
e-mail: chalons@mmv.org 
 
Sponsor’s Chief Medical 
Officer 
 
 
 
 
 
Dr Stephan Duparc 
Medicines for Malaria Venture 
Phone: +41 22 555 0351 
e-mail: duparcs@mmv.org 
 
Principal Investigator 
 
Dr Ulrike Lorch MD FRCA FFPM 
Phone: +44 (0)20 70428500 
e-mail: u.lorch@richmondpharmacology.com 
 
Co-investigators 
Dr Jörg Täubel MD FFPM  
 
 
 


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Study Site 
Richmond Pharmacology Ltd. 
Croydon University Hospital,  
Thornton Wing,  
530 London Road,  
Croydon, 
CR7 7YE,  
UK  
 
1A Newcomen Street 
London Bridge 
London, 
SE1 1YR 
UK 
 
Clinical Laboratory 
 
The Doctor’s Laboratory  
60 Whitfield Street  
London W1T 4EU, UK 
  
Data Management 
Richmond Pharmacology Ltd. 
 
Statistics 
Richmond Pharmacology Ltd. 
 
Qualified Person 
Dr Radivoj Arezina, MD MSc 
 
Pharmacovigilance 
 
Susanne Riester 
Operations Manager 
Quintiles AG 
Hochstr. 50 
CH-4053 Basel 
Switzerland 
Office: + 41 61 270 81 81  
Direct:  + 41 61 270 81 66 
Fax:     + 41 61 270 81 80 
susanne.riester@quintiles.com 
 
Medical Writing 
 
Dr Juleen Gayed MBBS MSc MFPM 
Dr Patrick de Barr MBBS BmedSci 
Dr Timothy Hill MBBS Bsc 
Mihaela Cardas PhD 
Richmond Pharmacology Ltd. 


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3. 
TABLE OF CONTENTS 
 
6. 
INTRODUCTION ............................................................................................ 20 
6.1 
Pharmacokinetic properties ............................................................................. 21 
6.2 
Rationale for conducting study ........................................................................ 23 
6.3 
Risk-benefit evaluation .................................................................................... 23 
6.3.1 
Potential Benefits ...................................................................................... 23 
6.3.2 
Potential Risks .......................................................................................... 23 
6.3.2.1 
Non-clinical studies ......................................................................... 23 
6.3.2.2 
Clinical Studies ............................................................................... 26 
6.3.2.3 
Serum folate levels ......................................................................... 27 
7. 
STUDY OBJECTIVES AND OUTCOMES ....................................................... 27 
7.1 
Objectives ....................................................................................................... 27 
7.1.1 
Primary objectives .................................................................................... 27 
7.1.2 
Secondary objectives ................................................................................ 27 
7.1.3 
Exploratory objectives ............................................................................... 27 
7.2 
Endpoints ........................................................................................................ 28 
7.2.1 
Primary endpoints ..................................................................................... 28 
7.2.2 
Secondary endpoints ................................................................................ 28 
7.2.3 
Exploratory endpoints ............................................................................... 28 
8. 
STUDY DESIGN ............................................................................................. 28 
8.1 
Overall study design and procedure ................................................................ 28 
8.2 
Rules for dose escalation/progression ............................................................ 42 
8.2.1 
Safety Review Committee......................................................................... 42 
8.2.2 
Data requirements .................................................................................... 42 
8.2.3 
SRC Meeting ............................................................................................ 43 
8.2.4 
Dose escalation/progression ..................................................................... 43 
8.3 
Toxicity rules ................................................................................................... 44 
8.3.1 
Group toxicity rules (Part A and Part B) .................................................... 44 
8.3.2 
Individual toxicity rules (Part B only) ......................................................... 47 
8.3.3 
PK exposure limit ...................................................................................... 47 
8.4 
Rationale for study design, doses and control groups ..................................... 48 
8.4.1 
Estimation of first dose ............................................................................. 48 
8.4.2 
Justification of the planned highest dose level .......................................... 50 
8.4.3 
Choice of subjects for study ...................................................................... 51 
8.4.4 
Route and rate of administration ............................................................... 51 
8.4.5 
Precautions to be applied for dosing between subjects within a cohort ..... 51 


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8.4.6 
Precautions to be applied for dosing between different cohorts ................ 51 
8.4.7 
Monitoring and communication of adverse events / reactions ................... 52 
8.4.8 
Investigator Site Facilities and Personnel ................................................. 52 
9. 
SELECTION AND WITHDRAWAL OF SUBJECTS ......................................... 52 
9.1 
Number and Source of Subjects ..................................................................... 52 
9.2 
Inclusion Criteria ............................................................................................. 52 
9.3 
Exclusion criteria ............................................................................................. 54 
Subjects will be prohibited from participating in this study if they meet any of these 
criteria: ............................................................................................................ 54 
9.4 
Subject Restrictions ........................................................................................ 56 
9.5 
Subject Inclusion and Randomisation ............................................................. 56 
9.6 
Criteria for withdrawal ..................................................................................... 57 
9.6.1 
Handling of Withdrawals ........................................................................... 57 
10. 
STUDY AND CONCOMITANT TREATMENTS ............................................... 57 
10.1 
Investigational Medicinal Products (IMPs) ....................................................... 57 
10.2 
Labelling of IMPs ............................................................................................ 59 
10.3 
Drug Accountability ......................................................................................... 59 
10.4 
Blinding and Procedures for Unblinding the Study .......................................... 59 
10.4.1 Methods for ensuring blinding ................................................................... 59 
10.4.2 Methods for unblinding the study .............................................................. 59 
10.5 
Concomitant Medications/Permitted medications ............................................ 60 
11. 
STUDY PROCEDURES .................................................................................. 60 
11.1 
Schedule of Study Procedures ........................................................................ 60 
12. 
STUDY METHODOLOGY ............................................................................... 60 
12.1 
Meals .............................................................................................................. 60 
12.2 
Haematology, biochemistry and coagulation ................................................... 60 
12.3 
Serology.......................................................................................................... 62 
12.4 
Urinalysis ........................................................................................................ 63 
12.5 
Pregnancy test ................................................................................................ 63 
12.6 
Drugs of Abuse ............................................................................................... 63 
12.7 
Alcohol Breath Test ......................................................................................... 63 
12.8 
Physical Examination, Height and Weight ....................................................... 63 
12.9 
Vital Signs ....................................................................................................... 63 
12.9.1 Blood pressure, heart rate and tympanic temperature .............................. 63 
12.10 Electrocardiographic (ECG) Measurements .................................................... 64 
12.10.1 Recording of 12-lead ECGs ...................................................................... 64 
12.10.2 Safety review of 12-lead ECGs ................................................................. 64 


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12.10.3 Real time display (ECG telemetry) ............................................................ 64 
12.10.4 Analysing and over-reading 12-lead ECG for the purpose of intensive 
cardiac assessments ................................................................................ 65 
12.11 Pharmacokinetic Assessments ....................................................................... 65 
12.11.1 PK blood samples ..................................................................................... 65 
12.11.2 PK urine samples ..................................................................................... 66 
12.11.3 Serum and Red Blood Cell folate levels .................................................... 66 
12.11.4 Malaria bioassay ....................................................................................... 66 
12.11.5 Pharmacogenetics ..................................................................................... 66 
12.12 Volume of Blood Sampling .............................................................................. 67 
13. 
ADVERSE EVENTS........................................................................................ 67 
13.1 
Adverse Events ............................................................................................... 67 
13.1.1 Definitions ................................................................................................. 67 
13.1.2 Classification ............................................................................................ 68 
13.1.3 Recording of adverse events and follow-up .............................................. 71 
13.1.4 Reporting of serious adverse events ......................................................... 71 
14. 
QUALITY ASSURANCE AND QUALITY CONTROL ....................................... 73 
14.1 
Quality Assurance and Quality Control ............................................................ 73 
14.2 
Monitoring ....................................................................................................... 73 
15. 
STATISTICAL ANALYSIS ............................................................................... 74 
15.1 
Statistical Analysis Plan .................................................................................. 74 
15.2 
Analysis Sets .................................................................................................. 74 
15.3 
Analysis and Presentation of Data .................................................................. 74 
15.4 
Subject Demographics and Baseline Characteristics (Parts A and B) ............. 74 
15.5 
Statistical analysis of safety ............................................................................ 74 
15.6 
Pharmacokinetics ............................................................................................ 75 
15.7 
Exploratory ...................................................................................................... 76 
15.7.1 Pharmacodynamics .................................................................................. 76 
15.7.2 Pharmacogenetics .................................................................................... 76 
15.8 
Handling of Missing and Incomplete Data ....................................................... 76 
15.9 
Determination of sample size .......................................................................... 76 
15.9.1 Sample Size Calculation ........................................................................... 76 
15.9.2 Part A (SAD): ............................................................................................ 76 
15.9.3 Part B (Food effect): ................................................................................. 76 
16. 
DATA MANAGEMENT .................................................................................... 77 
16.1 
Case Report Forms ......................................................................................... 77 


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17. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ........................... 78 
17.1 
Sponsor’s Responsibilities .............................................................................. 78 
17.1.1 GCP compliance ....................................................................................... 78 
17.1.2 Regulatory approval .................................................................................. 78 
17.1.3 Indemnity/liability and insurance ............................................................... 78 
17.1.4 Protocol management ............................................................................... 78 
17.1.5 End of trial notification .............................................................................. 78 
17.1.6 Submission of summary of clinical trial report to competent authorities of 
member states concerned and RECs Regulatory approval ....................... 78 
17.2 
Investigator’s Responsibilities ......................................................................... 79 
17.2.1 GCP compliance ....................................................................................... 79 
17.2.2 Protocol adherence and investigator agreement ....................................... 79 
17.2.3 Documentation and retention of records ................................................... 79 
17.3 
Ethical Considerations .................................................................................... 79 
17.3.1 Informed consent ...................................................................................... 79 
17.3.2 Research Ethics Committee (REC) approval ............................................ 80 
17.4 
Confidentiality ................................................................................................. 80 
17.5 
Publication Policy ............................................................................................ 80 
18. 
REFERENCES ............................................................................................... 81 
19. 
APPENDIX LIST ............................................................................................. 82 
 
 
 
 


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LIST OF TABLES 
Table 1. Adaptive protocol features ............................................................................. 29 
Table 2. Study Plan – Part A: Single Ascending Dose ................................................ 36 
Table 3. Study Plan – Part A (continuation) ................................................................ 38 
Table 4. Study Plan – Part B: Food effect ................................................................... 40 
Table 5. Study Plan – Part B (continuation) ................................................................ 41 
Table 6. WHO Toxicity Grading .................................................................................. 44 
Table 7. Group Toxicity Rules for progression to consecutive trial parts and/or 
escalation to higher exposure dosing regimens. ....................................... 41 
Table 8. Individual toxicity rules. ................................................................................. 43 
Table 9. IMP or matching placebo for each anticipated dose level (Part A) ................. 58 
Table 10. IMP or matching placebo for the anticipated dose level (Part B) .................. 58 
Table 11. Laboratory parameters. ............................................................................... 61 
 
 
 
LIST OF FIGURES 
Figure 1. Part A flow chart........................................................................................... 35 
Figure 2. Part B flow chart .......................................................................................... 35 
 
 


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4. 
LIST OF ABBREVIATIONS 
Abbreviation 
Explanation 
ACE 
: Angiotensin-converting enzyme 
ACT 
: Artemisinin containing combination therapies 
AESI 
: Adverse event of special interest 
ALT 
: Alanine aminotransferase 
 
API 
: Active pharmaceutical ingredient 
AUC0-t 
: The area under the plasma (or serum or blood) concentration-time curve 
from time zero to time ‘t’ where t is a defined time point after administration 
AUCinf 
: The area under the plasma (or serum or blood) concentration-time curve 
from time zero to infinity 
AUClast 
: The area under the plasma (or serum or blood) concentration-time curve 
from time zero to the time of the last quantifiable concentration 
BZD 
: Benzodiazepine 
Ca 
: Calcium 
CEREP 
: A broad screen of receptors, enzymes and channels 
CL 
: Clearance 
CL/F 
: Apparent total clearance of the drug from plasma after oral administration 
Cmax 
: The observed maximum plasma (or serum or blood) concentration 
following drug administration 
CNS 
: Central nervous system 
CRF 
: Case report form 
CYP 
: Cytochrome P450 
DBP 
: Diastolic blood pressure 
DNA 
: Deoxyribonucleic acid 
DHFR 
: Dihydrofolate reductase 
DRF 
: Dose range finding 
ECG 
: Electrocardiogram 
ED90 
: Effective dose for 90% of the animals 
F 
: Oral bioavailability 


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FSH 
: Follicule stimulating hormone 
GABA 
: Gamma-aminobutyric acid 
GCP 
: Good clinical practice 
GI 
: Gastrointestinal 
GLP 
: Good Laboratory Practice 
GMP 
: Good Manufacturing Practice 
G6PDH 
: Glucose 6-phosphate dehydrogenase 
Hb 
: Hemoglobin 
hERG 
: Human Ether-à-go-go related gene  
HEK 
: Human embryonic kidney cells 
HPMC 
: Hydroxypropylmethylcellulose 
HR 
: Heart rate 
huRBC 
: Human red blood cells 
IC90 
: Median Inhibitory Concentration (concentration that reduces the effect by 
90%) 
ICF 
: Informed consent form 
ICH 
: International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IPTp 
: Intermittent preventive treatment during pregnancy 
IV 
:Intravenous 
K 
: Potassium 
Ki 
: Inhibtion constant 
LC-MS/MS 
: Liquid chromatography coupled to tandem mass spectrometry 
LH 
: Luteinizing hormone 
LLOQ 
MAD 
: Lower limit of quantification 
: Multiple ascending dose 
MAO-B 
: Monoamine oxidase B 
M:E 
: Myeloid: erythroid ratio 
MIC 
: Minimum Inhibitory Concentration (minimum concentration that will inhibit 
growth of the target pathogen) 


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MTD 
: Maximum tolerated dose 
Na 
: Sodium 
NADPH 
NCE 
NHMRC 
: Nicotinamide adenine dinucleotide phosphate 
: New chemical entity 
: National statement on ethical conduct in human research 
NOAEL 
: No observed adverse effect level 
OTC 
: Over the counter 
Papp 
: Apparent permeability 
PD 
Pgp 
: Pharmacodynamic 
: P-glycoprotein 
PK 
: Pharmacokinetic 
PO 
: Oral dose 
PRR 
: Parasite reduction ratio 
R0 
: Accumulation ratio 
RH 
: Relative humidity 
RBC 
SBP 
SAD 
SAE 
: Red blood cell 
: Systolic blood pressure 
: Single ascending dose 
: Serious adverse event 
SCID 
: Severe combined immunodeficiency 
SD 
: Single dose 
SMFA 
: Standard membrane feeding assay 
SRT 
: Safety review team 
SUSAR 
: Suspected, unexpected serious adverse reaction 
TPMT 
: Thiopurine S-methyl transferase 
t1/2 
The terminal elimination half-life 
Tmax 
The time to reach the maximum concentration after drug administration 
UDPGA 
: Uridine 5'-diphospho-glucuronic acid 
UGT 
: Uridine diphosphoglucuronosyl transferase 


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Vss 
: Steady state volume of distribution 
Vz/F 
: Apparent volume of distribution during terminal phase after non-
intravenous administration 
 
WHO 
: World Health Organization 
WCBP 
WNCBP 
: Women of child bearing potential 
: Women of non-childbearing potential 
 
 


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5. 
STUDY SYNOPSIS 
Protocol Ref. MMV_P218_15_01 
Study drug: P218 
Title of the study: A Phase I study to investigate the safety, tolerability and pharmacokinetic profile and food 
effect of P218 in healthy adult volunteers 
Principal Investigator:  
Dr Ulrike Lorch, MD FRCA FFPM  
Study centre:  
Richmond Pharmacology Ltd. 
St George’s University of London, Cranmer Terrace, Tooting, London, SW17 0RE, UK 
Croydon University Hospital, Thornton Wing, 530 London Road, Croydon, CR7 7YE, UK 
 
1a Newcomen Street, London Bridge, London, SE1 1YR, UK 
Study Parts: A, B 
 
Clinical phase: 1 (The study does not have therapeutic or 
prophylactic intent and does not plan to assess efficacy) 
Objectives: 
Primary 
• 
To investigate the safety and tolerability of single escalating oral doses of P218 when administered to 
healthy volunteers (men and WNCBP) under fasted conditions. 
Secondary 
• 
To describe the pharmacokinetics of P218 and its major metabolites (P218 β acyl glucuronide, P218-OH 
and P218-OH β acyl glucuronide) in healthy volunteers (men and WNCBP) after administration of single 
escalating oral doses 
• 
To investigate the effect of a high fat meal on the pharmacokinetics and safety/tolerability of P218. 
Exploratory 
• 
To perform ex-vivo bioassay analysis against malaria parasites to confirm that P218 β acyl glucuronide is 
active against Plasmodium parasite and determine if other active metabolites are formed. 
• 
To assess the effects of P218 on serum folate levels in healthy subjects 
•       To evaluate the cardiovascular safety profile of P218, assessing qualitative and quantitative ECG variations 
from baseline following dosing, in particular any effects on the QTc interval. 
• 
To identify inherited genetic factors which may (1) predict response to treatment with P218, (2) explain 
variability in drug PK/PD, (3) predict susceptibility to drug-drug interactions, or (4) predict the occurrence of 
safety issues. The aim of such exploratory research will be to develop a better understanding of intrinsic 
and extrinsic factors that may affect the pharmacokinetics of P218 in human subjects. 
 
Endpoints: 
Primary 
• 
Safety and tolerability of P218: Incidence, severity and relationship to the investigational product of 
observed and self-reported adverse events following administration of a single oral dose of P218 to 
healthy volunteers under fasted conditions. 
 
 
 


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Secondary 
• 
Estimation of the following PK parameters following  administration of a single dose of P218 (in fasted 
and fed cohorts) using non-compartmental methods: AUClast, AUCinf, Cmax, Tmax, t1/2 ,MRT, CL/F (for 
parent only), Vz/F (for parent only) and metabolites ratio. 
Exploratory 
• 
To determine the efficacy of P218 against parasites using an ex-vivo malaria assay : IC50 
• 
Absolute change from baseline P218 on serum folate levels over time 
• 
The paired PK and QTc interval parameters pre-dose compared to post-administration of P218. Clinically 
significant ECG morphology and interval changes from baseline. 
• 
Exploration of CYP and Uridine diphosphate glucuronosyltransferase (UGT) isoforms. |Exploration of 
other enzymes and transporters in accordance with evolving data.   
 
Study Design: 
The study is divided into two parts: 
Part A  
This is a double-blind randomised, placebo-controlled, parallel group, ascending dose study and will comprise 
seven fasted cohorts (8 volunteers in each) that will receive a single, ascending dose (SAD) of P218 to assess 
its safety, tolerability and pharmacokinetic profile. Each subject will participate in only one dose group and will 
receive only one dose of study drug. In each cohort, 2 and 6 subjects will be randomized to placebo and P218, 
respectively. The data obtained from each cohort will undergo a formal review by the Safety Review Team (SRT). 
SRT will confirm that it is safe to proceed with the next dose/cohort. 
 
Part B  
This is the pilot food effect evaluation. The dose is to be selected so that the predicted P218 exposure remains 
3 fold below the maximum observed exposure achieved in part A and considered to be safe and well tolerated 
(in order to account for a possible increase in exposure with food). A new cohort of 8 subjects (all receiving active 
drug) will be evaluated for food effect in an open-label, randomized fed/fasted crossover design. Subjects 
participating in this food effect cohort will be randomized to two single dose sessions (fed/fasted). The second 
dose will be administered after a washout period of at least 5x observed human T1/2, to be confirmed once PK 
data are available from the relevant doses from Part A.  
Diagnosis and main criteria for admission: 
Healthy male and/or female (of non-child bearing potential) subjects will be included if they are aged between 18 
and 45 years with a body mass index (BMI) between 18-25 kg/m2; and a total body weight >50 kg (110 lbs), male 
subjects must agree to use an effective contraceptive method.  
Main exclusion criteria are: male subjects with a female partner(s) who is (are) pregnant or lactating from the 
time of the administration of study medication, women of childbearing potential (WCBP), subject has any 
surgical or medical condition possibly affecting drug absorption (e.g. cholecystectomy, gastrectomy, bowel 
disease, etc.), distribution, metabolism or excretion. Subjects with a medical history of cholecystitis and/or 
cholelithiasis. Subject has a clinically significant disease, allergy or clinical significant abnormal laboratory, 
ECG, vital signs or other safety findings as determined by medical history, physical examination or other 
evaluations conducted at screening or on admission. Subjects with documented megaloblastic anaemia 
secondary to folate deficiency. Subject has Serum folate levels below normal range (as determined by the local 
laboratory reference ranges) at screening. 
Test treatment(s) and mode of administration: 
Part A (Anticipated doses) 
Cohort 1: 10mg (one oral single dose of 10 mg) 
Cohort 2: 30mg (three oral single doses of 10 mg) 
Cohort 3: 100mg (two oral single doses of 50 mg) 
Cohort 4: 250mg (one oral single doses of 250 mg) 
Cohort 5: 500mg (two oral single doses of 250 mg) 


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Cohort 6: 750mg (three oral single doses of 250 mg) 
Cohort 7: 1000mg (four oral single doses of 250 mg) 
 
Anticipated doses will be determined after satisfactory review of all safety, tolerability and PK data by the Safety 
Review Committee in accordance with the Adaptive Features ( 
 
Table 1), rules for dose escalation/progression and toxicity. 
 
Part B 
Anticipated doses will be determined after satisfactory review of all safety, tolerability and PK data by the Safety 
Review Committee in accordance with the Adaptive Features ( 
 
Table 1), rules for dose escalation/progression and toxicity. 
 
Reference treatment(s) and mode of administration: 
Oral dose of placebo to match P218. 
 
Anticipated duration of treatment: 
Part A 
A single oral dose of P218 per study cohort on Day 1.  
 
Part B 
A single oral dose of P218 under fasted or fed conditions in two different dosing periods.  
Criteria for evaluation: 
Safety  
Safety and tolerability will be evaluated at regular time-points up to the last follow-up visit for reported adverse 
events (AEs), scheduled physical examinations, vital sign measurements (including orthostatic changes in BP 
and HR), cardiac rhythm monitoring (telemetry), 12-lead triplicate ECGs, and clinical laboratory test results. 
 
