Conditions: Malaria
Keywords: malaria PfSPZ Challenge chemoprotection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 32
Healthy volunteers: yes

Brief summary:
This was a single centre, randomised, double-blind, placebo-controlled Phase Ib study, to evaluate the safety, tolerability and chemoprotective activity of P218 in a controlled P. falciparum sporozoite infection model.

Healthy men and women, aged 18 to 45 years were to be enrolled in 3 study cohorts and to be administered either P218 or placebo twice, 48 hours apart. Subjects in cohorts 2 and 3 were to be inoculated with P. falciparum sporozoites. Enrolment in cohorts was to proceed sequentially, to facilitate review of data by a Safety Review Team (SRT) before proceeding with a subsequent cohort.

In cohort 1, safety and tolerability of P218 was assessed. In cohorts 2 and 3, chemoprotective activity of P218 against malaria infection was assessed, as well as the Influence of time of initiation of the P218 treatment on the protective effect.

Detailed description:
This was a single centre, randomised, double-blind, placebo-controlled Phase Ib study, to evaluate the safety, tolerability and chemoprotective activity of P218 in a controlled P. falciparum sporozoite infection model.

32 healthy men and women, aged 18 to 45 years were to be enrolled in 3 cohorts of respectively 8, 12 and 12 subjects. A subject could be enrolled in one cohort only and was to be randomised in a 3:1 ratio, to receive two consecutive administrations, 48 hours apart, of either P218 or placebo. Enrolment in cohorts proceeded sequentially, to facilitate review of data by a Safety Review Team (SRT) before populating a subsequent cohort.

Cohort 1 consisted of 2 subgroups of subjects, to be enrolled sequentially: subgroup 1 was to be composed of 2 subjects: one to receive two 1000 mg doses of P218 and one to receive placebo twice. Subgroup 2 was to be composed of 6 subjects: five to receive two 1000 mg doses of P218 and one to receive placebo twice. Subjects in subgroup 2 would not be treated until 24 hours after second IMP administration in the last subject of subgroup 1 and only after review of the safety data from subgroup 1 by the PI. Duration of each subject treatment and follow-up in Cohort 1 was 9 days. Progression to Cohort 2 was subject to review of the safety and tolerability data by a SRT.

Cohort 2 consisted of three subgroups of subjects, to be enrolled sequentially. Subgroup 1 was to be composed of 2 subjects: one to receive two 1000 mg doses of P218 and one to receive placebo twice. Subgroups 2 and 3 were to be composed of 5 subjects each: four to receive two 1000 mg doses of P218 and one to receive placebo twice. Subjects in subgroup 2 would not be treated until 24 hours after second IMP administration in the last subject of subgroup 1. On Day 1, each subject in Cohort 2 would be administered 3200 P. falciparum sporozoites (PfSPZ Challenge) by direct venous inoculation (DVI). First administration of 1000 mg of P218 or placebo will take place 2 hours after PfSPZ Challenge DVI; second administration of 1000 mg of P218 or placebo would take place 48 hours later. As of Day 7, parasitemia in every subject was to be assessed daily until the installation of malarial infection or until Day 28. Overall duration of each subject observation in Cohort 2 was 35 days. Progression to Cohort 3 was subject to assessment of safety and parasitemia data, as well as malaria signs and symptoms by a SRT.

Cohort 3 was to consist of two subgroups each with 6 subjects, to be enrolled sequentially. Treatment was to be allocated in a ratio of 3 active: 1 placebo. In each subgroup, at least 1 subject was to receive placebo and the remaining subjects would receive two 100 mg doses of P218 48 hours apart. Subjects in subgroup 2 would not be inoculated until 24 hours after second IMP administration in the last subject of subgroup 1. On Day 1, subjects were to be administered 3200 P. falciparum sporozoites by DVI. As of Day 7, parasitemia in every subject was to be assessed daily until the installation of malarial infection or until Day 28. Overall duration of each subject observation in Cohort 3 is 35 days.

All subjects in Cohorts 2 and 3 would receive antimalarial rescue therapy, either upon installation of malarial infection or on Day 28 or if leaving the study prematurely.