Pharmacokinetic  
Blood and urine samples will be obtained to determine the PK of orally administered P218. 
Part A and Part B 
Venous blood samples (0.5mL) will be obtained within 2 hours before P218 administration and at 0.25, 0.5, 1, 
2, 4, 6, 7, 8, 12, 24, 48, 72, 120, 168, 192 and 240 h after administration (Part A). For those subjects 
participating in the food-effect group (Part B), blood samples will be collected at the same times during both 
periods (fed/fasted). These time points will be; 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72 and 120 h after 
administration. 
Single-dose PK values such as Cmax, T1/2 and AUC (parent and metabolites) will be derived from the plasma 
concentration versus time and urinary excretion data. 
Urine samples will be collected for determination of P218 concentrations on Day 1 before test article 
administration and at 0 to 6, 6 to 12, 12 to 24, and 24 to 48 hours after administration (Part A only). The date, 
actual collection time, pH, collection volumes, and urine creatinine will be recorded in the source documents.  
For subjects participating in the food-effect group, urine samples will not be collected. 
A non-compartmental PK method, as appropriate, will be used to analyze the plasma concentrations of P218,  
P218 β acyl glucuronide, P218-OH and P218-OH β acyl glucuronide and urine concentrations of P218. 
Urine PK analysis for P218 will be conducted with the highest dose cohort achieved in the study [1 cohort] 
initially, using a non-validated assay. If significant amounts are detected [greater than 10% is detected], urine 
from this cohort and the lower dose cohorts will be assayed with a validated assay. If minimal amounts are 
detected [less than 10% is detected] in this cohort, no further analysis will be conducted (to be confirmed). 
 


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Pharmacodynamics  
• 
Malaria ex-vivo assay  
For Malaria ex-vivo assay, samples of approximately 2.5 mL of whole blood will be collected at the same time 
as PK samples into a serum separating tube (SST). 
These samples will be used for future bioassay analysis against malaria parasites in vitro to confirm that P218 
β acyl glucuronide metabolite is active against Plasmodium parasite.  The samples will be stored frozen at the 
clinical site at -15 °C or lower pending analysis. 
• 
Serum and Red Blood Cell Folate 
Part A: 
Samples of venous blood will be collected at the same time as safety samples (at screening, on admission and 
24, 72 and 240 hours after administration of P218).  
Part B: 
Samples of venous blood will be collected at the same time as safety samples (at screening, on admission and 
24, 72 and 120 hours after administration of P218).  
These samples may be used for potential future analysis of the possible effect of P218 on folate levels.  
• 
 Intensive cardiac assessments (Part A only) 
Triplicate 12-lead ECGs will be taken in parallel with every PK sample, enabling a potential PK/PD analysis of 
QT/QTC changes compared to baseline (3x triplicate ECGs pre-dose).  In addition, 3 triplicate ECGs will be taken 
within 4 hours post the scheduled lunch to confirm validity of the 12-lead ECGs by demonstrating shortening of 
the QTc interval. 
Statistical Methods:  
A statistical analysis plan (SAP) containing detailed statistical methodology will be written and signed off before 
the unblinding of the study. The plan will be updated to reflect Adaptive Features of the study as appropriate. 
 
Statistical analysis of safety parameters 
All subjects that were enrolled and received a dose of the study drug will be included in the data analysis. In Part 
A, subjects will be analysed as treated (i.e. in accordance with the study drug received, even if different from the 
one to which they were randomised).  In all treatment and dose group comparisons for Part A, data from all 
subjects who received placebo will be pooled. 
The subject disposition will be summarised. Data for background and demographic variables will be listed and 
summarised descriptively by treatment and dose.  Medical history, current medical conditions, results of 
laboratory screening tests, drug tests and any other relevant baseline information will be listed by treatment, 
dose and subject.  Previous and concomitant medication will be listed per treatment and dose level. 
Adverse event data will be summarised by treatment, dose, MedDRA system organ class, MedDRA preferred 
term and severity (WHO grading).  Vital signs, routine safety laboratory data and ECG parameters will be 
summarised descriptively by treatment, dose, and time point.  Absolute values and change from baseline will be 
presented. A categorical analysis of QTcF changes from baseline will be presented.  Listings of clinically relevant 
abnormal laboratory results will be generated. 


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Statistical analyses of pharmacokinetic parameters 
The following pharmacokinetic parameters will be determined using non-compartmental method(s) from plasma 
concentration-time data from all dose cohorts: AUClast, AUCinf, Cmax, Tmax, t1/2, MRT, CL/F (for parent only), Vz/F 
(for parent only) and metabolites ratio.  These data will be summarized descriptively by treatment and dose. 
Statistical analyses of exploratory data 
Pharmacodynamic parameters  
• 
Serum folate levels 
Serum Folate Levels values and changes from baseline will be listed and summarised using descriptive 
statistics per treatment and time point including graphs as applicable.  
• 
Ex-vivo malaria assay 
Analysis of bioassay sample results may be performed to assess the efficacy of the P218. 
• 
ECG analysis 
ECG analysis will be compliant with the correct recording and manual adjudication of ECGs in thorough 
QT/QTc studies. 
Pharmacogenetics  
Pharmacogenetics samples will be stored for future optional analysis.  
Rationale for sample size 
Part A  
Because the primary objective is an initial assessment of safety, each treatment group is limited to 6 subjects 
receiving P218. Administration of P218 to 6 subjects in each dose group 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 placebo subjects who received placebo from each 
cohort will provide an adequately sized control group. 
Part B 
This is a pilot evaluation designed to determine whether P218 PK is impacted by food. Historically 8 
participants in a dose cohort have proven sufficient to characterize the preliminary effects of food on safety and 
PK of a new chemical entity in healthy subjects. Therefore, the size of the current cohort (n=8) is considered 
adequate at this stage of the drug development process. 
 
 


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6. 
INTRODUCTION 
Malaria is an infectious disease that threatens half of the world’s population and is caused 
mainly by two protozoan parasites: Plasmodium falciparum and Plasmodium vivax. The World 
Health Organization (WHO) reported 198 million cases of the disease in 2013 out of an 
estimated 3.2 billion people at risk for the disease. In the same year, malaria caused 584,000 
deaths; 90% of the mortality was in Africa, with children <5 years of age attributing 78% of 
deaths (World Malaria Report, 2014). Around the world effective disease control programs 
relying on artemisinin containing combination therapies (ACT) such as Coartem® have 
contributed to a global reduction in the mortality rate of falciparum malaria. However, recent 
reports suggest that decades of continuous use of artemisinins as monotherapies may have 
fostered drug resistance against artemisinin-derivatives (the last widely effective antimalarial 
drugs). Malaria is a serious and life threatening disease and due to increasing resistance of 
the current antimalarial therapies, new antimalarial therapies are required to partner with 
existing therapies to address a growing unmet medical need. 
P218 was discovered by a consortium consisting of MMV, the London School of Hygiene and 
Tropical Medicine, Monash Centre for Drug Candidate Optimisation and the National Center 
for Genetic Engineering and Biotechnology (BIOTEC), a Thai research organization, with 
whom MMV is currently collaborating.  
P218 is a selective inhibitor of Plasmodium DHFR, an enzyme which catalyses the reduction 
of folates to tetrahydrofolates, which are essential for DNA biosynthesis in the malarial parasite 
(Yuthavong et al, 2012). DHFR inhibitors, which are selective to the Plasmodium DHFR vs the 
human DHFR, are a validated target for malaria treatment. Pyrimethamine, another DHFR 
inhibitor, marketed in combination with sulfadoxine, has been used for malaria treatment for 
decades. However, its usage for malaria treatment was stopped in many areas following 
emergence of resistance. P218 demonstrates activity in vitro and in vivo on pyrimethamine P. 
falciparum resistant strains suggesting that this molecule may offer a favourable treatment 
advantage over pyrimethamine.  
P218 is highly active on P. yoelli, P. chabaudi and P. berghei liver stage parasites, which are 
Plasmodium strains infecting murine species. These Plasmodium strains are used as murine 
models to evaluate compound potential activity on P. falciparum and P. vivax infecting the 
human liver. Recently, P218 was also shown to be active on P. falciparum liver stage. 
Targeting human liver parasites is essential for a compound to provide chemo protection 
against malaria. Pyrimethamine is also active on these Plasmodium parasites, albeit less than 
P218, and is now a component of the standard of care as second and third trimester 
Intermittent Preventive Treatment during Pregnancy (IPTp) in high malaria transmission areas.   
Due to its profile combining activity on pyrimethamine resistant strains and potential action on 
liver stage parasites, P218 is primarily considered for malaria chemo-protection. Acute 
uncomplicated malaria is also under consideration as a second indication for the new chemical 
entity (NCE). 
There have not been any concerns relating to safety, tolerability or PK data in 48 subjects in 
the 6 first cohorts tested up to 750mg in the FIH study. However, preliminary PK investigation 
revealed the presence of two β acyl glucuronides metabolites formed in large proportion in 
human upon oral administration of P218.  


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The potential reactivity of these acyl glucuronides is considered to be due to the chemical 
stability and rearrangement of the conjugate to interact with proteins. Given that the structure 
and in particular the site of conjugation is identical between both acyl glucuronides of P218, it 
is considered appropriate to assess safety in terms of total acyl glucuronide burden rather than 
consider each one independently.  
The toxicology coverage of human P218 β acyl glucuronide and P218-OH β acyl glucuronide 
was therefore assessed by considering both molecules as a whole, with the global human 
AUClast being the sum of the human AUClast of each molecule. Under this assessment all 
metabolites are considered qualified as exposure in the toxicology species was higher than 
the exposures observed or expected in humans. Importantly no toxicity that was not related to 
DHFR inhibition was observed in either species, supporting the conclusion that none of the 
metabolites pose an additional toxicological risk (refer to the pharmacokinetic properties 
paragraph below). 
Thus, it is considered safe to continue the FIH study and perform a 1000 mg dose cohort as 
originally planned. 
 
6.1 
Pharmacokinetic properties 
 
Non-Clinical Studies 
P218 and its major glucuronide metabolite (P218 β glucuronide) single-dose PK values were 
derived from the plasma concentration versus time and urinary excretion data obtained in 
animals. 
Plasma protein binding of P218 was moderate in all species, with no evidence of concentration 
dependency across the concentration range assessed.   
In animal species, following IV administration, P218 has moderate to high plasma clearance 
(~50% liver blood flow across species) and medium, consistent steady state volume of 
distribution in all species resulting in moderate terminal half-life (T1/2) values of several hours 
from mouse to dog. The predicted T1/2 is comprised in the range [31h–40h].  
Following single oral administration, P218 is rapidly absorbed in all species tested showing 
acceptable oral bioavailability of ~20-50% with enterohepatic recirculation observed in some 
animals. In a study in rats, the brain to plasma concentration ratio was very low suggesting 
that there was minimal distribution of P218 into the brain.   
Following repeated dose administration of P218 to rats and dogs for 14 days, P218 and P218 
β glucuronide generally increased in a dose proportional manner with respect to dose. In rats 
as well as in dogs no gender difference was observed for P218 at steady state (Day 14). No 
evidence of accumulation of parent or P218 β glucuronide metabolite was observed.   
Metabolites with primary (direct) glucuronidation (the P218 β glucuronide) and 
monooxygenation have been identified. Essentially all of the P218 dose in a bile duct 
cannulated rat study was excreted in bile, mostly as P218-glucuronide suggesting that 
glucuronidation followed by biliary excretion may represent the major route of elimination.  In 
a different rat PK study, P218 was also eliminated via the urine with approximately 18% of the 


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dose being recovered in rat urine suggesting that renal clearance may constitute a second 
independent clearance pathway (however apparently smaller). It is unlikely that oxidative 
Phase 1 metabolism constitutes a major clearance mechanism of P218 since mono-
oxygenation was shown to be a relatively minor metabolic pathway for P218. With and without 
pre-incubation, P218 did not cause significant inhibition of CYP1A2, CYP2A6, CYP2B6, 
CYP2C9, CYP2C19, CYP2D6 or CYP3A4 suggesting little or no potential to produce drug-
drug interactions via CYP450´s pathways.  
A quantitative analysis of human plasma from the FIH study has been conducted using LC 
MS/MS. According to the preliminary data collected, three major metabolites were identified in 
vivo by comparison to reference standards: P218 β acyl glucuronide conjugate, P218 OH and 
P218 OH β acyl glucuronide conjugate. These 3 metabolites are identical to the ones detected 
in the single dose rat and dog PK studies. 
To evaluate exposure to P218-OH and P218-OH β acyl glucuronide, additional studies in the 
rat and the dog were performed where these metabolites were quantified following a single 
dose of P218.  Single doses of 100 and 250 mg/kg to rats and a single dose of 20 mg/kg to 
dogs were administered and plasma concentrations measured. These doses were the highest 
tolerated doses in the 14 day (or 7 day) toxicology studies. In rats, calculation of the proportion 
of circulating P218 β acyl glucuronide as a ratio to the total circulating drug related material 
(∑AUClast of P218, P218-OH, P218 β acyl glucuronide and P218-OH P218 β acyl glucuronide) 
resulted in values of 18 to 22%. In the dog, this ratio was 43%. Applying the same calculation 
method, ratios of P218-OH and P218-OH β acyl glucuronide were <1% in both species. 
Clinical Studies 
A quantitative analysis of human plasma from this ongoing FIH study has been conducted 
using LC MS/MS. According to the preliminary data collected, three major metabolites were 
identified in vivo by comparison to reference standards: P218 β acyl glucuronide conjugate, 
P218 OH and P218 OH β acyl glucuronide conjugate. These 3 metabolites are identical to the 
ones detected in the single dose rat and dog PK studies  
Calculation of the proportion of circulating P218-OH as a ratio to the total of circulating drug 
related material in plasma (AUClast of P218, P218 β acyl glucuronide, P218-OH and P218 β 
acyl glucuronide) results in values below 10% in human.  With reference to ICH M3 and the 
FDA guidance for Safety Testing of Drug Metabolites (Metabolites in Safety Testing, MIST 
guidance) this metabolite is therefore considered to be qualified.P218 β acyl glucuronides (with 
and without the hydroxyl group on the phenyl ring) were prominent metabolites in healthy 
volunteers’ plasma, accounting for 72-78% of total drug related material. 
Individually these acyl glucuronides exist at circulating concentrations higher than 10%, 
however, the total acyl glucuronide exposure in the animal studies (rats and dogs: 37.2 to 74.6 
µg•h/mL) are similar to, or greater than, the total acyl glucuronide exposure in humans (48.2 
µg•h/mL). 
Given that the acyl glucuronide structure, potentially responsible for protein acylation, is 
identical in each metabolite, the chemical reactivity is considered to be the same and therefore, 
like the P218-OH metabolite, they are considered qualified according to MIST and ICH M3 
(see the IB, sections 5.2.4 and 5.3.9.1, for more information). 


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Additionally, preliminary PK data from FIH cohorts 1-6 (up to single doses of 750mg) has 
shown that at 72hrs post dose, negligible amounts of P218 and its main metabolites (P218 
OH, P218 β acyl glucuronide and P218 OH β acyl glucuronide) remain in circulation. It is 
therefore very unlikely that any biological activity will be observed beyond this timepoint.  
 
6.2 
Rationale for conducting study 
 
The main purpose of this phase 1 study with this selective Plasmodium DHFR inhibitor P218 
is to generate safety, tolerability and pharmacokinetic (PK) data when first administered to 
healthy men and women of non-childbearing potential (WNCBP) as escalating single 
ascending doses (Part A) under fasted conditions. In addition, the potential effect of food 
consumption on the previously stated objectives will be assessed. Furthermore, the study shall 
assess the effects of P218 against Plasmodium parasite and on serum folate levels, and 
identify the genetic factors that may affect the PK of P218 in human subjects.  
The rationale for taking P218 into further development is the expectation that this compound 
could be effective for the treatment of pyrimethamine P. falciparum resistant strains. Prior to 
initial testing in patients, the safety and the pharmacokinetic characteristics of the drug in 
healthy subjects must be investigated. 
 
6.3 
Risk-benefit evaluation 
6.3.1 
Potential Benefits 
P218 will be given to healthy subjects purely for research and development purposes and 
those subjects receiving IMP will experience no medical benefit except for a general health 
examination. 
 
6.3.2 
Potential Risks 
6.3.2.1 Non-clinical studies 
The toxicology testing of P218 in animals and in vitro has been conducted to support oral 
dosing in humans in accordance with ICH guidelines (ICH M3 [R2]). The pivotal toxicology, 
genetic toxicology and safety pharmacology studies were conducted in accordance with GLP 
and currently accepted guidance with respect to duration, animal numbers and dose level 
selection.  There are no known reasons to exclude the rat or dog as relevant for evaluating 
toxicity. 
P218 was evaluated in a wide range of receptor binding assays at a concentration of 10 µM. 
No major inhibition of binding was observed except against thromboxane A2/PGH2. A 
functional assay confirmed antagonist activity with an IC50 of 19 µM. An in vitro assessment of 
platelet aggregation in rat blood showed P218 to have no effect on aggregation mediated via 
either the Arachidonic Acid or Collagen pathways at a concentration up to 53µM/21.1µg/mL (a 


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concentration selected to exceed both the IC50 and the maximum concentration observed in 
the rat 14 day toxicology study). 
P218 plasma protein binding studies in rat, dog and humans showed small differences in free 
fraction with the free fraction in humans (6.3%) lower than in rats (11.4%) or dogs (21.5%). 
These differences were taken into account in assessment of toxicity and dose response. 
P218 was assessed in a series of exploratory and definitive repeat dose oral toxicity studies 
up to 14 days in duration in rats and dogs, genetic toxicology studies for mutagenicity and 
clastogenicity and phototoxicity studies. The oral route of exposure was selected for these 
studies since it is the intended route of clinical exposure. 
P218 was well tolerated following single dose administration. In the rat doses up to 2000 mg/kg 
P218 resulted in no mortality, no important clinical signs and no post mortem changes. In the 
dog single doses up to 100 mg/kg were well tolerated with no clinical observations. 
Repeated dose toxicity studies in both rat and dog demonstrated the gastrointestinal (GI) tract 
to be the main target for toxicity associated with P218. The primary mechanism of anti 
plasmodial activity is mediated through DHFR, an enzyme which catalyses the reduction of 
folates to tetrahydrofolates. Depletion of tetrahydrofolates, such as following dosing with 
methotrexate, has been associated with GI toxicity. At the highest doses administered in the 
pivotal 14 day studies (250 mg/kg/day in rat [UNX0029] and 40 mg/kg/day in dog [UNX0031]), 
P218 was not tolerated. At these doses, deterioration in the clinical condition of the animals 
necessitated the early termination of these groups. In a specific study to demonstrate GI 
toxicity was associated with depletion of tetrahydrofolates, P218 was administered to rats at 
250 mg/kg/day with and without concomitant administration of folinic acid (UNX0052). A single 
250 mg/kg dose of P218 did not induce any microscopic changes in the GI tract. Repeated 
dosing of P218 at 250 mg/kg/day induced GI pathology that was completely prevented when 
folinic acid was co administered. The IC50 of P218 against plasmodial DHFR (3.55 ng/mL) was 
substantially lower than the one needed to inhibit human DHFR (IC50 460 ng/mL) giving 
confidence that efficacy could theoretically be achieved in malaria patients without significant 
inhibition of human DHFR and risk of GI adverse effects.  
Although 10 mg/kg/day was found to be NOAEL dose level for in-life findings, the minor gall 
bladder changes identified in all males receiving 10 mg/kg/day prevented this dose being 
identified as a true NOAEL. The effects in the gall bladder showed evidence of reversibility and 
were consistent with the consequences of DHFR inhibition. 10 mg/kg/day can be considered 
as the dose associated with very minimal and reversible effect upon the gall bladder of the 
dog. As a NOAEL has not been identified, an additional safety factor of 3 was applied to 
calculate the study starting dose. 
When tested in a five strain Ames test, P218 was not mutagenic in bacteria, with or without 
metabolic activation. Weak induction of micronuclei in V79 Chinese hamster cells using 24 
hour exposure in the absence of metabolic activation was observed. Because of the weak 
activity in the in vitro cell assay, two in vivo tests were conducted. P218 was found to be 
negative in both a GLP rat bone marrow micronucleus test in the rat and in a GLP rat liver 
comet assay at doses up to 2000 mg/kg (maximum recommended according to ICH 


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guidelines). Since no evidence of activity was seen in the Ames test and two in vivo assays, it 
was concluded that P218 is not genotoxic. 
A UV-visible spectrum was obtained for P218 and absorption was noted at 290 nm. 
Consequently, the compound was tested in a reactive oxygen species assay and was found 
to be inactive. It was concluded that P218 presents no phototoxic risk. 
In vivo in NOD SCID mice engrafted with human A G6PDH deficient red cells, P218 showed 
no evidence of haemolytic toxicity as evidenced by comparable levels of human red blood cells 
(huRBC) to those found in A-huRBC NOD/ severe combined immunodeficiency (SCID) mice 
treated with vehicle alone. 
The nonclinical safety profile of this compound has been adequately characterised to support 
progression into clinical trials: P218 was tested in a GLP hERG patch clamp assay and had 
no effect on hERG tail current at 100  µM; a concentration substantially higher than expected 
therapeutic maximal concentrations.  No effects were seen in studies designed to evaluate the 
respiratory and nervous systems of rats following single doses up to 250 mg/kg.  P218 had no 
effect on arterial blood pressure, heart rate, body temperature or cardiac conduction times in 
dogs given single doses up to 50 mg/kg that resulted in peak plasma concentrations up to 
4740 ng/mL. An effect on QT prolongation and risk of Torsades de Pointes in humans is 
therefore considered to be low and was supported by absence of any effect in vivo in either 
telemetry studies or repeated dose toxicity assessment of electrocardiograms (ECGs). 
Reproductive toxicity studies have been completed in rat and rabbit. These studies indicate 
P218 induces maternal toxicity in both rat (80 mg/kg/day) and rabbit (50 mg/kg/day).  In the 
rat, doses not well tolerated by the dams (80 mg/kg/day) resulted in foetal abnormalities 
consistent with folate inhibition. In the rabbit, there were no P218 related minor or variant 
external, visceral or skeletal foetal abnormalities at the maximum dose that could be tested 
(30 mg/kg/day) due to maternal toxicity seen at 50 mg/kg/day and above.  The NOAEL for 
maternal and embryo foetal toxicity in the definitive rat and rabbit studies was considered to 
be ≥32 and ≥30 mg/kg/day P218, respectively with corresponding exposures of 6240 and 
34,900 ng•h/mL.  Examination of both male and female reproductive organs in the repeated 
dose studies did not reveal any effects therefore supporting administration of P218 to males 
and women who do not have potential for pregnancy. Three major human metabolites were 
identified in vivo by comparison to reference standards: P218 β acyl glucuronide conjugate, 
P218 OH and P218 OH β acyl glucuronide conjugate.  Metabolites ratio were calculated based 
on the Metabolites in Safety Testing (MIST) guidelines method by comparing a metabolite AUC 
to the sum of the AUC values of the total circulating drug related material.  
P218-OH ratio to total drug related material was calculated to be less than 10%.  With 
reference to ICH M3 and the FDA guidance for Safety Testing of Drug Metabolites (Metabolites 
in Safety Testing, MIST guidance) this metabolite is therefore considered to be qualified. 
P218 β acyl glucuronides, with and without the hydroxyl group on the phenyl ring, were formed 
in large proportions in healthy volunteers accounting for 72-78% of total drug related material.  
The estimated P218 β acyl glucuronides global human AUC at a 1000 mg dose (48.2µg•h/mL) 
is expected to remain below the highest tolerated, estimated cumulative glucuronides AUCs in 


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the dog 14 day toxicology study (74.6 µg•h/mL) and the rat folate supplementation study (62.5 
µg•h/mL). 
In conclusion, two acyl glucuronides have been identified to be present in all species but 
quantitative differences between the species used in toxicology and humans have been 
demonstrated. The potential reactivity of these acyl glucuronides is considered due to the 
chemical stability and rearrangement of the conjugate to interact with proteins. Given that the 
structure and in particular the site of conjugation is identical between both acyl glucuronides 
of P218, it is considered appropriate to assess safety in terms of total acyl glucuronide burden 
rather than consider each one independently.  
The toxicology coverage of human P218 β acyl glucuronide and P218-OH β acyl glucuronide 
was therefore assessed by considering both molecules as a whole, with the global human 
AUClast being the sum of the human AUClast of each molecule. Under this assessment all 
metabolites are considered qualified as exposure in the toxicology species was similar to or 
higher than the exposures observed or expected in humans. Importantly no toxicity that was 
not related to DHFR inhibition was observed in either species, supporting the conclusion that 
none of the metabolites pose an additional toxicological risk. 
 
6.3.2.2 Clinical Studies 
To date, there are currently no completed clinical studies with P218, however in this ongoing 
study (MMV_P218_15_01) there have not been any concerns relating to safety, tolerability or 
PK data in 48 subjects in the 6 first cohorts testing up to 750mg.  There are licensed anti-
malarial treatments with the same mechanism of action, e.g. pyrimethamine.  
Potential risks will be closely monitored for as part of the safety evaluations being performed 
in this study. Measures to minimise the risks to volunteers will include: 
• 
Selection of a starting dose below a dose level for which effects are expected. Please 
refer to protocol section 8.4.1. 
• 
Sentinel dosing of subjects in Part A (Cohorts 1, 2 & 3). Please refer to protocol section 
8.4.5. 
• 
Progression to consecutive study parts or higher exposure dosing regimens only after 
evaluation of data from previous parts/cohorts and approval from Safety Review 
Committee (SRC). Please refer to protocol section 8.2.3 and 8.2.4.12 
• 
Clinical and laboratory monitoring of study subjects. Please refer to protocol section 
12. 
• 
Adherence to the inclusion/exclusion criteria: only subjects considered suitable 
according to these criteria and who are not at any perceived risk will be included. 
Subjects with gallbladder disease (e.g. cholecystitis, cholelithiasis, cholecystectomy), 
or megaloblastic anaemia secondary to folate deficiency will not be included. 
• 
Predefined stopping rules based on safety and PK. 


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• 
Regular clinical chemistry (including Liver Function Tests and serum folate levels) and 
haematology blood tests will be performed at scheduled time points and if necessary 
will be repeated to ensure appropriate follow-up of any clinically relevant abnormality. 
Considering the risk management plan outlined in this protocol in conjunction with; 
adaptive boundaries, toxicity rules, the mode of action of the drug, the nature of the 
target, the relevance of the animal model, the toxicity profile and the fact that it is a 
single dose study, the overall risk to volunteers participating in the study is considered 
to be minimal and acceptable. 
• 
The analysis of interim safety and tolerability data up to single doses of 750mg (SAD) 
indicated good safety and tolerability, and no ongoing safety concerns. 
 
6.3.2.3 Serum folate levels 
As mentioned in section 6.3.2.1 repeated dose toxicity studies in both rat and dog 
demonstrated the gastrointestinal (GI) tract to be the main target for toxicity associated with 
P218. A potential cause of this toxicity is thought to be depletion of tetrahydrofolates. It is 
considered that the risk of depletion of serum folate levels in humans is theoretical. Subjects 
will not be included if they have any gallbladder or longstanding gastrointestinal conditions. 
They will also be excluded if they have a history of megaloblastic anaemia secondary to folate 
deficiency. Subjects will have samples taken to measure their serum folate levels and 
(optional) red blood cell folate levels at specified time points during the study. These samples 
will be analysed based on clinical need. 
 
7. 
STUDY OBJECTIVES AND OUTCOMES 
7.1 
Objectives 
7.1.1 
Primary objectives 
• 
To investigate the safety and tolerability of single escalating oral doses of P218 when 
administered to healthy volunteers (men and WNCBP) under fasted conditions. 
 
7.1.2 
Secondary objectives 
• 
To describe the pharmacokinetics of P218 and its major metabolites (P218-OH, P218 
β acyl glucuronide and P218-OH β acyl glucuronide) in healthy volunteers (men and 
WNCBP) after administration of single escalating oral doses 
• 
To investigate the effect of a high fat meal on the pharmacokinetics and 
safety/tolerability of P218 
 
7.1.3 
Exploratory objectives 
• To perform ex vivo bioassay analysis against malaria parasites to confirm that P218 
β acyl glucuronide is active against Plasmodium parasite and determine if other active 
metabolites are formed. 


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• 
To assess the effects of P218 on serum folate levels in healthy subjects. 
• 
To evaluate the cardiovascular safety profile of P218, assessing qualitative ECG 
variations from baseline following dosing, in particular any effects on the QTc interval 
• 
To identify inherited genetic factors which may (1) predict response to treatment with 
P218, (2) explain variability in drug PK/PD, (3) predict susceptibility to drug-drug 
interactions, or (4) predict the occurrence of safety issues. The aim of such exploratory 
research will be to develop a better understanding of intrinsic and extrinsic factors that 
may affect the pharmacokinetics of P218 in human subjects. 
 
7.2 
Endpoints 
7.2.1 
Primary endpoints 
• 
Safety and tolerability of P218: Incidence, severity and relationship to the 
investigational product of observed and self-reported adverse events following  
administration of a single oral dose of P218 to healthy volunteers. 
 
7.2.2 
Secondary endpoints 
• 
Estimation of the following PK parameters following administration of a single dose of 
P218 (in fasted and fed cohorts) using non-compartmental methods: AUClast, AUCinf, 
Cmax, Tmax, t1/2, MRT, CL/F (for parent only), Vz/F (for parent only) and metabolites ratio. 
 
7.2.3 
Exploratory endpoints 
• 
To determine the efficacy of P218 against parasites using an ex-vivo malaria assay: 
IC50. 
• 
Absolute change from baseline P218 on serum folate levels over time 
• 
The paired PK and QTc interval parameters pre-dose compared to post-
administration of P218. Clinically significant ECG morphology and interval changes 
from baseline. 
 
• 
Exploration of CYP and Uridine diphosphate glucuronosyltransferase (UGT) isoforms. 
Exploration of other enzymes and transporters in accordance with evolving data. 
 
 
8. 
STUDY DESIGN 
8.1 
Overall study design and procedure 
Part A 
This is a randomized, double-blind, placebo-controlled, parallel group, Phase I study which will 
assess the safety, tolerability, pharmacokinetics of single (SAD) ascending oral doses of P218 
in healthy subjects (men and WNCBP). 
Part B 


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This is an open-label, randomised fed/fasted crossover study in healthy subjects (men and 
WNCBP) to examine the food effect of a high fat meal on the PK, safety and tolerability of 
P218.  
This study incorporates the use of an adaptive design. Study specific adaptive features and 
their limits are described in  
 
Table 1. Adaptive protocol features. 
 
 
Table 1. Adaptive protocol features  
 
Adaptive Study 
Design Areas  
Features 
Limits 
Dose 
1. 
All anticipated dosing levels can be 
adjusted in accordance with PK, 
safety and tolerability data collected 
up to the decision making time-
point. 
 
I. The PK derived mean exposure for a 
dosing regimen will not exceed the 
defined PK exposure limit (based on 
Cmax and AUC0-last). Please refer to 
section 8.3.3 
PART A: 
II. The starting dose for Part A of the study 
will not exceed 10 mg.  
III. The highest dose for Part A of the study 
will not exceed 2000 mg.  
IV. The dose increments between the dose 
levels 1 to 5 in Part A will be no more 
than 4-fold.  
V. The dose increments between the next 
dose levels (from dose level 5 onwards) 
in Part A will be no more than 2-fold. 
PART B: 
VI. The planned dosing regimens’ 
anticipated mean exposures will not 
exceed mean exposures (based on Cmax 
and AUC0-last) previously explored in Part 
A with acceptable safety and tolerability, 
i.e. exposure levels at which no study 
specific criteria stopping dose 
progression and/or escalation were met. 
VII. A potential food effect of no less than 3-
fold will be taken into account when 
setting the dose for Part B. 
 


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Adaptive Study 
Design Areas  
Features 
Limits 
Timing 
2. 
Part B can overlap with Part A 
I. 
Minimum data requirements for initiating 
each dose level in Parts A and B apply 
as outlined in Rules for 
escalation/progression. 
 
3. 
Cohorts/dosing regimens may be 
split into sub-groups. 
I. A mandatory sentinel dosing strategy of 
dosing 2 subjects (1 subject on IMP, 1 
subject on placebo) will be used for 
cohorts 1, 2 and 3 in Part A. If safety 
and tolerability is acceptable, the 
remaining subjects of this cohort can be 
dosed with a minimum interval of 24 
hours following the dosing of the first 
subject of the sentinel group. Sentinel or 
sequential dosing for all cohorts and 
study parts can be performed at the 
discretion of sponsor and PI. 
II. If  PK for cohorts 1, 2 and 3 are within 
expectation and safety tolerability is 
acceptable then no further sentinel 
dosing is necessary. 
Flexible Cohort 
Sizes 
4. 
Withdrawn subjects can be replaced 
at the discretion of the sponsor and 
PI. 
5. 
Replacement subjects may be 
enrolled in an ongoing cohort, or 
dosed together as a group or dosed 
separately.  
6. 
The number of subjects in a cohort 
in Part B can be extended to gather 
further information on this dose 
level. 
I. The maximum extension of Part B is 
100% of the original cohort size at the 
selected dosing regimen. 
 
Samples and 
Assessments 
 
7. 
The in-house stay may be 
shortened if: 
a. 
The evolving PK data 
demonstrates a shorter t½ than 
anticipated. 
b. 
The Safety Review Committee 
(SRC) considers it appropriate 
from a safety/tolerability point 
for an upcoming dose cohort. 
 
8. 
The in-house stay or follow-up 
period may be prolonged if: 
I. A minimum in-house period of 24 hours 
post dose. 
II.  If the in-house stay is shortened the 
minimum in-house period for study 
cohorts will be based on evolving safety, 
tolerability, and PK data and will not be 
less than 2 x t½ of the IMP following the 
last dose.  
 
 
 


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Adaptive Study 
Design Areas  
Features 
Limits 
a. It is considered clinically 
necessary by the PI for 
individuals on a case-by-case 
basis. 
b. The Safety Review Committee 
(SRC) considers it necessary 
from a safety/tolerability point 
for an upcoming dose cohort. 
c. The follow-up period for a dose 
cohort may be prolonged if 
evolving PK data require a 
longer follow-up period. 
I. 
A maximum extended in-house or follow-
up period cannot be defined as the 
extension will be as long as necessary to 
ensure the safety of the individual 
participant(s).  
II. The maximum extended in-house or 
follow-up period for study cohorts will be 
based on evolving safety, tolerability, 
and PK data and will not usually exceed 
10 x t½ of the IMP following the last 
dose.  
 
 
8. 
Additional safety blood and/or urine 
samples/variables may be taken or 
analyzed if: 
d. It is considered clinically 
necessary by the PI for 
individuals on a case-by-case 
basis. 
e. The SRC considers it necessary 
from a safety/tolerability point 
for an upcoming dose cohort. 
I. For individuals, a maximum number of 
safety blood samples will be determined 
on a case-by-case basis and cannot be 
pre-defined as investigations will be 
performed as necessary to ensure the 
safety of the individual participants.  
II. Study specific maximum blood volume 
will not be exceeded (Please refer to 
section 12.12).  
 
9. 
Timing of blood and urine PK and/or 
exploratory assessments/PD may 
be adjusted in accordance with 
evolving data and dosing schedule. 
10. Additional or less blood and urine 
PK/PD and/or exploratory 
assessments may be taken in 
accordance with evolving data and 
dosing schedule. 
I. Minimum: sufficient PK samples to 
establish full protocol specific serum PK 
profile.  
II. Study specific maximum blood volume 
will not be exceeded (Please refer to 
section 12.12). 
 
11. Timing of safety assessments 
including but not limited to 
laboratory safety samples, vital 
signs and ECGs may be adjusted in 
accordance with evolving data and 
dosing schedule. 
12. Additional safety assessments 
including but not limited to 
laboratory safety samples, vital 
signs and ECGs may be taken in 
accordance with evolving data and 
dosing regimens. 
I. 
Alterations in timing of the safety 
assessments need to be a reflection of 
the established PK, safety and 
tolerability profile up to the decision 
making time-point. 
II. 
Alterations need to be made in the spirit 
of the current CSP (i.e. focus on the 
capture of essential and useful data) and 
not affect the risk profile of the study. 
 
13. Specialist referrals (e.g. to a 
cardiologist) may be made (and 
I. 
A maximum for individuals will be 
determined on a case-by-case basis and 


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Adaptive Study 
Design Areas  
Features 
Limits 
may include all relevant 
assessments and investigations) if it 
is considered clinically necessary by 
the PI or Sponsor or SRC for 
individuals on a case-by-case basis. 
cannot be pre-defined as investigations 
will be performed as necessary to 
ensure the safety of the individual 
participants. 
 
14. Except for those subjects that have 
been randomized, screening 
assessments, including Holter ECG 
recordings performed at Richmond 
Pharmacology Ltd on volunteers 
screened for another study can be 
used for this study to avoid 
unnecessary tests. 
 
 
I. The assessments must meet protocol 
criteria (e.g. the method to be used). 
II. The assessments must be performed 
within the protocol defined screening 
window. 
III. Holter ECG recordings are valid for a 
period of three months.  
 
15. ECG analysis for the purpose of 
exploratory QT/QTc analysis / 
intensive cardiac assessments may 
be performed on selected or all 
dose levels in Part A. Under these 
circumstances : 
 
a. 
If PK sampling times are 
changed then the ECG 
sampling times will be changed 
accordingly, for the purpose of 
exploratory QT/QTc 
analysis/intensive cardiac 
assessments.  
b. 
If the meal times need to be 
changed, ECG times will also 
be changed in accordance to 
maintain the sampling schedule 
stipulated to capture the food 
effect, for the purpose of 
exploratory QT/QTc 
analysis/intensive cardiac 
assessments with confirmation 
of assay sensitivity. 
16. Telemetry data gathered during the 
study may be used in the 
exploratory analysis of drug related 
QT/QTc interval changes. 
I. 
For the purpose of exploratory 
QT/QTc analysis and to confirm 
assay sensitivity a minimum of three 
postprandial time points will be 
recorded in triplicate between 1-4h 
after the start of the meal. 
 
 
17. Analysis of ex-vivo samples obtained 
in Parts A and B is optional, and can 
be limited to only those from select 
 


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Adaptive Study 
Design Areas  
Features 
Limits 
dose levels or not done at all. If PK 
sampling times are changed then the 
assay sampling times will be 
changed. 
 
18. Exploratory analysis of post-dose 
serum folate levels may be 
performed on selected or all dose 
levels. 
19. Exploratory analysis of RBC folate 
samples may be performed on 
selected or all dose levels. 
 
 
20. Exploratory analysis of CYP 
isoforms and transporters may be 
performed on selected or all dose 
levels. 
21. The CYP isoforms and transporters 
analysed can be adjusted according 
to emerging data. 
 
 
The study will be performed in two parts: (A) double-blind randomised, placebo-controlled, 
parallel group, single ascending dose (SAD) in healthy men and WNCBP under fasted 
conditions; (B) food effect in an open-label, randomised fed/fasted crossover design. The study 
will be conducted as an adaptive integrated design. Dose escalation to a consecutive higher 
exposure dosing regimen or to Part B will only occur after satisfactory review of all safety, 
tolerability and PK data by the Safety Review Committee (SRC) in accordance with the 
Adaptive Features ( 
 
Table 1), rules for dose escalation/progression and toxicity. 
 
 


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Part A (SAD) 
In Part A, the safety, tolerability and pharmacokinetics of single ascending doses of P218 will 
be studied in healthy men and WNCBP. Part A is a double-blind randomised, placebo-
controlled, parallel group, ascending dose study and will comprise up to eight fasted cohorts 
(8 volunteers in each) that will receive a single, ascending dose (SAD) of P218. Within each 
cohort 6 subjects will receive a single dose of P218 and 2 subjects will receive a single dose 
of matching placebo (3:1 ratio).  
Subjects will be screened within 28 days prior to entering the study on Day -1. Each subject 
will receive verbal and written information followed by signing of the Informed Consent Form 
(ICF) prior to any screening procedures taking place. Subjects will be admitted to the study 
unit on Day-1 and will be discharged by Day 4. All subjects will attend the unit for an outpatient 
visit on Days 6, 8, 9 and a follow-up visit 11 days post-dose. All the assessments performed 
during the study are detailed in the study schedule of assessments (Table 2, Table 3, Table 4, 
Table 5). Study design features may be adapted according to the Adaptive Features ( 
 
Table 1). 
 
 
 
Figure 1. Part A flow chart. 
 
 
 


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Part B (Food effect)  
 
For the pilot food effect evaluation, a separate cohort of 8 subjects will receive a P218 dose 
associated with the targeted efficacious exposure ( in human subjects in fasted conditions) in 
an open-label fashion at two occasions separated by a minimal washout of 5 x T1/2 (that will 
not exceed 3 weeks). The treatment conditions (fed-fasted) will be randomized according to 
a two-way crossover design. For the fed period, a standard high fat breakfast is given as per 
FDA guidance; the breakfast is given 30 minutes prior to the scheduled dosing time, and 
should be completed 10 minutes before dosing 
(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126833.pdf).  
 
 
 
 
 
Figure 1. Part B flow chart 
 


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Table 2. Study Plan – Part A: Single Ascending Dose  
 
Study day 
Screening  
-28 to -2 
Admission 
-1 
Pre-dose 
1 
2 
3 
4 
6 
8 
9 
11 
Time point (h) 
 
 
 
0h 
0.25 
0.5 
1 
2 
4 
6 
7 
8 
12 
24 
48 
72 
120 
168 
192 
240 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Social history: Smoking, 
alcohol, drugs status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test & urine 
drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
assessment 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH for confirmation of 
hormonal status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety haematology, 
biochemistry, coagulation 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X a 
 
X a 
 
 
 
X 
Serum folate levels + RBC 
folate levels 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Pharmacogenetic samples 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
X 
Xb 
 
 
 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
Xb 
Vital Signsc 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 lead ECGs (triplicates) 
X 
X 
Xd 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Dosing 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood collection 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK urine collection  
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 


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Study day 
Screening  
-28 to -2 
Admission 
-1 
Pre-dose 
1 
2 
3 
4 
6 
8 
9 
11 
Time point (h) 
 
 
 
0h 
0.25 
0.5 
1 
2 
4 
6 
7 
8 
12 
24 
48 
72 
120 
168 
192 
240 
Telemetry e 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Adverse event assessment 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant  medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
In-house 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Standard Mealsf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Malaria bioassay blood 
collection 
 
 
X 
 
X 
 
X 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
 
X 
 
 
a Haematology and biochemistry only. 
b Brief physical examination. 
c Vital signs includes supine systolic and diastolic blood pressure, heart rate and tympanic temperature. Standing blood pressure will be measured at 
Screening, pre-dose, 2 and 8 hours post-dose. 
d Three triplicate ECGs to be done at -2, -1 and -0.5 hours pre-dose for the purpose of intensive ECG monitoring. 
e Telemetry is to be measured from between a minimum of 1 hour pre-dose  up to  12 hours post dose. 
 
f Lunch will be provided 4 hours after dosing. Dinner will be provided approximately 9 to 10 hours after dosing. An evening snack will be permitted. While 
confined, the total daily nutritional composition should be approximately 50% carbohydrate, 35% fat and 15% protein.  The daily caloric intake per subject 
should not exceed approximately 3200 kcal. 
 
 
 
 


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Table 3. Study Plan – Part A (continuation) 
 
Study Day 
Time (h) 
PK blood sampling 
PK urine 
samplingA 
Vital signsB 
12-lead ECGC 
Malaria 
Bioassay 
D1 
-2 
 
 
 
X 
 
-1 
 
 
 
X 
 
-0.5 
X 
 
X 
X 
X 
0 
 
X 
 
 
 
0.25 
X 
 
 
 
X 
0.5 
X 
 
X 
X 
 
1 
X 
 
X 
X 
X 
2 
X 
 
X 
X 
X 
4 D 
X 
 
X 
X 
 
6 
X 
X 
X 
X 
X 
7 
X 
 
X 
X 
 
8 
X 
 
X 
X 
 
12 
X 
X 
X 
X 
X 
D2 
24 
X 
X 
X 
X 
X 
D3 
48 
X 
X 
X 
X 
X 
D4 
72 
X 
 
X 
X 
 
D6 
120 
X 
 
X 
X 
X 
D8 
168 
X 
 
X 
X 
 
D9 
192 
X 
 
X 
X 
 
D11 
240 
X 
 
X 
X 
X 
 
A: Pooled urine collection at 0-6, 6-12, 12-24 and 24-48 hours. 
B: Vital signs will be measured after rest of at least 10 min in supine position. 
C: 12-lead ECG will be measured in triplicate after a rest period of at least 10 min. 
D: Lunch. 
 
 
 
 


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Table 4. Study Plan – Part B: Food effect  
 
 
 
Period 1 and Period 2 
Study day 
Screening  
-28 to -2 
Admission 
-1 
Pre-dose 
1 
2 
3 
4 
6 
Time point (h) 
 
 
 
0h 
0.25 
0.5 
1 
2 
4 
8 
12 
24 
48 
72 
120 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Social history: Smoking, 
alcohol, drugs status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test & urine 
drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
assessment 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH for confirmation of 
hormonal status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety haematology, 
biochemistry, coagulation 
X 
X 
 
 
 
 
 
 
 
 
 
X a  
 
X a 
X 
Serum folate levels + RBC 
folate levels 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Pharmacogenetic samples 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
X 
X b 
 
 
 
 
 
 
 
 
X b 
 
 
X b 
Vital Signsc 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 lead ECGs (triplicates) 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Dosing 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
PK blood collection 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Period 1 and Period 2 
Study day 
Screening  
-28 to -2 
Admission 
-1 
Pre-dose 
1 
2 
3 
4 
6 
Time point (h) 
 
 
 
0h 
0.25 
0.5 
1 
2 
4 
8 
12 
24 
48 
72 
120 
Malaria bioassay blood 
collection 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event assessment 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant  medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
In-house 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Standard Mealsd 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Meal record 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
a Haematology and biochemistry only. 
b Brief physical examination. 
c Vital signs includes supine systolic and diastolic blood pressure, heart rate and tympanic temperature. Standing blood pressure will be measured at 
Screening, pre-dose, 2 and 8 hours post-dose. 
d. For the fed period, a standard high fat breakfast is given as per FDA guidance; the breakfast is given 30 minutes prior to the scheduled dosing time, and 
should be completed 10 minutes before dosing.   
 
 
 
 
 


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Table 5. Study Plan – Part B (continuation) 
 
Study Day 
Time (h) 
PK blood sampling 
Malaria 
Bioassay 
Vital signsA 
12-lead ECGB 
High fat 
breakfast 
D1 
-0.5 
X 
X 
X 
X 
X 
0 
 
 
 
 
 
0.25 
X 
X 
 
 
 
0.5 
X 
X 
X 
X 
 
1 
X 
X 
X 
X 
 
2 
X 
X 
X 
X 
 
4  
X 
X 
X 
X 
 
8 
X 
X 
X 
X 
 
12 
X 
X 
X 
X 
 
D2 
24 
X 
X 
X 
X 
 
D3 
48 
X 
X 
X 
X 
 
D4 
72 
X 
X 
X 
X 
 
D6 
120 
X 
X 
X 
X 
 
 
A: Vital signs will be measured after rest of at least 10 min in supine position. 
B: 12-lead ECG will be measured in triplicate after a rest period of at least 10 min. 
 
 


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8.2 
Rules for dose escalation/progression 
A safety review committee (SRC) will review and assess at least the minimum required data 
from the previous cohort(s) to make decisions on the dose(s) for the next dose levels. The 
SRC will assess if any of the group or individual toxicity criteria are met and if the concerned 
AEs have a causal relationship with the IMP. If so, the SRC will take action in accordance with 
the rules stipulated in section 8.2.  
There is an option to have ad-hoc SRC meetings to discuss urgent issues should the need 
arise. 
 
8.2.1 
Safety Review Committee 
The SRC will consist of, as a minimum: 
• 
MMV Medical Director or delegate (voting member) 
• 
Principal Investigator (RPL) or delegate (voting member) 
MMV Project Director or further internal or external experts such as a pharmacokineticist 
and/or a statistician may be consulted by the SRC as necessary. Any additional information, if 
required will be included in the SRC charter, located in the study operations manual (SOM). 
 
8.2.2 
Data requirements 
After each cohort the SRC will assess the minimum safety, tolerability and PK data required 
prior to dose escalation/progression (refer to section 8.2.2 ). Prior to each SRC meeting, an 
interim safety report will be prepared for that cohort presenting the relevant safety and 
tolerability data. These will be signed by the PI and/or delegate. PK data will be provided 
separately by the analytical laboratory. As the initial data review will be blinded, there will be 
no link between the safety data and the PK data. 
The following data will be required: 
Safety: 
• 
AEs; 
• 
Vital sign parameters (temperature, blood pressure, heart rate);  
• 
12-lead ECGs and telemetry recordings; 
• 
Clinical laboratory parameters (hematology, coagulation, biochemistry and urinalysis). 
 
Pharmacokinetic data  
For availability of PK data, refer to section 8.2.4 below. 
 
Additional data that may be available at the time of report writing: 
• 
Other relevant clinical tests conducted on a case-by-case basis.  
• 
Other exploratory samples. 
 


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8.2.3 
SRC Meeting  
The SRC will determine dose escalations/progression according to the Clinical Study Protocol 
(CSP), anticipated doses, adaptive features and group toxicity rules. The decision will be 
signed by one of the Sponsor’s representatives and by the PI or delegate. For logistical 
reasons, the signature of the Sponsor or Investigator may be communicated via email. 
Initially the data will be reviewed blinded, but if the SRC consider it necessary due to a safety 
concern, either individual subjects or the entire cohort may be unblinded to enable their 
decision-making. Before breaking the code, the potential decisions and actions should be 
determined and documented. 
The decision of the SRC on the next dose will be taken in consensus between the members 
of the SRC. If consensus cannot be reached then the most cautious approach will proceed. 
The decisions and decision-making of the SRC on the next dose level will be documented and 
provided to the PI and Pharmacist prior to the next scheduled dosing day. 
 
8.2.4 
Dose escalation/progression 
Dose escalation/progression is defined as either of the following: 
1. Escalation to a higher exposure dosing regimen within Part A (SAD) cohorts. 
2. Progression from Part A (SAD) to Part B (food effect evaluation) cohort. 
 
Minimum data requirements for dose escalation/progression are: 
1. Escalation to a higher exposure dosing regimen within Part A (SAD) cohorts. 
A minimum of 168 hours post-dose safety and PK data from a minimum of 6 subjects (of which 
a minimum of 4 will have received the active compound) from the cohort with the next lower 
exposure level will be required. 
2. Progression from Part A (SAD) to Part B (food effect evaluation).  
A minimum of 168 hours post-dose safety and PK data from a minimum of 6 subjects (of which 
a minimum of 4 will have received the active compound) from a previous Part A cohort on a 
relevant dose level will be required. 
“Relevant dose level” is defined as the dose that demonstrated acceptable safety/tolerability 
at a mean exposure which is not anticipated to be exceeded by the dosing regimen in Part B, 
taking into account a potential food effect of 3-fold. 
  
 
 
 
 
 
 
 


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8.3 
Toxicity rules   
For the purpose of this CSP: 
1. 
Toxicity means clinically significant and at least possibly drug related adverse 
reaction(s). 
Table 6. WHO Toxicity Grading 
WHO intensity grades are defined as follows: 
1 
Mild – No interference with routine activity. 
2 
Moderate – Interferes with performance of some activities of 
daily living, but responds to symptomatic therapy or rest. 
3 
Severe – Significantly limits ability to perform activities of 
daily living despite symptomatic therapy. 
4 
Very severe – Incapacitates patient despite symptomatic 
therapy; requires hospitalization. 
WHO Handbook for Reporting Results of Cancer Treatment.  WHO Offset Publication No.  
48.  World Health Organization; Geneva, Switzerland.  1979:16–21. 
For more detailed documentation on WHO Toxicity Grading see Appendix A 
8.3.1 
Group toxicity rules (Part A and Part B) 
 
Table 7. Group Toxicity Rules for progression to Part B and/or escalation to higher exposure 
dosing regimens in part A. 
 
 
 
Number of 
subjects 
Toxicity Rules for progression to part B /or 
escalation to higher exposure dosing 
regimens within part A 
WHO 
Grade 
Severity 
Seriousness 
Number 
of 
subjects 
affected 
in one 
SOC 
Total 
Number 
of 
subjects 
affected 
Showing 
signs of 
reversibility 
within 7 
days 
Action 
1 
Mild 
N/A 
Any 
Any 
N/A 
No action required  
2 
Moderate 
N/A 
2 
≤3 
Yes 
Progression to part B and/or 
escalation to higher exposure 
dosing regimens in part A on 
hold until results of full (or 
extended) dosing regimen are 
available, to which toxicity 
rules will be applied.  
Progression/escalation can 
then proceed, unless the data 
meet suspension rules.  
  
  
≥3 
≥4 
Yes 
Progression to lower exposure 
dosing regimens is permitted.  
Progression to part B and/or 
escalation to higher exposure 
dosing regimens require 
substantial amendment. 


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Number of 
subjects 
Toxicity Rules for progression to part B /or 
escalation to higher exposure dosing 
regimens within part A 
WHO 
Grade 
Severity 
Seriousness 
Number 
of 
subjects 
affected 
in one 
SOC 
Total 
Number 
of 
subjects 
affected 
Showing 
signs of 
reversibility 
within 7 
days 
Action 
  
  
N/A 
1 
No 
Progression to part B and/or 
escalation to higher exposure 
dosing regimens in part A on 
hold until results of full (or 
extended) dosing regimen are 
available, to which toxicity 
rules will be applied.  
Progression/escalation can 
then proceed, unless the data 
meet suspension rules. 
  
 
  
N/A 
≥2 
No 
Progression to lower exposure 
dosing regimens is permitted.  
Progression to part B and/or 
escalation to higher exposure 
dosing regimens require 
substantial amendment. 
3 
Severe 
Not serious 
N/A 
1 
Yes 
Progression to part B and/or 
escalation to higher exposure 
dosing regimens in part A on 
hold until results of full (or 
extended) dosing regimen are 
available, to which toxicity 
rules will be applied.  
Progression/escalation can 
then proceed, unless the data 
meet suspension rules. 
  
  
N/A 
≥2 
Yes 
Progression to lower exposure 
dosing regimens is permitted.  
Progression to part B and/or 
escalation to higher exposure 
dosing regimens require 
substantial amendment. 
  
  
N/A 
≥1 
No  
3 
Severe 
Serious 
N/A 
≥1 
N/A 
4 
Very 
Severe  
Serious 
N/A 
≥1 
N/A 
Study suspended 
 


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Table 8. Group Toxicity Rules for continuation within a dosing regimen.  
 
 
 
Number of 
subjects 
Toxicity Rules for continuation within a 
dosing regimen 
WHO 
Grade 
Severity 
Seriousness 
Number 
of 
subjects 
affected 
in one 
SOC 
Total 
Number 
of 
subjects 
affected 
Showing 
signs of 
reversibility 
within 7days  
Action 
1 
Mild 
N/A 
Any 
Any 
N/A 
No action required  
2 
Moderate 
N/A 
2 
≤4 
Yes 
Dosing of the remainder of the 
dosing regimen can continue as 
per CSP.  
 
≥3 
≥5 
Yes 
Dosing of the remainder of the 
dosing regimen suspended; 
Continuation requires 
substantial amendment 
N/A 
1 
No 
Dosing of the remainder of the 
dosing regimen can continue as 
per CSP.  
 
≥2 
No 
Dosing of the remainder of the 
dosing regimen suspended; 
Continuation requires 
substantial amendment 
3 
Severe 
Not serious 
N/A 
1 
Yes 
Dosing of the remainder of the 
dosing regimen can continue as 
per CSP.  
 
≥2 
Yes 
Dosing of the remainder of the 
dosing regimen suspended; 
Continuation requires 
substantial amendment 
≥1 
No  
3 
Severe 
Serious 
N/A 
≥1 
N/A 
4 
Very 
Severe  
Serious 
N/A 
≥1 
N/A 
Study suspended 
 
 
 
 
 
 
 
 
 
 


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8.3.2 
Individual toxicity rules (Part B only) 
 
Table 9. Individual toxicity rules.  
 
 
 
 
Individual toxicity rules 
WHO 
Grade 
Severity 
Seriousness 
Showing signs of 
reversibility 
within 7 days 
Action 
1 
Mild 
N/A 
N/A 
No action required  
2 
Moderate 
N/A 
Yes 
IMP administration may be continued, 
amended, temporarily suspended or 
discontinued in accordance with 
Investigator’s clinical judgement and 
relevant algorithms for the treatment of 
toxicities 
  
  
  
  
No 
IMP administration will be discontinued  
3 
Severe 
Not serious 
N/A 
IMP administration will be discontinued  
3 
Severe 
Serious 
N/A 
IMP administration will be discontinued  
4 
Very Severe  
Serious 
N/A 
IMP administration will be discontinued  
 
Standard toxicity grading (according to the WHO Toxicity Grading) will be used to grade the 
AEs for the purpose of applying the toxicity rules. This owes to the fact that this toxicity grading 
is more relevant to the population which P218 is aiming to treat. 
 Local laboratory normal values will be applied. Abnormal laboratory and other tests and 
measurements will be repeated whenever feasible and or appropriate, prior to grading in order 
to ensure consistency and to exclude technical errors. Diurnal variations in laboratory variables 
and other measurements as well as baseline status and conditions will be taken into account 
when assessing whether abnormalities constitute a drug related AE and when grading, if 
applicable. 
Non-clinical data as well as potential class effects have identified the risks outlined in section 
6.3.2.1 (GI toxicity).    
The grading of the WHO criteria related to toxicities and potential AEs (including study related 
sections on:  ‘stomatitis’, ‘nausea’ and ‘vomiting’, ‘diarrhoea’ and ‘constipation’) is considered 
suitable for this particular IMP, study design and the study populations in conjunction with the 
CSP specific toxicity and dose progression/escalation rules.  No further qualifications are 
required.    
8.3.3 
PK exposure limit 
In addition to the above rules, progression and escalation will also be limited by PK exposure 
limits. 


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14-day GLP toxicology studies conducted in rat and dogs have shown that dog is the most 
sensitive species with the lowest dose tested (10mg/kg/day) associated with reversible 
microscopic findings in the gallbladder. Studies in both rats and dogs showed GI tract toxicity 
that was consistent between species and reflected consequence of DHFR inhibition and 
depletion of folate. Supplementation of P218 with folinic acid in the rat abolished all GI 
pathology confirming this to be related to chronic DHFR inhibition. Single dose administration 
of P218 did not induce any GI tract toxicity in animals.  
Based on the high exposures achieved at the rat NOAEL (40mg/kg/day) and the ability to 
monitor the observed toxicity (primarily GI) in the dog at doses > 10mg/kg/day, the dog 
exposure achieved at the next dose level in dogs (20mg/kg/day – 71.9µg.hr/mL) is identified 
as the highest acceptable human exposure for this FIM study with single dose administration 
of P218 to healthy subjects. The corresponding unbound exposure is 15.5µg.hr/mL) 
71. 9µg.hr/mL is the cumulative AUC over the 14 days of the dog study. As subjects will 
receive only a single dose of P218, it is considered that mean exposure in human, AUClast is 
equivalent to AUC0-336 PK derived exposure limit in the 14 day toxicology study with dogs. 
In this FIM study, preliminary PK of each dose level  in Part A will be analyzed after completion 
of each cohort to ensure that the mean group exposure of the subsequent cohort will not 
exceed the highest achievable human exposure (71.9µg.hr/mL). 
 
8.4 
Rationale for study design, doses and control groups 
This study is the first time that P218 will be given to humans. 
Part A 
A single dose escalation ascending dose design is used for this study to evaluate the safety, 
tolerability and PK of the P218 in healthy male and female subjects of non-child bearing 
potential. The study is randomised and double blinded  to minimise bias and includes placebo 
to facilitate identification of effects related to administration of drug rather than the study 
procedures or situation (Part A).  
Part B 
There will be no placebo as this is a cross-over design to investigate the food effect on the 
safety, tolerability and PK of P218. Each subject will be their own control, and therefore 
minimise inter-subject bias and allow identification of effects related to the adminstration of 
drug with food rather than the study procedures or situation.  
8.4.1 
Estimation of first dose 
The maximum recommended safe starting dose (MRSD) of 10mg was calculated based on 
results from pre-clinical studies and in accordance with the 2005 FDA Guidance (Guidance for 
Industry - Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics 
in 
Adult 
Healthy 
Subjects, 
FDA 
2005) 
(1) 
and 
the 
2007 
EMEA 
Guidance 
EMEA/CHMP/SWP/28367/07 (2).  
 
The NOAEL in the 14-day rat toxicology study was 40mg/kg/day, while the corresponding value 
in the 14-day dog toxicology study was <10mg/kg/day (due to minimal reversible microscopic 
gallbladder lesions in male animals at the lowest dose tested).  On the basis of body surface 
area, the corresponding extrapolated human equivalent doses for a human body weight range 
of 50-70kg were 322-451mg (rat NOAEL) and 277-388mg (dog  exposure at 10mg/kg/day), 
respectively.  Utilizing the lower of the two calculated doses (human equivalent dose of 277-
388 mg on the basis of the dog data) and applying a safety factor of 10, a starting dose of 28 
mg could be supported from a toxicology perspective. As the lowest dose tested in dogs was 


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associated with reversible microscopic findings in the gallbladder (in male dogs only), a 
conservative approach is used and a human starting dose of 10mg is identified for this protocol.  
This proposed starting dose of 10mg was predicted to generate mean Cmax and AUC values of 
0.220µg/ml and 1.27µg∙h/ml, respectively in the most conservative scenario from a safety point 
of view (lowest human predicted clearance, highest exposure).  These estimates provide a 
predicted safety margin of 4.2- and 34.7-fold when compared to the Cmax (0.921µg/ml) and 
cumulative AUC0-336 (44.1 µg∙h/ml) in the most sensitive species (dog) at 10mg/kg/day. When 
compared to unbound Cmax (0.198µg/ml) and unbound cumulative AUC0-336 (9.48µg∙h/ml), the 
margins increase to 15.2 and 124.7 respectively. 
The Predicted unbound Cmax at starting dose (10 mg) is 13 ng/mL. Minimal inhibition on the 
human DHFR should occur when the free concentration of P218 reaches IC10 (51.1 ng/ml). 
This represents a  3.9-fold safety margin.   
The table below indicates the margins between the starting dose (and the subsequent clinical 
doses) and the following value: 44.1 µg.h/mL, which represents the AUC0-336 reached at 10 
mg/kg/day (dose with minimal toxicology effect – close to NOAEL).  
 
Table 7  Margins between the clinical doses predicted AUCinf and the 10 mg/kg/day AUC0-
336 in the dog  
 
If low Cl = 0.7  ml/min/kg 
Dose  
(for 70 kg) 
AUCinf 
(µg.h/ml) 
Cum AUC0-336 
margin 
Unbound 
AUCinf 
(µg.h/ml) 
Unbound 
cum AUC0-
336 margin 
10 
1.27 
34.72 
0.08 
118.5 
30 
3.82 
11.54 
0.23 
41.22 
100 
12.71 
3.47 
0.76 
12.47 
250 
31.82 
1.39 
1.91 
4.96 
500 
63.60 
0.69 
3.82 
2.48 
1000 
127.20 
0.35 
7.63 
1.24 
1500* 
190.80 
0.23 
11.45 
0.83 
2000* 
254.43 
0.17 
15.27 
0.62 
 
   *- Dose not administered. 
The table below indicates the margins between the starting dose (and the subsequent clinical 
doses) and the following value: 35.7 ug/mL, which represents the highest Cmax observed in 
animal, i.e. single dose of 2000mg/kg in rat (35.7 ug/mL). 
 
 
 
 
 
 
 


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Table 8    Margins between the clinical doses predicted Cmax and the highest Cmax observed 
in animals  
 
If low Cl = 0.7  ml/min/kg 
Dose  
(for 70 kg) 
Cmax (µg/mL) Cmax margin 
Unbound 
Cmax (µg/mL) 
Unbound 
Cmax margin 
10 
0.22 
162.3 
0.013 
302.1 
30 
0.66 
54.1 
0.040 
98.2 
100 
2.20 
16.2 
0.132 
29.8 
250 
5.52 
6.5 
0.331 
11.9 
500 
11.04 
3.2 
0.662 
5.9 
1000 
22.07 
1.6 
1.324 
3.0 
1500* 
33.11 
1.1 
1.987 
2.0 
2000* 
44.16 
0.8 
2.649 
1.5 
  *- Dose not administered.  
 
8.4.2 
Justification of the planned highest dose level 
Efficacy 
Preclinical studies using SCID mice inoculated with P. falciparum-infected red blood cells link 
doses and exposures to the efficacy of P218. The active dose in the SCID model causing 
maximum effect (ED90) against the parasites is 1.6 mg/kg/day. The minimal parasiticidal 
concentration (MPC) and the minimal inhibitory concentration (MIC) derived from the SCID 
data are 4.4 ng/ml and 1.3 ng/ml, respectively. 
A human dose that could maintain blood concentrations above MIC for seven days was 
identified as a target minimal efficacious dose for the chemoprevention of Pf malaria.   With 
this approach and the preliminary PK data collected during the FIH cohorts 1 to 6, it is likely 
that a human dose ≥ 750 mg may be needed in malaria patients to maintain P218 plasma 
concentration above mouse blood MIC.  
Due to cost limitations associated with Malaria prevention in endemic countries, 1 g is 
considered the highest feasible dose which would be economically and technically 
sustainable, and therefore 1g is the highest dose that we intend to investigate. The predicted 
P218 exposure at this dose is 16.5 µg•h/mL and the resulting margin to P218 AUC cap is 4.4 
folds. 
Toxicology 
Two acyl glucuronides have been identified to be present in all species but quantitative 
differences between the species used in toxicology and humans have been demonstrated 
(preliminary QCed results). Given that the structure, and in particular the site of conjugation, 
is identical between both acyl glucuronides of P218; it is considered appropriate to assess 
safety in terms of total acyl glucuronide burden rather than consider each one independently.  
The toxicology coverage of human P218 β acyl glucuronide and P218-OH β acyl glucuronide 
will therefore be assessed by considering both molecules as a whole, with the global human 


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AUC being the sum of the human AUClast of each molecule. Importantly no toxicity that was 
not related to DHFR inhibition was observed in either species, supporting the conclusion that 
none of the metabolites pose an additional toxicological risk. The predicted P218 β acyl 
glucuronides global human AUC at a 1000 mg dose (based on linear extrapolation to be 48.2 
µg•h/mL) is projected to remain below the highest tolerated, estimated cumulative 
glucuronides AUCs in the dog 14 day toxicology study (74.6 µg•h/mL) and the rat folate 
supplementation study (62.5 µg•h/mL). In addition, as indicated above, at this dose, P218 
should also remain below the AUC cap of 71.9µg•h/mL. Thus, it is considered safe to 
perform a 1000 mg dose cohort in the FIH study.  
 
8.4.3 
Choice of subjects for study 
The target population of patients with malaria will not be included. Since reproductive 
toxicology data are not available before study initiation, the study will be performed in males 
and WNCBP. 
 
8.4.4 
Route and rate of administration 
P218 will be administered via the oral route, as this is the most appropriate for the target 
population. In this study, planned dose levels were calculated from pre-clinical data. Dose 
escalation will proceed with accordance with section 8.28.2 and  
 
Table 1 and will not exceed the mean maximum exposure limits. 
 
8.4.5 
Precautions to be applied for dosing between subjects within a cohort 
For each cohort, treatment of subjects will begin on Day 1. Subjects will be randomised on Day 
1 at each dose level. A mandatory sentinel dosing strategy of dosing 2 subjects (1 subject on 
IMP, 1 subject on placebo) will be used for the first three cohorts in Part A. If safety and 
tolerability is acceptable, the remaining subjects of this cohort may be dosed, with a minimum 
interval of 24 hours between the first subject of the sentinel group and the remaining subjects 
of that dose level being dosed.  
The Investigator will make a judgement (based on the clinical data available at the time) 
whether the drug administration to the remaining subjects in the cohort can continue. The 
assessment will be based on the clinical safety data available at the time and the protocol 
toxicity rules (Section 8.3). The Investigator will document the decision in an e-mail to the 
Sponsor. The e-mail does not require Sponsor’s response, unless there is disagreement with 
the Investigator’s decision.  
Sentinel dosing for all other study parts is not considered necessary as the dose escalation 
and progression rules, PK exposure limits and toxicity rules provide appropriate rules and 
boundaries to ensure safety.  
 
8.4.6 
Precautions to be applied for dosing between different cohorts 
Progression between cohorts will be determined by the SRC according to the anticipated 
doses, Adaptive Features ( 
 


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Table 1) and group toxicity rules (Section 8.3.1). Safety and PK data will be continuously 
evaluated in line with the dose progression rules and minimum data requirements. Please refer 
to section 8.2. 
 
8.4.7 
Monitoring and communication of adverse events / reactions 
Adverse events (AEs) will be continuously monitored throughout the study from first dose until 
the last follow up assessment. Each AE reported will be assessed by a trained Research 
Physician who will ensure that the event is dealt with as appropriate based on clinical need, 
study protocol, study operations manual and Richmond Pharmacology standard operating 
procedures (SOPs). AEs will be documented in the subjects’ Case Report Forms (CRFs) and 
reviewed regularly by the Research Physicians and the Investigator.  
If any information relating to the study drug in this study becomes available after the 
submission of a final protocol to the Competent Authority which may impact on the conduct of 
the study, including but not limited to the risk and benefit evaluations underpinning approvals 
and volunteer’s consent, MMV shall notify RPL in writing as soon as practically possible and 
the parties will agree, in writing, what steps need to be taken if any. 
 
8.4.8 
Investigator Site Facilities and Personnel 
This study will be conducted in a specialised early phase CPU within an acute hospital setting 
with Critical Care facilities, thus ensuring direct access to equipment and staff for resuscitating 
and stabilising subjects in acute medical conditions and emergencies. The study is conducted 
by an experienced PI and well trained medical, nursing and technical staff with ample 
experience in the conduct of early phase clinical trials.   
The study is designed to closely monitor, treat and communicate potential expected adverse 
reactions (based on the known mode of action of the IMP and the previous studies with similar 
compounds) as well as potential unexpected adverse events. 
A specialist medical advisor will be available to provide input to the PI and Sponsor on any 
gynaecological queries. 
 
9. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
9.1 
Number and Source of Subjects 
 
9.2 
Inclusion Criteria  
Subjects must meet all of the following criteria to be eligible for enrolment in this study: 
1. Subject is a healthy male or female (of non-childbearing potential), aged 18 to 45 years, 
inclusive. 
 
2. Satisfactory medical assessment with no clinically significant or relevant abnormalities as 
determined by medical history, physical examination, vital signs, 12-lead ECG, and clinical 
laboratory evaluation (haematology, biochemistry, coagulation, and urinalysis) that is 
reasonably likely to interfere with the subject's participation in or ability to complete the 
study as assessed by the Investigator. 
 


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3. Subject has a body weight of at least 50 kg and a body mass index (BMI) of 18-25 Kg/m2, 
inclusive. 
 
4. Female subjects must be of non-childbearing potential:  
 
a. Natural (spontaneous) post-menopausal defined as being amenorrheic for at least 
12 months without an alternative medical cause with a screening follicle stimulating 
hormone level > 25 IU/L (or at the local laboratory levels for post-menopause). 
b. Premenopausal 
with 
irreversible 
surgical 
sterilization 
by 
hysterectomy 
 and/or 
bilateral 
oophorectomy 
or 
salpingectomy 
at 
least 
6 
months 
 before screening (as determined by subject medical history). 
 
5. Heterosexually active male subjects with a female spouse/partner of childbearing potential 
must agree to use barrier contraception (male condom), even with documented medical 
assessment of surgical success of a vasectomy, if your partner could become pregnant 
from the time of the first administration of P218 and for 100 days following this.  Your 
partner must also use a method of highly effective contraception including: 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
o Oral 
o Intravaginal 
o Transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o Oral 
o Injectable 
o Implantable  
• 
Intrauterine device  
• 
Intrauterine hormone-releasing system  
• 
Bilateral tubal occlusion 
 
6. Subjects are non-smokers or ex-smokers for more than 90 days prior to screening or 
smoke no more than 5 cigarettes per day. If users of nicotine products (i.e. spray, patch, 
e-cigarette, etc.) they should use the equivalent of no more than 5 cigarettes per day. 
Subjects must agree to abstain from smoking while in the unit.  
 
7. Ability to swallow multiple capsules at a time or (consecutively) 1 capsule at a time. 
 
8. Subjects must be capable of fully understanding and complying with the requirements of 
the study and must have signed the informed consent form prior to undergoing any study-
related procedures. 
 
9. Subjects who are willing and able to comply with all scheduled visits, treatment plan, 
laboratory tests, and other study procedures. 


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9.3 
Exclusion criteria  
Subjects will be prohibited from participating in this study if they meet any of these criteria: 
 
1. Male subjects with a female partner(s) who is (are) pregnant or lactating from the time of 
the administration of study medication. 
 
2. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, including women whose career, lifestyle, or sexual orientation 
precludes intercourse with a male partner and women whose partners have been sterilized 
by vasectomy or other means. 
 
3. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, 
gastrointestinal (including gallbladder), cardiovascular, hepatic, psychiatric, neurologic, or 
allergic disease (including drug or food allergies, anaphylaxis or other severe allergic 
reactions but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).  
 
4. Current or relevant history of physical or psychiatric illness that may require treatment or 
make the subject unlikely to fully comply with the requirements or complete the study, or 
any condition that presents undue risk from the investigational product or study procedures. 
 
5. Any surgical or medical condition possibly affecting drug absorption (e.g. cholecystectomy, 
gastrectomy, bowel disease, etc.), distribution, metabolism or excretion. 
 
6. Any history of gallbladder disease, including cholecystitis and/or cholelithiasis. 
 
7. Any other significant disease or disorder which, in the opinion of the investigator, may either 
put the subject at risk because of the participation in the study may influence the result of 
the study, or the subject’s ability to participate in the study. 
 
8. History of photosensitivity. 
 
9. History of megaloblastic anaemia or folate deficiency. 
 
10. History or clinical evidence of substance and/or alcohol abuse within the 12 months before 
screening. Alcohol abuse is defined as regular weekly intake of more than 21 units for 
males 
and 
14 
units 
for 
females 
(using 
alcohol 
tracker 
http://www.nhs.uk/Tools/Pages/NHSAlcoholtracker.aspx).  
 
11. Treatment with an investigational drug within 90 days or 5 half-lives preceding the first dose 
of study medication (or as determined by the local requirement, whichever is the longer).  
 
12. Donation of blood or blood products (excluding plasma) within 90 days prior to study 
medication administration. 
 
13. Use of moderate/strong inhibitors or inducers of CYP450 cytochromes or transporters 
within 30 days or 5 half-lives (whichever is the longer) prior to the first dose of study 
medication. 


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14. Consumption of grapefruit, grapefruit juice or grapefruit-related citrus fruits (e.g. Seville 
oranges, pomelos) within 30 days prior to the first dose of study medication. 
 
15. Ingestion of any poppy seeds within the 24 hours prior to screening. 
 
16. Use of prescription or non-prescription drugs and dietary supplements within 7 days or 5 
half-lives (whichever is the longer) prior to the first dose of study medication. With the 
exception of paracetamol, which may be used incidentally or for a short-term treatment at 
a maximum dose of 1 gr. per day. 
 
17. Use of herbal supplements at least 30 days prior to the first dose of study medication. 
 
18. Any clinically significant abnormal laboratory, vital signs or other safety findings as 
determined by medical history, physical examination or other evaluations conducted at 
screening or on admission. 
 
19. The history or presence of any of the following cardiac conditions: known structural cardiac 
abnormalities; family history of long QT syndrome; cardiac syncope or recurrent, idiopathic 
syncope; exercise related clinically significant cardiac events. 
• 
Any clinically important abnormalities in rhythm, conduction or morphology of 
resting ECG that may interfere with the interpretation of QTc interval changes. 
This includes subjects with any of the following (at screening):  
• 
Sinus node dysfunction. 
• 
Clinically significant PR (PQ) interval prolongation. 
• 
Intermittent second or third degree AV block. 
• 
Incomplete or complete bundle branch block.  
• 
Abnormal T wave morphology. 
• 
Prolonged QTcB >450 ms or shortened QTcB < 350 ms. Any other ECG 
abnormalities in the standard 12-lead ECG and 24-hour 12 lead Holter ECG or 
an equivalent assessment which in the opinion of the Investigator will interfere 
with the ECG analysis.  
Subjects with borderline abnormalities may be included if the deviations do not pose a 
safety risk, and if agreed between the appointed Cardiologist and the PI.  
  
20. Confirmed positive results from urine drug screen (amphetamines, benzodiazepines, 
cocaine, cannabinoids, opiates, barbiturates, and methadone) or from the alcohol breath 
test at screening or on admission. 
 
21.  A positive human immunodeficiency virus (HIV) I and II antibodies, hepatitis B surface 
antigen (HBsAg), anti Hepatitis core antibody (anti HBc Ig G [and anti HBc IgM if IgG is 
positive], or hepatitis C virus (HCV) antibody at screening. 
 


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22. Subjects have veins unsuitable for intravenous puncture or cannulation on either arm (e.g. 
veins that are difficult to locate access or puncture veins with a tendency to rupture during 
or after puncture). 
 
23. Any conditions which in the opinion of the investigator would make the subject unsuitable 
for enrolment or could interfere with the subjects’ participation in or completion of the study. 
 
9.4 
Subject Restrictions  
Subjects will have to comply with the following restrictions during the study: 
1. Whenever subjects are confined in the ward, only the drinks and meals provided by the 
trial personnel will be allowed.  
2. Standard meals will be provided at the standard unit times as stated in the study plan, 
and meals should be completed each time.  
3. Subjects will be required to fast for a period of at least 4 hours prior to laboratory safety 
tests on screening and the post/study visit days. On Day 1 of study Part B will receive 
breakfast before study drug administration. On all other dosing days, subjects will fast 
for at least 8 hours pre-dose. 
4. Subjects will be provided water ad libitum up to 1 hour pre-dose and from 1 hour post-
dose.  
5. Abstain from consumption of caffeine from 24 hours prior to screening and study drug 
administration until collection of the final PK sample.  
6. Abstain from consumption of energy drinks containing taurine or glucuronolactone from 
24 hours prior to screening and study drug administration until collection of the final PK 
sample.  
7. Abstain from eating or drinking grapefruit or grapefruit-related citrus fruits (e.g. Seville 
oranges, pomelos) within 30 days prior to the first dose of study medication until 
collection of the final pharmacokinetic blood sample. 
8. Abstain from drinking alcohol from 24 hours prior to screening and study drug 
administration until collection of the final PK sample. Subjects may undergo an alcohol 
breath test at the discretion of the investigator. 
9. Abstain from smoking and/or using nicotine containing products for 24 hours prior to 
study drug administration and throughout confinement in research unit. 
10. Abstain from any new or unaccustomed strenuous physical activity or any excessive 
strenuous activity (e.g. heavy weight lifting, long distance running) for at least 48 hours 
prior to screening and study drug administration until collection of final PK sample. 
11. Abstain from blood and plasma donation during the study and up to three months after 
completion of the study. 
 
9.5 
Subject Inclusion and Randomisation  
Subjects in this study will be assigned to a treatment regimen according to a randomization 
schedule generated by a statistician using PROC Plan. Details regarding the unique 
screening and subject number will be included in the SOM. 
Subjects who meet the eligibility criteria will be randomly assigned on Day 1. In Part A 
subjects will be randomly assigned in a 3:1 ratio to either P218 or placebo. In Part B, all 
subjects will receive P218.  


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9.6 
Criteria for withdrawal  
The Investigator or designee may withdraw a subject from the study if the subject: 
• 
Is in violation of the protocol; 
• 
Has an AE; 
• 
Meets individual stopping criteria; 
• 
Use of/need for a prohibited medication which in the opinion of the Sponsor or 
Investigator may jeopardize the study results or represent a risk to the participant; 
• 
Requests to be withdrawn from the study (subject withdrawal of consent); 
• 
Is found to be considerably non-compliant with the protocol-required visits; 
• 
In the Investigator’s opinion, is unable to continue study participation; 
• 
Is withdrawn from the study upon the request of Sponsor or the SRC, including if 
Sponsor terminates the study. 
 
9.6.1 
Handling of Withdrawals 
In the event a subject withdraws or is withdrawn from the study, the Investigator will inform the 
Medical Monitor and the Sponsor immediately. The SRC will be notified. If there is a medical 
reason for withdrawal, the subject will remain under the supervision of the Investigator for 
protocol-specified safety follow up procedures.  
Should any of the subjects be withdrawn from the study after being dosed, all the relevant 
assessments in relation to last dose should be completed as per protocol. 
Investigator and/or Sponsor may decide to perform additional assessment in accordance with  
 
Table 1 – Adaptive Features. 
When a subject withdraws or is withdrawn from the study, every effort should be made to 
conduct a complete Early Termination (ET) at an appropriate time-point. 
A subject who fails to return for final evaluations will be contacted by the site in an attempt to 
have the subject comply with the protocol in accordance with the site SOPs.  
When a subject withdraws from the study, the primary reason for discontinuation must be 
recorded in the appropriate section of the case report form (CRF). 
 
10. 
STUDY AND CONCOMITANT TREATMENTS 
10.1 
Investigational Medicinal Products (IMPs)  
The following IMPs will be used in this study: 
• 
P218 as capsule 
• 
Placebo to match P218, as capsule. 
P218 will be supplied by Penn Pharma-UK, as capsules. 


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Due to the favourable physicochemical properties of P218, the API was formulated in capsules 
without excipients. Capsules (size 0 HPMC capsules comprising a VCaps®Plus Swedish 
orange body cap) were produced via hand-filling of API and contained 10, 50 and 250 mg of 
P218. 
P218 capsules (10, 50 and 250 mg) are packaged into high density polypropylene containers 
with a twist-off polypropylene screw cap lid with up to 30 units per container. 
A detailed description of the physical, chemical and pharmaceutical properties of P218 can be 
found in Section 4 of the Investigator’s Brochure (IB) and in the Investigational medicinal 
product dossier (IMPD). 
Placebo capsules will be used for the purpose of the clinical trial. The placebo capsules have 
been developed to match the drug product. They are contained in the same packaging as the 
drug product.  
 
Table 9. IMP or matching placebo for each anticipated dose level (Part A) 
Treatment: 
IMP Dispensed: 
Administration 
10 mg P218 
1 x P218 10 mg capsule 
 
 
Oral 
doses 
will 
be 
administered with 240 mL of 
water. Subjects will be in the 
sitting position. For doses of 
6 capsules or more subjects 
will be offered additional 
water 50 mL x2 
30 mg P218 
3 x P218 10 mg capsules 
100 mg P218 
2 x P218 50 mg capsules 
250 mg P218 
1 x P218 250 mg capsule 
500 mg P218 
2 x P218 250 mg capsules 
750 mg P218 
3 x P218 250 mg capsules 
1000 mg P218 
4 x P218 250 mg capsules 
Placebo 
Oral dose of placebo to match 
P218 
 
Table 10. IMP or matching placebo for the anticipated dose level (Part B) 
Treatment: 
IMP Dispensed: 
Administration 
250 mg P218 
1 x P218 250 mg capsule 
Oral 
doses 
will 
be 
administered with 240 mL of 
water. Subjects will be in the 
sitting position. If the dose 
consists of 6 capsules or 
more subjects will be offered 
additional water 50 mL x2 
The dose will be selected, based on the safety, tolerability, and PK profile of the fasted dose 
cohorts as the dose corresponding to the predicted human efficacious dose. 
The study drugs will be repackaged into individual subject doses according to the dose level 
and randomisation schedule by the pharmacy staff at the clinical study site. 
 


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10.2 
Labelling of IMPs  
The labelling of the study drugs will be in compliance with Good Manufacturing Practice (GMP) 
specifications, as described in The Rules Governing Medicinal Products in the European 
Union, Volume 4, Annex 13, Investigational Medicinal Products, and any other or local 
applicable regulations. 
Sample label(s) will be submitted to the UK health authorities according to the submission 
requirements. 
 
10.3 
Drug Accountability  
The designated pharmacy staff at the clinical study site will maintain accurate records of receipt 
and the condition of all study drugs, including dates of receipt. In addition, accurate records 
will be kept by the pharmacy staff of when and how much study drug is dispensed and used 
by each subject/patient in the study. Any reason for departure from the protocol dispensing 
regimen must also be recorded.  
Drug accountability records and inventory will be available for verification by the Sponsor or 
designee. Upon completion of the study, there will be a final reconciliation of all study drugs 
and copies of study drug accountability records will be provided to MMV. Original records will 
be maintained at the clinical site with the rest of the study records.  
Study drug must not be used for any purpose other than the present study. Remaining study 
drug will be returned to the Sponsor or its agent or its destruction arranged by the clinical study 
site according to applicable regulations and only after receipt of written authorization from the 
Sponsor. 
10.4 
Blinding and Procedures for Unblinding the Study  
10.4.1 
Methods for ensuring blinding 
The study will be conducted in a double-blind fashion whereby subjects and clinical study site 
staff are blinded to study drug/dose assignment. 
The pharmacy staff preparing the investigational products will not be blinded to study drug 
assignment. During the study, the randomisation codes will be kept in the site's clinical trials 
pharmacy, accessible to the pharmacy personnel only. Upon completion of the study, after the 
database lock and after the blind is revealed, the randomisation list will be filed in the Study 
Master File. 
P218 and Placebo capsules are identical in appearance. 
 
10.4.2 
Methods for unblinding the study 
In the event of an emergency, an envelope for each subject containing their study drug 
assignment will be available in the pharmacy at the clinical study site. Unblinding should only 
be considered for the safety of the subject. If unblinding is deemed necessary by the 
investigator, the investigator or designee can unblind the subject’s treatment allocation using 
the envelope available from the pharmacy. The investigator or designee must note the date, 
time and reason for unblinding and inform the sponsor of unblinding as soon as practicably 
possible. 
 


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10.5 
Concomitant Medications/Permitted medications  
Intake of any medication is prohibited from 7 days before IMP administration until the end of 
the hospitalisation in order to avoid interference with study assessments. As an exception, a 
maximum dose of 1g/day of paracetamol may be used.  
During the study, medications other than IMP must only be taken exceptionally and with the 
consent of the investigator. The need for other medication may lead to subject’s withdrawal 
from the study. In any case, the investigator will inform the sponsor about the concurrent 
medication given. 
Details of prior and concomitant medications should be recorded by the investigator on the 
CRF and source record. 
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 
 
11. 
STUDY PROCEDURES 
11.1 
Schedule of Study Procedures 
The study assessments are described in the sections below and the timing of these 
assessments are detailed in the Study Plans (Table 2, Table 3, Table 4, and Table 5). It is 
important that PK sampling occurs as close as possible to scheduled time. The sequence of 
assessments at particular time-points will be described in the SOM. 
 
12. 
STUDY METHODOLOGY 
12.1 
Meals 
Standardised meals will be provided during the study period according to the timings described 
in the Study Plan (Table 2, Table 3, Table 4, and Table 5). 
On Day 1 of either, Period 1 or Period 2, of Part B, subjects will have the IMP administered in 
the fed state. Thirty minutes prior to dosing, the subjects will receive a high-fat breakfast 
based on that recommended by the FDA, details regarding this will be described in the SOM.  
  
12.2 
Haematology, biochemistry and coagulation 
Blood samples for determination of biochemistry and haematology parameters will be taken at 
the times given in the Study Plans (Table 2, Table 3, Table 4, and Table 5). The date and time 
of collection will be recorded on the appropriate CRF pages. The analyses will be done using 
routine methods. Further details will be described in the SOM.  
Laboratory values outside the reference limits, which are suspected to be of any clinical 
significance, will be repeated. Subjects in whom the suspected clinical significance is 
confirmed on repeated sampling will either not be included or, if already included, may be 
withdrawn from further participation in the study in accordance with the toxicity rules in section 
8.3 and/or followed until normalisation or for as long as the Investigator considers necessary. 
Laboratory parameters to be measured are presented in Table 11. 
 


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Table 11. Laboratory parameters. 
Biochemistry 
Haematology 
Coagulation 
Serology 
Urinalysis 
Urine Screen for 
Drugs of Abuse 
Aspartate 
aminotransferase 
Red blood cell count 
Prothrombin 
time (PT) 
Hepatitis B 
surface 
antigen 
(HBsAG) 
Leukocytes 
Benzodiazepines 
 
Haemoglobin 
International 
Normalised 
Ratio (INR) 
Hepatitis B 
core 
antibody 
(anti-HBC 
IgG/IgM + 
isolated 
IgM, if IgG 
positive) 
Nitrite 
Opiates 
 
Mean corpuscular volume (MCV) 
 
 
 
 
 
Mean corpuscular haemoglobin 
concentration (MCHC) 
 
 
 
 
Alanine 
aminotransferase 
Mean cell haemoglobin (MCH) 
Activated 
partial 
thromboplast
in time 
(aPTT) 
Hepatitis C 
antibody 
(anti-HCV) 
Urobilinogen 
Amphetamines 
Alkaline 
phosphatase 
Reticulocytes  
 
HIV I and II 
antibodies 
Protein 
Methadone 
Blood urea 
nitrogen 
Haematocrit  
 
 
pH 
Cocaine 
Gamma glutamyl 
transferase 
Platelets   
 
 
Blood 
Cannabinoids 
Total bilirubin 
Direct bilirubin 
White blood cells 
 
 
Specific 
gravity 
Barbiturates 
Creatinine 
Neutrophils 
 
 
Ketones 
Benzodiazepines 
 
Eosinophils 
 
 
Bilirubin 
Opiates 
Total serum 
proteins 
Basophils 
 
 
Glucose 
Phencyclidine 
Albumin 
Lymphocytes 
 
 
Nitrites 
Tricyclic 
antidepressants 
Glucose – fasting 
Monocytes 
 
 
Urine 
microscopy 
Methamphetamine 
Sodium 
 
 
 
 
 
Potassium 
 
 
 
 
 
Calcium 
 
 
 
 
 
Magnesiuma 
 
 
 
 
 


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Biochemistry 
Haematology 
Coagulation 
Serology 
Urinalysis 
Urine Screen for 
Drugs of Abuse 
Follicle 
stimulating 
hormonea 
 
 
 
 
 
Serum 
pregnancy test 
 
 
 
 
 
Chloride 
 
 
 
 
 
Bicarbonate/CO2 
 
 
 
 
 
Urate  
 
 
 
 
 
C-reactive 
protein  
 
 
 
 
 
Globulin 
 
 
 
 
 
 
 
 
 
 
 
Lactate 
Dehydrogenase 
 
 
 
 
 
Creatine 
phosphokinase  
 
 
 
 
 
Inorganic 
phosphate 
Serum folate 
 
 
 
 
 
 
 
 
 
 
 
 
a measured at screening only 
 
12.3 
Serology 
Serology will be performed at Screening as detailed in the Study Plans (Table 2 and Table 4). 
At the screening visit all subjects will be tested for the parameters listed in Table 11. This is 
done for the safety of the study personnel and the result from the tests will not be entered into 
the study database. If a volunteer is found to be confirmed positive in any of these tests, they 
will be referred for further examination/treatment and will not be included in the study, with the 
exception of volunteers with a confirmed positive anti-HBc IgG and negative anti-HBc IgM and 
HBsAg, indicative of natural immunity due to a past infection without active chronic or acute 
infection 
The serology tests will be analysed in the same blood sample used for biochemistry. 
Laboratory results at screening and/or baseline that fall outside of the specified eligibility 
criteria may be repeated once prior to enrolment and/or randomisation in order to exclude a 
possible laboratory error. Should the repeat value remain outside of the required range for 
eligibility, the subject will be excluded from participation.  
 


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12.4 
Urinalysis 
Urine samples for determination of urinalysis parameters will be taken at the times given in the 
Study plans (Table 2 and Table 4). If deemed necessary, based on a clinically significant 
positive test, microscopic examination of urine will be performed. 
 
12.5 
Pregnancy test 
To exclude pregnancy, a serum β-HCG blood sample will be performed as described in Study 
Plans (Table 2 and Table 4) and whenever pregnancy is suspected. Any subject with a positive 
pregnancy test will be excluded or withdrawn. 
 
12.6 
Drugs of Abuse 
Urine will be tested for the drugs of abuse as described in the Study Plans (Table 2 and Table 
4). If a subject fails the drug abuse screen, they will be excluded from the study. A repeat drug 
screen can be done where methodological reasons are believed to have led to a false positive. 
If subjects are suspected to be positive due to medication e.g. flu/cold remedies, they may 
undergo a repeat drug screen. The results from the tests will not be entered into the database. 
 
12.7 
Alcohol Breath Test 
An alcohol breath test will be done using an alcometer as described in the Study Plans ((Table 
2 and Table 4)). The results from this test will not be entered into the clinical study database. 
If a subject tests positive to the test they will be excluded from the study. 
 
12.8 
Physical Examination, Height and Weight 
The physical examination performed at screening will include an assessment of the following: 
general appearance, skin, eyes, ears, nose, mouth (including dentition), head, neck (including 
thyroid), lymph nodes, throat, heart/circulation, chest, lungs, abdomen, musculo-skeletal 
system, neurological examination and extremities. The timings of the physical examinations 
are described in the Study Plans (Table 2 and Table 4). 
After screening, an abbreviated, symptom-directed physical examination will be performed 
focused on changes since the previous examination, but will always include at least: general 
appearance, ski, heart/circulation, chest, lungs, abdomen and brief neurological examination. 
Height will be measured in centimetres and weight in kilograms. Measurements should be 
taken with subjects wearing light clothing and without shoes using calibrated scales for all 
measurements. BMI will be calculated from the height and weight. 
 
12.9 
Vital Signs 
12.9.1 
Blood pressure, heart rate and tympanic temperature 
Blood pressure and heart rate will be measured in supine position after the subject has rested 
comfortably for at least 5 minutes, followed by the standing position after the subject has stood 
for 1 minute, using automated Criticon Dynamap® monitors. Vital signs (blood pressure and 
heart rate) will be measured at the time points as detailed in the Study Plans (Table 2, Table 
3, Table 4, and Table 5). Temperature will be measured using tympanic thermometers. 


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12.10 
Electrocardiographic (ECG) Measurements 
12.10.1 Recording of 12-lead ECGs 
12-lead ECGs will be recorded at the time-points described in Study Plans (Table 2, Table 3, 
Table 4, and Table 5) using a GE Marquette MAC1200® /MAC1200ST® recorder connected 
via a fixed network connection to the MUSE® Cardiology Information System (MUSE). ECGs 
recorded during screening will be stored electronically on the MUSE information system. Only 
ECG recorded electronically will be valid ECG for any purpose other than safety assessment. 
ECG printouts may be filed in the subject’s CRF for medical safety reviews. 
Each ECG recorder will be set up to the required technical specifications and containing the 
information required to identify the records. Each ECG recording will be clearly identified 
(Subject ID, visit date, and the actual times of ECG recordings).  
12-lead ECG recordings will be made after the subjects have been resting in a supine position 
for at least 10 minutes. The subjects will avoid postural changes during the ECG recordings 
and clinical staff will ensure that subjects are awake during the ECG recording. At each time 
point, triplicate 12-lead ECGs will be recorded. 
At each time point, the ECG will be recorded in triplicate, to reduce variance and improve the 
precision of measurement. The triplicates will be performed at approximately 1-minute 
intervals. Each ECG recording (trace) will last 10 seconds. Repeat ECG will be performed until 
at least three 10-second ECG records per scheduled time-point meet the quality criteria set 
out in the SOM and the applicable SOP so to enable reading and analysing at least 5 
complexes per derivation. 
 
12.10.2 Safety review of 12-lead ECGs 
All recorded ECGs will be reviewed by a Research Physician and the review be documented 
in the CRF. With regards to the clinical assessment of QTc interval, QTcB will be assessed as 
this is automatically calculated by the equipment. If there is any indication of potential 
significant QTcB prolongation, QTcF will also be calculated and assessed by a Research 
Physician.  If a subject shows an abnormal ECG, additional safety recordings (including the 
use of 5 or 12 lead Holter equipment) may be made and the abnormality be followed to 
resolution if required. 
Further details will be included in the SOM. 
 
12.10.3 Real time display (ECG telemetry) 
A 12-lead real time ECG will be recorded as described in the Study Plan (Table 2, Table 3). 
ECG telemetry will be monitored by the Investigator or qualified member of clinical staff. This 
will allow the extraction of ten-second 12-lead ECG data files, which can be transferred onto 
the MUSE. All ECG files so acquired will then be analysed and over-read using the same 
process as for any other 12-lead ECG. 
The system will be managed according to local working practices. The ECG telemetry reports 
will be archived with study documents. 
 


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12.10.4 Analysing and over-reading 12-lead ECG for the purpose of intensive cardiac 
assessments 
Each electronic ECG will contain the ECG data as well as the result of the automated ECG 
analysis performed by the Marquette® 12SL™ ECG Analysis Program (MEAP), a program 
resident in each of the ECG machines. All ECG and their associated automated interval 
measurements will subsequently be reviewed by qualified Cardiologists in accordance with the 
ICH E14 Guidance for Industry document and ICH E14 Implementation Working Group 
Questions and Answers document before any of the ECG are used for the thorough ECG 
analysis. The manual adjudication process applied in this study is also referred to in the ICH 
guidance and relevant literature as “manual over-read”, “computer-assisted” or “semi-
automated” ECG measurements. The following parameters on each ECG (but not limited to) 
will be assessed by a cardiologist using the commercially available MUSE® in its latest version: 
•QT interval 
•RR interval 
•Heart rate (HR) 
•PR interval 
•Presence or absence of U-wave 
•Quantitative and qualitative ECG variations 
Manual on-screen over-reading using electronic callipers in MUSE® will be performed by a 
small and select group of cardiologists with extensive experience with manual QT 
measurement (including on-screen measurement with electronic callipers). For all study ECG 
the over-reading cardiologists will be blinded to time, date, treatment and any data identifying 
the subject. All ECG of a given subject will be over-read by the same cardiologist (or 
cardiologists in case manual adjustments of the automated measurement are necessary). 
 
12.11 
Pharmacokinetic Assessments 
For timing of individual samples refer to the Study Plans (Table 2, Table 3, Table 4, and Table 
5). The date and time of collection will be recorded on the appropriate CRF. 
 
12.11.1 PK blood samples 
Venous blood samples for the determination of concentrations of P218 and metabolite in 
plasma will be taken at the times presented in the Study Flow Charts (Table 2, Table 3, Table 
4, and Table 5). For blood volume see Section 12.2. Samples will be collected, stored and 
shipped as detailed in a separate SOM. 
All sample handling procedures, including the time of each sample collection, the time of 
placement into frozen storage (at the end of the sample workup), and the date of transfer or 
shipment of the samples to the responsible analyst will be documented in detail in the SOM. The 
procedures and materials used, e.g. collection and storage tubes, will be examined prior to any 
analytical measurements as part of the analytical method validation, to rule out any possible 
interference with the analyte. 
Plasma samples for determination of P218 and metabolite concentration will be analysed by 
Swiss BioQuant laboratory on behalf of MMV using a validated HPLC/MS/MS method. Full details 
of the analytical methods used will be described in a separate bioanalytical report.   


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12.11.2 PK urine samples  
Urine samples for determination of concentration of P218 will be taken from the total urine 
sample provided during each collection period presented in the Study Plans (Table 2, Table 3, 
Table 4, and Table 5). Samples will be collected, stored and shipped as detailed in a separate 
SOM. 
Urine samples for determination of P218 and metabolite concentration will be analysed by 
Swiss BioQuant laboratory on behalf of MMV using a non-validated method. Should more than 
10 % compound be found in the urine then a validated method will be used. Full details of the 
analytical methods used will be described in a separate bioanalytical report. 
 
12.11.3 Serum and Red Blood Cell folate levels 
Venous blood samples for the determination of the effect of P218 on serum and red blood cell 
folate levels will be taken at the times presented in the Study Plans (Table 2 and Table 4). For 
blood volume see Section12.2.  
All sample handling procedures, and the date of transfer or shipment of the samples to the 
responsible analyst will be documented in detail in the SOM. The procedures and materials used, 
e.g. collection and storage tubes, will be examined prior to any analytical measurements as part 
of the analytical method validation, to rule out any possible interference with the analyte. 
This procedure will be further detailed in the SOM. 
 
12.11.4 Malaria bioassay 
Venous blood samples taken to confirm that P218 β acyl glucuronide is active against 
Plasmodium parasite and to determine if other active metabolites are formed will be taken at 
the times presented in the Study Plans (Table 2, Table 3, Table 4 and Table 5). For blood 
volume see section 12.12. These samples will be analysed by Swiss TPH laboratory on behalf 
of MMV. 
All sample handling procedures, and the date of transfer or shipment of the samples to the 
responsible analyst will be documented in detail in the SOM. The procedures and materials used, 
e.g. collection and storage tubes, will be examined prior to any analytical measurements as part 
of the analytical method validation, to rule out any possible interference with the analyte.  
This procedure will be further detailed in the SOM. 
 
12.11.5 Pharmacogenetics 
This study includes an optional, exploratory pharmacogenetic component.  
This blood sample (10-15 mL) should be collected prior to drug administration. Only one blood 
sample per subject will be collected. 
Samples will be collected, stored and shipped as detailed in a separate SOM. 
All sample handling procedures, including the time of each sample collection, the time of 
placement into frozen storage (at the end of the sample workup), and the date of transfer or 
shipment of the samples to the responsible analyst will be documented in detail in the SOM. 


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12.12 
Volume of Blood Sampling 
The maximum total blood volume collected from subjects participating in this study will not 
exceed 600 mL. Details will be described in the SOM. The total volume of blood will be obtained 
in small volumes over an extended time period and is not anticipated to propose any risk to 
the subjects.  
 
13. 
ADVERSE EVENTS 
The collection, evaluation and reporting of adverse events/reactions arising from this clinical 
study will be performed in accordance with: 
• 
“Detailed guidance on the collection, verification and presentation of adverse 
event/reaction reports arising from clinical trials on medicinal products for human use 
(‘CT-3’) (2011/C 172/01). 
• 
International Conference on Harmonization (ICH) guideline E2F “Note for guidance on 
development safety update reports (DSUR)”. 
 
13.1 
Adverse Events  
It is the Investigator’s responsibility to document and report all adverse events occurring in the 
clinical trial. The period of observation for collection of adverse events extends from the 
screening visit up to the final visit (including any wash-out or run-in periods). 
All adverse events which come to the attention of the Investigator within 4 weeks from the end 
of the study treatment must also be recorded. 
 
13.1.1 Definitions 
According to ICH Topic E6, an adverse event (AE) is any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with the 
use of a medicinal product, whether or not considered related to it. 
An adverse reaction (ADR) is a response to a medicinal product which is noxious and 
unintended and which occurs at any dose (in pre-approval clinical experience) or at doses 
normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of 
physiological function (in post-approval clinical experience). The term "response” means that 
a causal relationship between a medicinal product and an adverse event is at least a 
reasonable possibility. This means that there are facts (evidence) or arguments to suggest a 
causal relationship. 
According to ICH Topic E9 a treatment emergent adverse event/adverse reaction is an 
event that emerges during treatment, having been absent pre-treatment, or worsens relative 
to the pre-treatment state. 
In a clinical trial, in addition to the above mentioned “treatment-emergent” AEs/ADRs, any 
unfavourable and unintended sign, symptom or disease occurring in the study during any 
wash-out periods must also be recorded as an AE/ADR. 
An AE/ADR may be: 
• 
a new symptom or medical condition; 


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• 
a new diagnosis; 
• 
an inter-current illness or an accident; 
• 
a worsening of a medical condition/diseases existing before the start of the clinical trial; 
• 
the recurrence of a disease; 
• 
an increase in frequency or intensity of episodic diseases; 
• 
a change in a laboratory parameter. 
The criteria for determining whether an abnormal test result should be reported as an AE/ADR 
are as follows: 
• 
the test result is associated with accompanying symptoms, and/or 
• 
it requires additional diagnostic testing or medical/surgical intervention, and/or 
• 
it leads to a change in trial dosing outside of protocol-stipulated dose adjustments, or 
discontinuation from the trial, significant additional concomitant drug treatment, or other 
therapy, and/or 
• 
it is considered to be an adverse event by the Investigator or Sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE/ADR. Any abnormal test result that is determined to be an error does not 
require reporting as an adverse event. 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions 
that require surgery. The condition for which the surgery is required may be an AE/ADR. 
Planned surgical measures permitted by the clinical trial protocol and the condition(s) leading 
to these measures are not AEs, if the condition leading to the measure was present before 
inclusion in the trial. In the latter case the condition should be reported as medical history. 
13.1.2 Classification 
Seriousness 
An adverse event/reaction is defined as serious if: 
• 
it results in death; 
• 
it is life-threatening (the term "life-threatening" in the definition of "serious" refers to an 
event in which the subject was at immediate risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it was more 
severe); 
• 
it requires an hospitalisation or prolongs existing hospitalisation; 
• 
it results in persistent or significant disability/incapacity; 
• 
it is a congenital abnormality/birth defect; 
• 
it is considered medically important (medical and scientific judgement should be 
exercised in deciding whether other AE/ADRs are to be considered serious, such as 
important medical events that may not be immediately life-threatening but may 
jeopardise the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias; convulsions 
that do not result in hospitalisation; development of drug dependency or drug abuse). 
A non-serious AE/ADR is any symptom or sign which does not fulfil any of the above-
mentioned seriousness criteria. 


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A Suspected Unexpected Serious Adverse Reactions (SUSAR) is any SAE where a causal 
relationship with the IMP is at least a reasonable possibility, but the event is not listed in the 
Investigator Brochure and/or Summary of Product Characteristics. 
For the purpose of this study, the following adverse events of special interest (AESIs) are 
defined: 
Hepatic 
• 
possible Hy’s law case: defined as a subject with any value of ALT or AST above 3x 
ULN together with an increase in bilirubin to a value higher than 2x ULN and not 
associated with an ALP value higher than 2x ULN (to be reported as an SAE as detailed 
above) 
• 
any ALT or AST above 3x ULN 
• 
any elevation in bilirubin 2x ULN 
• 
any AST or ALT above 2x ULN and (TBL >1.5x ULN or INR >1.4) 
• 
any AST or ALT above 2x ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia (eosinophil percent 
or count above the ULN). 
Cardiac 
• 
QTcF prolongation from baseline (ECG within 1 hour prior to IMP administration) of 
>60 msec 
• 
QTcF at any time >480 msec 
• 
bundle branch block 
• 
any arrhythmia. 
Haematological  
• 
Hb drop >2 g/dL from baseline (considered Day -1 for Part A, or pre-dose on Day D0 
for Part B) 
• 
Absolute neutrophil count <1000 /µL. 
Cutaneous  
• 
Dermatitis 
• 
Rash 
• 
Rash erythematous  
• 
Rash macular 
• 
Rash papular 
• 
Rash maculo-papular 
• 
Rash pruritic 
• 
Rash pustular 
• 
Rash vesicular 
Gastrointestinal 


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• 
Nausea 
• 
Vomiting 
• 
Anorexia 
• 
Constipation 
• 
Stomatitis/Pharyngitis 
• 
Diarrhea 
• 
Dyspepsia/Heartburn 
Although not considered an adverse event, pregnancy in the partner of a male subject will be 
reported as an event of special interest. 
 
Expectedness 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
reference safety information (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 serious adverse reaction are 
unexpected events. The expectedness of an adverse reaction is determined by the Sponsor 
in the reference safety information. This should be done from the perspective of events 
previously observed, not on the basis of what might be anticipated from the pharmacological 
properties of a medicinal product. 
For this protocol, the reference document for the assessment of expectedness is the 
Investigator’s Drug Brochure for P218; however no clinical data are so far available for this 
compound.   
 
Intensity 
Please refer to section 8.3 
Standard toxicity grading  
Please refer to section 8.3 
Causality assessment 
The following criteria, based on WHO definitions, are used for causality assessment: 
Definite: 
• 
it has a reasonable time relationship to drug administration, and 
• 
it cannot be explained by other factors (concurrent diseases or medications), and 
• 
it regresses upon withdrawal of the drug, and 
• 
it clearly follows a known pattern of response and it reappears after restart in case of 
re-challenge. 
Probable: 
• 
it has a reasonable time relationship to drug administration, and 
• 
it cannot be reasonably explained by other factors (concurrent diseases or 
medications), and 
• 
it regresses upon withdrawal of the drug. 


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Possible: 
• 
it has a reasonable time relationship to drug administration, but 
• 
it can be explained by other factors (concurrent diseases or medications). 
Not-related: 
• 
it has not a reasonable time relationship to drug administration or there is a time 
relationship, but the event does not follow a known pattern of response and, 
• 
it is due to other factors 
Treatment-emergent adverse events with a definite or probable or possible relationship to the 
medicinal product are to be considered as drug-related, i.e. adverse reactions. 
The Investigator should also comment on the adverse event page of the Case Report Form 
whether an adverse event is not related to the study treatment, but it is related to the study 
participation of the subject (study procedures, wash-out periods etc). 
 
13.1.3  Recording of adverse events and follow-up 
All (serious and non-serious) adverse events detected by the Investigator or delegates, or 
spontaneously notified by the subject at each visit/examination must be reported on the special 
section of the CRF. 
The following information should be reported for each adverse event, whether or not it can be 
attributed to trial drug: 
• 
description of adverse event 
• 
date of onset/date of disappearance 
• 
characteristics of the event (seriousness, intensity) 
• 
actions taken (treatment required or dose adjustments must be reported in the CRF) 
• 
outcome 
• 
relationship with trial drug (causality assessment) and/or study participation 
All adverse events must be documented and followed up until the event is either 
resolved or a satisfactory explanation is found, or the investigator considers it 
medically justifiable to terminate the follow-up. 
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.  
 
13.1.4 
Reporting of serious adverse events  
If any SAE/SUSAR occurs, the investigators will take appropriate action immediately and will 
strive to identify the causes of the events. 
Any SAE/SUSAR will be notified by the Investigator to the Sponsor within 24 hours by email 
or fax, using the MMV “Serious Adverse Event Report Form for Clinical Trials”, to;  
MMV Medical Monitor: 


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Stephan Chalon 
Email: chalons@mmv.org 
Phone: +41 79 962 9244 
Fax: +41 22 555 0369 
Project Manager:  
Susanne Riester 
Operations Manager 
Quintiles AG 
Hochstr. 50 
CH-4053 Basel 
Switzerland 
Office: + 41 61 270 81 81  
Direct:  + 41 61 270 81 66 
Fax:     + 41 61 270 81 80 
susanne.riester@quintiles.com 
 
The initial report will be followed up by a full written report within three working days or five 
calendar days, whichever comes first unless no further information is available when the follow-
up report will be provided as soon as possible when new information becomes available. 
Further follow-up reports will be provided as and when new information becomes available. 
Photocopies of results, consultant report(s), a summary of the outcome of the reaction and the 
Investigator's opinion of IMP relationship to the SAE/SUSAR will accompany the SAE form if 
and when available.  
The Sponsor will also perform an evaluation of the seriousness, causality and expectedness 
of all SAEs. All SAEs judged by either the Investigator or the Sponsor as having a reasonable 
suspected causal relationship to an IMP (i.e. definitively, probably or possibly related) will 
qualify as serious adverse reactions. If the Sponsor disagrees with the Investigator’s causality 
assessment, both the opinion of the Investigator and the Sponsor are provided with the report. 
All SAEs will be included in the MMV pharmacovigilance database.  
SUSARs will be notified to the Competent Authority by MMV and to the relevant REC within 7 
(for fatal and life-threatening SUSARs) or 15 days (all other SUSARs).  
Annual safety reporting to the national Competent Authority and the Ethics Committee will be 
in agreement with ICH guideline E2F “Note for guidance on development safety update reports 
(DSUR)”. 
In addition, any other safety issue which may alter the current benefit–risk assessment of the 
IMP will be reported by the Sponsor (or delegate) on an expedited basis to Health Authorities, 
Ethics Committees and the Investigator.   
The detailed procedure of the SAE/SUSAR reporting will be described in a Safety Management 
Plan that will be finalized before the start of the study to exactly define the different tasks of 
the Investigator, the Sponsor and RPL (on behalf of the Sponsor). 
 
 


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14. 
QUALITY ASSURANCE AND QUALITY CONTROL 
14.1 
Quality Assurance and Quality Control 
A regulatory inspection of this study may be carried out by regulatory agencies. Such 
audits/inspections can occur at any time during or after completion of the study. If an audit or 
inspection occurs, the PI and RPL agree to allow the auditor/inspector direct access to all 
relevant documents and to allocate their time and the time of their staff to the auditor/inspector 
to discuss any findings or relevant issues.  
Quality Control (QC) procedures at the CPU will be implemented to ensure data recorded into 
the CRFs are accurate before CRFs are sent for data entry purposes. QC checks will be carried 
out on critical phases in the execution of the study. These control checks will be carried out 
according to the relevant SOPs. Records of these procedures will be documented and 
available for review. 
 
14.2 
Monitoring 
All aspects of the study will be carefully monitored by the sponsor, or designee, for compliance 
with applicable government regulations with respect to Good Clinical Practice (GCP) and 
current standard operating procedures. 
The monitoring of this study will be performed by the Sponsor’s Monitor(s) or a designee in 
accordance with the principles of GCP as laid out in the International Conference on 
Harmonisation (ICH) “Good Clinical Practice: Consolidated Guideline”. 
The clinical monitor, as a representative of the Sponsor, has an obligation to follow the study 
closely. In doing so, the monitor will visit the Investigator and site periodically as well as 
maintain frequent telephone and letter contact. The monitor will maintain current personal 
knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the Investigator and staff. 
Further details will be described in the SOM. 


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15. 
STATISTICAL ANALYSIS 
15.1 
Statistical Analysis Plan 
A statistical analysis plan (SAP) containing detailed statistical methodology will be written and 
signed off before the unblinding of the study. The plan will be updated to reflect adaptive 
features of the study as appropriate. 
Because the nature of this study is primarily exploratory, the p-values from hypothesis tests 
and the confidence intervals (CIs) obtained in the statistical analyses are not intended to make 
inferences but to identify potential patterns and quantify the uncertainty of estimation. 
15.2 
Analysis Sets 
The analysis of data will be based on different analysis sets according to the purpose of 
analysis. Subject eligibility for each analysis set will be finalised before unblinding of the data. 
A subject who withdraws prior to the last planned observation in a study period will be included 
in the analyses up to the time of discontinuation. 
All subjects that were enrolled and received a dose of the study drug will be included in the 
data analysis. Subjects will be analysed as treated (i.e. in accordance with the study drug 
received, even if different from the one to which they were randomised).   
Specific analysis populations (safety, PK and PD populations) will be defined in the SAP. 
15.3 
Analysis and Presentation of Data 
Continuous data will be summarised using descriptive statistics (mean, median, standard 
deviation, minimum, maximum). Categorical data will be presented using N and % (using the 
number of subjects without missing data in the calculation).   
In all treatment and dose group comparisons, data from all subjects who received placebo 
(Part A) will be pooled to form one placebo comparison group. 
 
15.4 
Subject Demographics and Baseline Characteristics (Parts A and B) 
The subject disposition will be summarised. Study completion, study withdrawals and inclusion 
in  analysis sets will be summarised and the reasons for withdrawal, exclusions from analysis 
sets and protocol violations will be listed. 
Data for demographic variables will be listed by treatment, dose and subject. Descriptive 
statistics will be provided by treatment and dose.  
Medical history, current medical conditions, results of laboratory screening tests, drug tests 
and any other relevant baseline information will be listed by treatment, dose and subject. 
Previous and concomitant medication taken at any stage from 4 weeks prior to dosing and 
during the study period will be listed per treatment and dose level. 
Other baseline characteristics will be listed only.  
15.5 
Statistical analysis of safety 
Adverse events (AE) data will be listed and summarised . The number (and %) of subjects who 
had any AEs will be summarised for each dose and fasted state. All AEs will be listed by using 
system organ class (SOC) and preferred term (PT) assigned to the event using Medical 
Dictionary for Regulatory Activities (MedDRA). Furthermore, subjects who had an AE will be 
summarised by maximum severity of the AE(s). The number of subjects who had drug-related 
AEs will also be summarised.  Any serious adverse events (SAEs) and/ or adverse events that 
led to withdrawal will be listed. 


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Vital signs data (SBP, DBP, HR, Temperature) will be listed and summarised, along with 
changes from baseline, using descriptive statistics. Out-of-reference-range values and 
postural drops (SBP>20mmHg, DBP>10mmHg) will be flagged. 
All safety clinical laboratory data will be listed. Laboratory test results will also be compared to 
laboratory reference ranges and those values outside of the applicable range will be flagged 
as high (H) or low (L). The quantitative laboratory data, along with changes from baseline will 
be summarised using descriptive statistics. Change from baseline values at each assessment 
will be calculated as the assessment value minus the baseline value. The qualitative urinalysis 
data will be listed only. 
Physical Examination data will be listed. 
All ECG data automatically measured by ECG devices (PR, QRS, QT, QTcB, QTcF and HR) 
and overall ECG evaluation will be listed. The ECG data, along with changes from baseline 
will be summarised using descriptive statistics. 
Furthermore, categorical analysis of QTcF data will be presented as follows: 
• 
Absolute QTcF interval prolongation 
- 
QTcF interval > 450 ms 
- 
QTcF interval > 480 ms 
- 
QTcF interval > 500 ms 
• 
Change from baseline in QTcF interval 
- 
QTcF interval increases from baseline > 30 ms 
- 
QTcF interval increases from baseline > 60 ms 
 
15.6 
Pharmacokinetics 
The following PK parameters will be determined using non-compartmental method(s) from 
plasma concentration-time data : AUClast, AUCinf, Cmax, Tmax, t1/2, MRT, CL/F (for parent only), 
Vz/F (for parent only) and metabolites ratio. 
Serum concentrations will be listed and summarised by time point. The PK parameters will be 
listed for each subject and summarized for each treatment group using descriptive statistics 
(N - the number of subjects, arithmetic mean, SD - standard deviation, CV - coefficient of 
variation, geometric mean, median, minimum, maximum). 
AUCinf and Cmax (dose-normalized and/or transformed, when appropriate) of P218 will be 
compared among the fasting dose-groups with dose as a fixed effect. 
A preliminary assessment of dose proportionality for maximum observed concentration (Cmax) 
and AUC will be conducted using a power model. In addition to visual inspection techniques a 
lack-of-fit test will be used to determine the validity of the power model.  
A 90% CI will be constructed on the ratio of Cmax fed to Cmax fasting and a similar one will 
be constructed for AUC to obtain a preliminary estimate of the food effect of P218 on 
transformed parameters with fasting/fed treatment, period and sequence as fixed effects and 
subject as a random effect.  
 


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15.7 
Exploratory  
15.7.1 
Pharmacodynamics 
Serum folate levels 
Serum folate levels and changes from baseline will be listed and summarised using descriptive 
statistics per treatment and time point.The figures of mean differences from baseline for each 
treatment versus time point on linear scale will be plotted. 
Ex-vivo malaria assay 
Bioassay analysis results will be listed and summarised together with changes from baseline, 
and individual subject plots of the results over time presented. 
ECG analysis 
ECG analysis may be performed and will comprise of adjudicated ECG triplicates selected 
from each timepoint which will be compliant with the correct recording and manual adjudication 
of ECGs in thorough QT/QTc studies. QTcF will be used for ECG analyses, unless there is a 
substantial heart rate effect, in which case the correction used for QTc (the most appropriate 
heart rate correction) will be calculated under blinded conditions by the statisticians. Details of 
the analysis will be given in the statistical analysis plan. 
15.7.2 
Pharmacogenetics 
Pharmacogenetics samples will be stored for future optional analysis. 
 
15.8 
Handling of Missing and Incomplete Data 
Unrecorded values will be treated as missing. The appropriateness of the method(s) for 
handling missing data may be reassessed at the data review prior to database lock.  
 
15.9 
Determination of sample size 
15.9.1 
Sample Size Calculation 
Because the nature of this study is primarily exploratory, the p-values from hypothesis tests 
and the confidence intervals obtained in the statistical analyses are not intended to make 
inferences but to identify the potential patterns and quantify the uncertainty of estimation. The 
following factors were taken into consideration when determining the sample size: 
15.9.2 
Part A (SAD): 
Because the primary objective is an initial assessment of safety, each treatment group is 
limited to 6 subjects receiving P218. Administration of P218 to 6 subjects in each dose group 
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 placebo subjects who received 
placebo from each cohort will provide an adequately sized control group. 
15.9.3 
Part B (Food effect): 
This is a pilot evaluation designed to determine whether P218 PK is impacted by food. 
Historically 8 participants in a dose cohort have proven sufficient to characterize the preliminary 
effects of food on safety and PK of a new chemical entity in healthy subjects. Therefore, the 


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size of the current cohort (n=8) is considered adequate at this stage of the drug development 
process. 
 
16. 
DATA MANAGEMENT  
Data Management will be performed by the Data Management department of RPL. The data 
management process will be described in detail in the Data Handling Protocol (DHP). 
The RPL Data Management department will be responsible for developing and maintaining the 
DHP; setting-up and validating the clinical study database; programming validation checks; 
entering data into the clinical study database; reviewing data for accuracy, completeness and 
consistency between the CRF and the database; and verifying adherence to the clinical 
pharmacology study protocol and the DHP. 
The study database will be built using Oracle Clinical based on the CRF design. Data Entry 
will be performed using double independent data entry method with second pass verification. 
Safety laboratory data will be loaded into the database as an electronic data transfer file 
according to the Data transfer specification document. 
Clinical data queries will be generated and resolved according to the DHP. They are 
documented individually on a Data Clarification Form (DCF) which is generated in Oracle 
Clinical. The DCF is a form designed to maintain an audit trail of modifications of the data in 
the clinical study database and the justification for those modifications. Clinical data queries 
are resolved with the assistance of RPL clinical staff. 
After all clinical data queries are resolved, final error rate is confirmed and QC checks are 
acceptable the database will be locked. 
Standard SAS® datasets are generated from the final study database ready for analyses. A 
complete audit trail of all corrections will be available for inspection. Medical coding will be 
performed by RPL.  
AEs, diagnoses from Medical History and procedures from Surgical History will be classified 
according to MedDRA. Concomitant medication will be coded using WHODRUG.  
SAEs in the clinical database will be reconciled with the safety database. 
Final raw SAS® datasets will be transferred to statistician and sponsor (as applicable) 
according to the Data Structures Document (DSD). 
 
16.1 
Case Report Forms 
Case Report Forms will be used to record the data in the study. Data should be recorded 
legibly onto the CRFs in black ballpoint pen. Correction fluid or covering labels must not be 
used.   
The monitor will check data at the monitoring visits to the study site. The PI will ensure that the 
data in the CRFs are accurate, complete, and legible.  
Data from the completed CRFs will be entered into RPL’s clinical study database and validated 
under the direction of the Data Manager. Screening failures (subjects who signed consent to 
take part in the study but were not randomised) as well as admission data for Reserves will 
not be entered into the clinical study database. Any missing, impossible (inconsistent with 
human life), or inconsistent recordings in the CRFs will be referred back to the PI using a DCF 
and be documented for each individual subject before clean file status is declared. 


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17. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
17.1 
Sponsor’s Responsibilities 
17.1.1 
GCP compliance 
MMV and any third party to whom aspects of the study management or monitoring have been 
delegated will undertake their roles for this study in compliance with all applicable regulations 
and ICH GCP Guidelines. 
Visits to Investigator sites will be conducted by representatives of MMV to inspect study data, 
subjects’ medical records, and CRFs in accordance with current GCP and the respective local 
and national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by competent authorities. 
 
17.1.2 
Regulatory approval  
MMV will ensure that Local Competent Authority requirements are met before the start of the 
study.  
 
17.1.3 
Indemnity/liability and insurance  
MMV will adhere to the recommendations of the Association of British Pharmaceutical Industry 
(ABPI) Guidelines. A copy of the Indemnity document will be supplied to the Investigator before 
study initiation.  
MMV will ensure that suitable insurance cover is in place prior to the start of the study. An 
insurance certificate and a statement of insurance will be supplied to RPL. 
 
17.1.4 
Protocol management  
All protocols and amendments will be prepared by MMV and/or RPL. If it becomes necessary 
to issue a protocol amendment during the course of the study, MMV will notify the Investigator 
and collect documented Investigator Agreement to the amendment.  
 
17.1.5 
End of trial notification  
MMV will submit an end of trial notification to the competent authority of the Member State 
within 90 days of the end of the trial in accordance with EU Directive 2001/20/EC. The PI will 
be responsible for submitting these to the REC within 90 days of the end of the trial. 
For the purposes of this notification, the end of the trial will be defined as the last subject/last 
visit. 
 
17.1.6 
Submission of summary of clinical trial report to competent authorities of 
member states concerned and RECs Regulatory approval  
MMV will provide a summary of the clinical trial report within one year of the end of the complete 
trial to the competent authority of the Member State concerned as required by the regulatory 
requirement and to comply with the Community guideline on Good Clinical Practice. 
 


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17.2 
Investigator’s Responsibilities 
17.2.1 
GCP compliance 
The Investigator must undertake to perform the study in accordance with ICH GCP Guidelines, 
EU Directive 2001/20/EC, and the applicable regulatory requirements.  
It is the Investigator’s responsibility to ensure that adequate time and appropriate resources 
are available at the study site prior to commitment to participate in this study. The Investigator 
should also be able to estimate or demonstrate a potential for recruiting the required number 
of suitable subjects within the agreed recruitment period. 
The Investigator will maintain a record of appropriately qualified persons to whom the 
Investigator has delegated significant trial-related tasks. An up-to-date copy of the curriculum 
vitae for the Investigator, Sub-investigator(s), and essential study staff will be provided to MMV 
(or designee) before starting the study. 
Agreement with the final Clinical Study Report will be documented by the dated signature of 
the PI, in compliance with Directive 75/318/EC, Directive 2001/83/EC, and ICH E3. 
 
17.2.2 
Protocol adherence and investigator agreement 
The PI and delegates must adhere to the CSP as detailed in this document. The PI will be 
responsible for enrolling only those subjects who have met CSP eligibility criteria. The PI will 
be required to sign an Investigator Agreement to confirm acceptance and willingness for 
themselves and delegates to comply with the CSP. 
 
17.2.3 
Documentation and retention of records  
After completion of the study, all documents and data relating to the study will be kept in an 
orderly manner and securely by the PI in a secure file and/or electronically. The data will be 
available for inspection by MMV or their representatives. Essential documents must be 
retained for 2 years after the final marketing approval in an ICH region or at least 2 years 
have elapsed since the discontinuation of clinical development of P218. The PI or delegate 
must contact MMV before destroying any study-related documentation and it is the 
responsibility of MMV to inform the investigative site of when these documents can be 
destroyed. In addition, all subject records and other source documentation will be kept for a 
longer period if required by the applicable regulatory requirements.  
 
17.3 
Ethical Considerations 
This protocol complies with the principles of the World Medical Assembly (Helsinki 1964) and 
subsequent amendments. 
 
17.3.1 
Informed consent  
The informed consent is a process by which a subject voluntarily confirms his/her willingness 
to participate in a clinical study. It is the responsibility of the PI or delegate to obtain written 
informed consent from subjects. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject is requested to sign the Informed Consent Form 
(ICF) after they have received and read the written subject information and received an 
explanation of what the study involves, including but not limited to: the objectives, potential 
benefits and risk, inconveniences, and the subject’s rights and responsibilities. Signed ICFs 


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must remain on file and must be available for verification by Study Monitors at any time. 
Another signed original of the ICF must be given to the subject or the subject’s legally 
authorized representative. The PI or delegate will provide the Sponsor with a copy of the REC 
approved consent forms, and a copy of the REC written approval, prior to the start of the study.  
 
17.3.2 
Research Ethics Committee (REC) approval 
It is the responsibility of the PI to submit this CSP, the informed consent document (approved 
by MMV), relevant supporting information, and all types of subject recruitment information to 
the REC for review, and all must be approved prior to the start of subject screening. In addition, 
advertisements must be approved by the REC prior to use at the site. Prior to implementing 
changes in the study, MMV and the REC must also approve any substantial amendments to 
the CSP and corresponding updates to informed consent documents. For non-substantial 
protocol amendments (that do not require REC approval) and subsequent updates of the ICF 
all changes will be done in agreement with MMV and RPL. 
 
17.4 
Confidentiality 
Data collected during this study may be used to support the development, registration, or 
marketing of medicinal product. MMV will control all data collected during the study, and will 
abide by the EU Directive on Data Privacy concerning the processing and use of subjects’ 
personal data. For the purpose of data privacy legislation, MMV will be the data controller. 
After subjects have consented to take part in the study, their medical records and the data 
collected during the study will be reviewed by MMV and/or its representatives. These records 
and data may, in addition, be reviewed by the following: independent auditors who validate the 
data on behalf of MMV; national or local regulatory authorities, and the REC which gave its 
approval for this study to proceed. 
Although subjects will be known by a unique number, their initials and date of birth will also be 
collected and used to assist MMV to verify the accuracy of the data, for example, that the 
results of study assessments are assigned to the correct subject. The results of this study 
containing the unique number, initials, date of birth, and relevant medical information including 
ethnicity may be recorded and transferred to and used in other countries throughout the world, 
which may not afford the same level of protection that applies within the EU. The purpose of 
any such transfer would be to support regulatory submissions made by MMV in such countries. 
 
17.5 
Publication Policy 
If the Sponsor and RPL agree that it will be desirable to publish the results of this study; both 
parties will liaise in good faith to publish the results, RPL agree to obtain the Sponsor’s prior 
written approval of such publications. 


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18. 
REFERENCES 
 
Ferber G, Wang D, Täubel J. Concentration-effect modelling based on change from baseline 
to assess the prolonging effect of drugs on QTc together with an estimate of the circadian time 
course. J Clin Pharmacol 2014, doi: 10.1002/jcph.3478. 
World 
Malaria 
Report 
2014. 
World 
Health 
Organization. 
Geneva, 
Switzerland 
(http://www.who.int/publications/en/). Accessed January 2015. 
Yuthavong Y, Tarnchompooa, B, Vilaivanb T et al. Malarial dihydrofolate reductase as a 
paradigm for drug development against a resistance-compromised target. PNAS 2012; 
109(42): 16823-16828. 
 
 
 


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19. 
APPENDIX LIST 
 
APPENDIX A – WHO Toxicity Grading Scale for determining severity of adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SAP_001.pdf: 


Statistical Analysis Plan 
 
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Page 2 of 14 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or 
Specialist Term  
Explanation  
λz  
terminal elimination rate constant  
AE  
adverse event  
Aet1–t2 
amount of unchanged drug and metabolite excreted into the 
urine within time spans 
Ae48h 
amount of unchanged drug and metabolite excreted into the 
urine from time 0 to 48 hours 
Ae% 
Percent of dose recovered unchanged in the urine 
AUC∞ 
area under the plasma concentration versus time curve from 
time 0 extrapolated to infinity 
AUClast  
area under the plasma concentration versus time curve from 
time 0 to the last quantifiable concentration 
BLQ 
below the limit of quantitation 
CL/F  
total apparent oral clearance  
CLr 
renal clearance of unchanged drug and metabolite 
Cmax  
maximum observed plasma concentration  
CSR 
clinical study report 
CI 
confidence interval 
CV 
coefficient of variation 
CYP 
Cytochrome P450 
DBP 
diastolic blood pressure 
ECG  
electrocardiogram  
FDA 
Food and Drug Administration 
HR 
heart rate 
ICF 
informed consent form 
IMP 
Investigational Medicinal Product 
LLQ 
lower limit of quantitation 
MedDRA 
medical dictionary for regulatory activities 
PD  
pharmacodynamic(s)  
PDF 
portable document format 
PI 
principal investigator 
PK  
pharmacokinetic(s)  
PT 
preferred term 
QTcB  
QT interval corrected for heart rate using Bazett’s formula  
QTcF  
QT interval corrected for heart rate using Fridericia’s formula  
RBC 
red blood cell 
RPL 
Richmond Pharmacology Ltd 
SAD 
single ascending dose 
SAE  
serious adverse event  
SAP 
statistical analysis plan 
SAS 
statistical analysis software 
SD 
standard deviation 
SOC 
system organ class 
SBP 
systolic blood pressure 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TFL 
tables figures and listings 
t½ 
terminal elimination half-life  
tmax  
time to maximum observed plasma concentration  


Statistical Analysis Plan 
 
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Vz/F  
apparent volume of distribution 
WHO 
world health organization 
WNCBP 
women of non-childbearing potential 
 


Statistical Analysis Plan 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................. 2 
1. 
INTRODUCTION ................................................................................... 5 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..................................................... 5 
2.1 
Study objectives ............................................................................ 5 
2.2 
ENDPOINTS ................................................................................... 6 
3. 
STUDY DESIGN .................................................................................... 6 
3.1 
Overall study design ....................................................................... 6 
3.2 
Randomization and Blinding............................................................. 7 
4. 
STATISTICAL ANALYSES ....................................................................... 8 
4.1. 
Analysis Populations ....................................................................... 8 
4.2. 
Sample Size and Power ................................................................... 9 
4.3. 
Demographics, Baseline Characteristics, and Subject Disposition.......... 9 
4.4. 
Safety Analysis .............................................................................. 9 
4.5 
Pharmacokinetic Analysis .............................................................. 11 
4.6. 
Pharmacodynamic Analyses ........................................................... 13 
4.8 
Methods for Withdrawals, Missing Data, and Outliers ........................ 13 
4.9 
Protocol deviations ....................................................................... 14 
5. 
CONVENTIONS ................................................................................... 14 


Statistical Analysis Plan 
 
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1. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to define the variables and 
analysis methodology to address the study objectives. 
Protocol Version 2 dated 22 Aug 2016 was used in the preparation of this SAP. 
Pharmacokinetic parameters will be calculated by MMV or its designee. Richmond 
Pharmacology Ltd (RPL) is responsible for performing statistical analyses. Tables, 
figures, and listings will be produced using Statistical Analysis Software (SAS) V9.3 
or higher. 
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study objectives 
The objectives of this study are: 
Primary 
 
To investigate the safety and tolerability of single escalating oral doses of P218 
when administered to healthy volunteers (men and women of non-childbearing 
potential [WNCBP]) under fasted conditions. 
Secondary 
 
To describe the pharmacokinetics (PK) of P218 and its major glucuronide 
metabolite (P218 acyl glucuronide) in healthy volunteers (men and WNCBP) 
after administration of single escalating oral doses 
 
To investigate the effect of a high fat meal on the PK and safety/tolerability of 
P218. 
Exploratory 
 
To perform ex vivo bioassay analysis against malaria parasites to confirm that 
P218 acyl glucuronide is active against Plasmodium parasite and determine if 
other active metabolites are formed. 
 
To assess the effects of P218 on serum folate levels in healthy subjects 
 
To evaluate the cardiovascular safety profile of P218, assessing qualitative and 
quantitative electrocardiogram (ECG) variations from baseline following dosing, 
in particular any effects on the QTc interval. 
 
To identify inherited genetic factors which may (1) predict response to 
treatment with P218, (2) explain variability in drug PK/pharmacodynamics 
(PD), (3) predict susceptibility to drug-drug interactions, or (4) predict the 
occurrence of safety issues. The aim of such exploratory research will be to 
develop a better understanding of intrinsic and extrinsic factors that may affect 
the PK of P218 in human subjects. 
 
Exploration 
of 
Cytochrome 
P450 
(CYP) 
and 
Uridine 
diphosphate 
glucuronosyltransferase (UGT) isoforms. Exploration of other enzymes and 
transporters in accordance with evolving data.   


Statistical Analysis Plan 
 
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2.2 
ENDPOINTS 
Primary 
 
Safety and tolerability of P218: Incidence, severity and relationship to the 
investigational product of observed and self-reported adverse events (AEs) 
during 11 days post administration of a single oral dose of P218 to healthy 
volunteers. 
Secondary 
 
Estimation of the following PK parameters over 11 days post 
administration of a single dose of P218 (in fasted and fed cohorts) using 
non-compartmental methods: AUClast, AUCinf, Cmax, Tmax, t1/2 , CL/F (for 
parent only) and Vz/F (for parent only). 
Exploratory 
 
To determine the efficacy of P218 against parasites using an ex-vivo 
malaria assay: IC50 
 
Absolute change from baseline P218 on serum folate levels over time 
 
3. 
STUDY DESIGN 
3.1 
Overall study design 
Part A 
This is a randomized, double-blind, placebo-controlled, parallel group, Phase I 
study which will assess the safety, tolerability, PK of single (SAD) ascending oral 
doses of P218 in healthy subjects (men and WNCBP). 
Part B 
This is an open-label, randomised fed/fasted crossover study in healthy subjects 
(men and WNCBP) to examine the food effect of a high fat meal on the PK, safety 
and tolerability of P218.  
This study incorporates the use of an adaptive design. 
Part A (SAD) 
In Part A, the safety, tolerability and PK of single ascending doses of P218 will be 
studied in healthy men and WNCBP. Part A is a double-blind randomised, placebo-
controlled, parallel group, ascending dose study and will comprise up to eight 
fasted cohorts (8 volunteers in each) that will receive a SAD of P218. Within each 
cohort 6 subjects will receive a single dose of P218 and 2 subjects will receive a 
single dose of matching placebo (3:1 ratio).  
Subjects will be screened within 28 days prior to entering the study on Day -1. 
Each subject will receive verbal and written information followed by signing of the 
Informed Consent Form (ICF) prior to any screening procedures taking place. 
Subjects will be admitted to the study unit on Day-1 and will be discharged by Day 
4. All subjects will attend the unit for an outpatient visit on Days 6, 8, 9 and a 


Statistical Analysis Plan 
 
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follow-up visit 11 days post-dose. All the assessments performed during the study 
are detailed in the study schedule of assessments. Study design features may be 
adapted according to the Adaptive Features. 
Part A flow chart 
 
Part B (Food effect) 
For the pilot food effect evaluation, a separate cohort of 8 subjects will receive a 
P218 dose associated with the targeted efficacious exposure ( in human subjects 
in fasted conditions) in an open-label fashion at two occasions separated by a 
minimal washout of 5 x T1/2 (that will not exceed 3 weeks). The treatment 
conditions (fed-fasted) will be randomized according to a two-way crossover 
design. For the fed period, a standard high fat breakfast is given as per Food and 
Drug Administration (FDA) guidance; the breakfast is given 30 minutes prior to 
the scheduled dosing time, and should be completed 10 minutes before dosing. 
Part B flow chart 
 
 
 
 
 
3.2 
Randomization and Blinding 
Subjects in this study will be assigned to a treatment regimen according to a 
randomization schedule generated by a statistician using PROC Plan. 


Statistical Analysis Plan 
 
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Subjects who meet the eligibility criteria will be randomly assigned on Day 1. In 
Part A subjects will be randomly assigned in a 3:1 ratio to either P218 or placebo. 
In Part B, all subjects will receive P218 but will be randomly assigned to the two 
treatment sequences (fed followed by fasted or fasted followed by fed). 
4. 
STATISTICAL ANALYSES 
All data will be listed and separate listings will be produced for Parts A and B. 
In general, descriptive statistics for continuous variables will include number of 
non-missing values, arithmetic mean, standard deviation (SD), median, minimum, 
and maximum, by treatment group. 
Descriptive statistics for PK parameters will include number of non-missing 
observations, arithmetic mean, SD, arithmetic coefficient of variation (CV), 95% 
confidence interval (CI) of the arithmetic mean, geometric mean, geometric CV, 
median, minimum and maximum, by treatment group. 
Categorical variables will be summarized using frequency counts and percentages 
by treatment group.  
Treatment group refers to pooled placebo and dose cohorts of P218 for Part A and 
to fasted vs. fed for Part B. Parts A and B will be analysed separately.  
Baseline will be defined as the last value of the assessment recorded prior to first 
administration of Investigational Medicinal Product (IMP). For post-dose 
assessments the first scheduled value will be used for summary analysis if 
repeated measurements are made at a time-point. 
A subject who withdraws prior to the last planned observation in a study period 
will be included in the analyses up to the time of discontinuation. 
All subjects that were enrolled and received a dose of the study drug will be 
included in the data analysis. Subjects will be analysed as treated (i.e. in 
accordance with the study drug received, even if different from the one to which 
they were randomised). 
Deviations from the planned analyses will be described in the final integrated 
clinical study report. 
4.1. Analysis Populations 
The safety population will consist of all subjects who received their dose of study 
drug. Subjects in this population will be used for the safety analyses. 
The PK population will consist of all subjects in the safety population who have 
at least one concentration measurement, even if Below the Limit of Quantitation 
(BLQ). The PK population will be used for PK summaries. 
The PD population will consist of all subjects in the safety population who have 
sufficient serum folate levels + red blood cell (RBC) folate levels/Ex-vivo malaria 
assay data. The PD population will be used for PD summaries. 
Inclusion and exclusion from each analysis set will be decided and documented at 
the Data Review Meeting prior to database lock. 


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4.2. Sample Size and Power 
Because the nature of this study is primarily exploratory, the p-values from 
hypothesis tests and the CIs obtained in the statistical analyses are not intended 
to make inferences but to identify the potential patterns and quantify the 
uncertainty of estimation. The following factors were taken into consideration when 
determining the sample size: 
Part A (SAD): 
Because the primary objective is an initial assessment of safety, each treatment 
group is limited to 6 subjects receiving P218. Administration of P218 to 6 subjects 
in each dose group 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 placebo subjects who 
received placebo from each cohort will provide an adequately sized control group. 
Part B (Food effect): 
This is a pilot evaluation designed to determine whether P218 PK is impacted by 
food. Historically 8 participants has proven sufficient to characterize the 
preliminary effects of food on safety and PK of a new chemical entity in healthy 
subjects. Therefore, the size of the current cohort (n=8) is considered adequate 
at this stage of the drug development process. 
4.3. Demographics, Baseline Characteristics, and Subject Disposition 
All subjects will be included in the summary of subject disposition, which will 
summarize the frequency and percentage of subjects screened, treated, who 
completed or discontinued the study, along with reason for discontinuation, and 
the number of subjects in the analysis populations, by pooled placebo and dose 
groups for Part A and overall for Part B. Demographics and baseline characteristics 
will be summarized for all subjects by the same groups as for disposition on the 
safety population. If the remaining populations are different from the safety 
population, separate demographic tables may be produced.  
4.4. Safety Analysis 
Safety analyses will be performed on the safety population, and will be reported 
by treatment group if not specified otherwise. Safety analyses will include an 
analysis of all AEs, ECGs, clinical laboratory data, and vital sign measurements and 
will be presented using descriptive statistics. No inferential statistical analyses are 
planned on the safety parameters of this study.  
Adverse Events 
The incidence of treatment-emergent (after dosing) AEs (TEAEs) will be 
summarized using the safety population. The Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary Version 19.0 (or higher) will be used to classify all 
AEs reported during the study by System Organ Class (SOC) and Preferred Term 
(PT). A summary of AEs including the incidence of subjects who experience TEAEs 
and incidence of TEAEs (number of events) will be presented by pooled placebo, 
pooled active and dose groups for Part A, and by fed/fasted state for Part B. The 


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summary will include all TEAEs, TEAEs by maximum severity, TEAEs with 
suspected relationship to study drug, treatment-emergent serious AEs (TESAEs), 
TESAEs by maximum severity and TESAEs with suspected relationship to study 
drug.  In addition, TEAEs and TESAEs will be summarized by SOC and PT, by pooled 
placebo, pooled active and dose group for Part A, and by fed/fasted state for Part 
B. Tables by SOC and PT will be presented for all TE(S)AES, TE(S)AEs by maximum 
severity and T(S)AEs with suspected relationship to study drug. In study Part A, 
AEs will be categorized by the treatment being received (i.e., P218 at actual dose 
or placebo). In study Part B, AEs will be categorized by the actual state (i.e., fed 
or fasted). Serious AEs (SAEs) and AEs resulting in withdrawal from the study will 
be listed. Subjects having multiple AEs within a category (e.g., overall, SOC and 
PT) will be counted once in that category. For maximum severity tables, a subject's 
most severe event within a category will be counted. In each table, SOC and PT 
within SOC will be presented in descending order of overall incidence rate 
(alphabetical order will be used in case of equal rates). 
 
Medical history 
Medical history data will be coded using the MedDRA dictionary Version 19.0 (or 
higher) and listed. 
 
Previous and concomitant medications 
All previous (taken and stopped before dosing) and concomitant (taken after 
dosing even, if started predose) medications will be coded using the World Health 
Organization (WHO) Drug Dictionary version June 1, 2016 and will be listed per 
treatment. 
 
Study drug administration 
Study drug administration data will be listed.   
 
Vital signs 
Vital signs data (systolic and diastolic blood pressure [SBP and DBP], heart rate 
[HR], temperature) will be listed. Out-of-reference-range values (SBP 80-
140mmHg, DBP 40-90mmHg, HR 40-100bpm) and postural drops (supine - 
standing) (SBP>20mmHg, DBP>10mmHg) will be flagged. Summary statistics of 
absolute values and changes from baseline will be calculated for each parameter 
by each treatment group.  
 
Laboratory data  
Safety Laboratory parameters (blood chemistry hematology, coagulation) will be 
listed and values outside the laboratory reference ranges will be flagged as high 
(H) or low (L). Absolute values and changes from baseline (continuous variables) 
will be summarized by each treatment group by scheduled time. The first value 


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will be used for summary analysis if repeated measurements are made at the same 
scheduled time.  
For summary statistics, the lab value with “<” will be replaced with numeric value 
by removing the “<” sign. In the listings the values will be displayed as originally 
reported by the laboratory. 
 
ECG 
All ECG data automatically measured by ECG devices (PR, QRS, QT, QTcB, QTcF 
and HR) and overall ECG evaluation will be listed. The ECG data, along with 
changes from baseline will be summarised using descriptive statistics. For 
summary statistics the average of the ECG readings at the time-points will be 
calculated. 
Furthermore, categorical analysis of QTcF data will be presented for each individual 
ECG as follows: 
• 
Maximum absolute QTcF interval prolongation 
- 
QTcF interval < 450ms 
- 
QTcF interval ≥ 450 ms 
- 
QTcF interval ≥ 480 ms 
- 
QTcF interval ≥ 500 ms 
• 
Maximum increase from baseline in QTcF interval 
- 
QTcF interval increases from baseline < 30ms 
- 
QTcF interval increases from baseline ≥ 30 ms 
- 
QTcF interval increases from baseline ≥ 60 ms 
Physical examination 
Physical examination data will be listed.  
4.5 
Pharmacokinetic Analysis 
All plasma (and if applicable urine) concentration data of P28 and metabolite P28 
acyl glucuronide will be listed and summarized at each time point by treatment 
group using descriptive statistics. The figures of individual and overlaid individual 
concentrations vs. actual time, and of mean (± SD) and median (± range) 
concentrations versus nominal time on linear and semi-log scale will be plotted. If 
nominal time is used in an analysis, concentrations with a sampling time deviation 
>10% of the nominal time will be excluded from the analysis. 
For all tabulation, graphical representation and calculation purposes, when a BLQ 
value occurs in a profile before the first measurable concentration, it is assigned a 
value of zero concentration. When a BLQ value occurs after a measurable 
concentration in a profile and is followed by a value above the Lower Level of 
Quantitation (LLQ), then the BLQ will be omitted following visual inspection of the 
serum concentration versus time profile to assess the appropriateness of this 
assignment. When a BLQ value occurs at the end of a collection profile (after the 
last quantifiable concentration), the value is treated as missing data. When two 
BLQ values occur in succession, the profile is deemed to have terminated at the 


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first BLQ value and any subsequent concentrations are omitted from PK 
calculations. 
Samples with no reportable value due to a bioanalytical issue or missing samples 
should be set to missing, and will not be included in the PK calculations. 
 
The individual plasma concentration data for P218 treated subjects, with actual 
sampling dates and times calculated relative to the dose, will be used to derive the 
PK parameters by non-compartmental analyses. 
The following PK parameters will be derived for P28 and metabolite P28 acyl 
glucuronide, using standard methods: 
Plasma: 
- 
area under the plasma concentration versus time curve from time zero to 
the last quantifiable concentration (AUClast)  
- 
area under the curve from time zero extrapolated to infinity (AUC∞,  
calculated as  AUClast + Clast / λz where Clast is the last quantifiable 
concentration)  
- 
maximum observed plasma concentration (Cmax) 
- 
time to first maximum observed plasma concentration (Tmax) 
- 
terminal elimination half-life (T½)  
- 
terminal elimination rate constant (λz) 
- 
total apparent clearance (CL/F) for parent only 
- 
apparent volume of distribution (Vz/F) for parent only 
Urine (if applicable): 
- 
amount of unchanged drug and metabolite excreted into the urine within 
time spans (Aet1–t2, …) 
- 
amount of unchanged drug and metabolite excreted into the urine from time 
zero to 48 hours (Ae48h)  
- 
percent of dose recovered unchanged in the urine (Ae%) 
- 
renal clearance of unchanged drug and metabolite (CLr) 
All PK parameters will be listed and summarized by treatment group using 
descriptive statistics.  
Some PK parameters may not be calculated for all or some subjects if the 
concentration data are not deemed to be amenable to evaluation. Explanations for 
PK parameters that could not be estimated will be provided in the clinical study 
report (CSR). 
To preliminarily assess dose proportionality for Cmax and AUC in Part A, dose-
normalized plasma Cmax, AUClast and AUC∞ will be calculated and summarized 
descriptively. In addition a power model with log(PK parameter) as response 
variable and log(dose) as predictor will be fitted to the data for plasma Cmax, AUClast 
and AUC∞. A slope of 1 in this model corresponds to dose proportionality. The slope 


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will be estimated with its 2-sided 90 % and 95 % CI. In addition to visual inspection 
techniques, a lack-of-fit test (using a model with dose as categorical variable added 
to the above specified model) will be used to determine the validity of the power 
model. 
A food effect will be assessed in Part B using a mixed effect model with log(PK 
parameter) as the response variable. Treatment sequence, period and food status 
(fasted vs. fed) will be included in the model as fixed effects, and subject as a 
random effect. This model will be applied to the parameters Cmax, AUClast and AUC∞. 
Based on the model, the estimated food effect (fed – fasted) and its 90 % CI will 
be presented. Values will be exponentiated to provide the geometric means for 
each group (µfed and µfasted), the ratio of the geometric means (µfed/µfasted) and the 
ratio’s 90% CI. The absence of a food effect will be concluded if the 90 % CI of 
the ratio µtest/µreference is fully contained within the acceptance range (0.8, 1.25) for 
Cmax and AUC parameters. 
4.6. 
Pharmacodynamic Analyses 
Pharmacodynamic data (serum folate levels and ex-vivo malaria assay) will be 
listed and absolute (observed values) as well as changes from baseline will be 
summarized at each time point by treatment group using descriptive statistics.   
For serum folate levels the figures of mean (± SD) changes from baseline for each 
treatment groupwill be plotted against time. 
 
Bioassay analysis individual subject results will be plotted over time. 
 
ECG analysis may be performed and will comprise of adjudicated (manually over-
read by a cardiologist) ECG triplicates selected from each timepoint. The analysis 
will be compliant with the correct recording and manual adjudication of ECGs in 
thorough QT/QTc studies. QTcF will be used for ECG analyses, unless there is a 
substantial heart rate effect, in which case the correction used for QTc (the most 
appropriate heart rate correction) will be calculated under blinded conditions by 
the statisticians. Details of the analysis, if deemed necessary, will be given in a 
Supplementary SAP. 
4.8 
Methods for Withdrawals, Missing Data, and Outliers 
The individual plasma concentration data, and the actual time for IMP 
administration and blood sampling will be used throughout the analyses. If there 
is any doubt in the actual time a sample is taken, then the scheduled time will be 
used. For PK data analysis, please see Section 4.5 for the handling of missing and 
BLQ values. No further imputation of missing values will be performed for the 
analysis of dose proportionality or food effect. For PD data analysis, there will be 
no imputation for missing values. 
If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  
AEs with unknown start date/time will be assumed to be treatment-emergent 
unless the end date/time is known to be before the first administration of IMP. 
Otherwise missing or partial dates will be listed as such. 


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There will be no further imputation of missing data i.e. subjects who prematurely 
discontinue from the study will not be included in summary statistics or analyses 
beyond the time of discontinuation. If a subject is withdrawn from study treatment 
but continues to participate in the study, the data collected will be included 
according to the treatment initially received/randomized for the safety set. 
Depending on the extent of missing values, the appropriateness of the methods 
described for handling missing data may be reassessed prior to database lock (to 
examine the sensitivity of results to handling of missing data). 
4.9 
Protocol deviations 
A protocol deviation is defined as a lack of compliance with the protocol which may 
interfere with the outcome of the trial. The protocol deviations will be identified 
and reviewed throughout the study, reviewed by principal investigator 
(PI)/Sponsor and graded as minor or major. The final review of protocol deviations, 
including any impact on populations and analyses, will be performed at the Blind 
Data Review Meeting prior to database lock. The protocol deviations will be listed.  
5. 
CONVENTIONS 
In Part A, listings will be ordered by cohort, treatment and subject number; in Part 
B, listings will be ordered by subject number. All listings will include all enrolled 
subjects.  
All listings with post-baseline data will have study day (defined as date minus date 
of dosing plus one day) presented for Part A and study period and day presented 
for Part B. 
For all tables except PK parameter tables, descriptive statistics for min, max will 
be presented with the same decimal digits as the original values, and with one 
more decimal place than the original data for mean, standard deviation and median. 
Percentages will be presented with one decimal digit if they are larger than zero 
and smaller than 100%. If the count is zero, percentages will not be presented. If 
the percentage is 100%, no decimal digit will be presented.  
For PK, the individual and summaries of PK parameter results will be reported with 
3 significant digits in the listings and in the tables with the following exceptions: 
 
Tmax will be presented as follows: individual minimum, and maximum values 
will be reported exactly as the raw data are reported 
 
% CV will be presented to 1 decimal place. 
Page layout of tables and listings in landscape mode will be produced as Portable 
Document Format (PDF).  Details of page layout will be provided in the tables 
figures and listings (TFL) shell document.