In Cohort 1, safety and tolerability of two 1000 mg doses of P218 administered 48 hours apart was to be assessed over 9 days of observation. Pharmacokinetic assessments of P218 and its main metabolites were to take place over 9 days of observation.

In Cohorts 2 and 3, chemoprotective activity of two doses P218 (1000 mg or 100 mg respectively) administered 48 hours apart, were to be assessed over 28 days. Safety and tolerability of two doses of P218 (1000 mg or 100 mg respectively) administered 48 hours apart were to be assessed over 35 days of observation. Pharmacokinetic assessments of P218 would take place over 9 days of observation.

Arms:
arm 1: Two administrations of 1000 mg P218 (capsules p.o.), 48 hours apart arm 2: Two administrations of P218 placebo (capsules p.o.), 48 hours apart arm 3: One administration of 1000 mg P218 (capsules p.o.), 2 hours after PfSPZ Challenge and one administration of 1000 mg P218 (capsules p.o.), 48 hours after first administration. arm 4: One administration of P218 placebo (capsules p.o.), 2 hours after PfSPZ Challenge and one administration of P218 placebo (capsules p.o.,) 48 hours after first administration. arm 5: One administration of 100 mg P218 (capsules p.o.), 2 hours after PfSPZ Challenge and one administration of 100 mg P218 (capsules p.o.), 48 hours after first administration. arm 6: One administration of P218 placebo (capsules p.o.), 2 hours after PfSPZ Challenge and one administration of P218 placebo (capsules p.o.), 48 hours after first administration.

Interventions: intervention 1: P218 (1000 mg) Oral Capsules intervention 2: Placebo Oral Capsules intervention 3: P218 (100 mg) Oral Capsules intervention 4: PfSPZ Challenge
Intervention descriptions: intervention 1: 1000 mg P218 (4 x 250 mg capsules) intervention 2: Placebo capsules matched to the P218 capsules with regard to appearance and taste intervention 3: 100 mg P218 (2 x 50 mg capsules) intervention 4: 3200 P. falciparum Sporozoites by direct venous inoculation (DVI)

Protocol document:
Prot_000.pdf: 
Life Sciences, a division 
of SGS Belgium NV 
 
 
REVISED CLINICAL STUDY PROTOCOL 
 
CONFIDENTIALITY STATEMENT 
The information in this document contains trade secrets and commercial information that are privileged 
or confidential and may not be disclosed unless such disclosure is required by applicable law or 
regulations. In any event, persons to whom the information is disclosed must be informed that the 
information is privileged or confidential and may not be further disclosed without 
written authorization of MMV. 
 
This study will be conducted in compliance with this protocol,  
the ICH Note for Guidance on Good Clinical Practice (CMPM/ICH/135/95)  
and with the applicable regulatory requirement(s). 
 
A single centre, randomised, double-blind, placebo-controlled, 
Phase Ib study to evaluate the safety, tolerability and 
chemoprotective antimalarial activity of P218 against controlled 
human malaria infection with Plasmodium falciparum sporozoite 
challenge in non-immune healthy adult volunteers 
 
Product P218 
Protocol Number MMV_P218_17_01 
EudraCT Number 2018-003004-39 
Clinical Phase Ib 
Clinical Indication Malaria infection 
Issue Date (Version) 20-mar-2019 (Final 2.0) 
(Final Approved Protocol dated 25-sep-2018 
[Final 1.0]) 
 
Sponsor Medicines for Malaria Venture (MMV) 
Sponsor Medical Director  Farouk Chughlay, MD 
Phone: +41 22 555 0355 
Mobile: +41 79 123 4289 
Fax: +41 22 555 0369 
Sponsor Clinical Lead Myriam El Gaaloul, PharmD 
Phone: +41 22 555 0377 
Mobile: +41 76 442 6502 
Fax: +41 22 555 0369 
 






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PROTOCOL HISTORY 
Protocol Historya 
Medicines for Malaria Venture (MMV) – MMV_P218_17_01 
Document  
Issue Date 
Amendment Type 
Comments 
Final Approved Protocol [Final 1.0] 
25-sep-2018 
Not applicable 
- 
Amendment 1 
20-mar-2019 
Substantial 
Revised Clinical Study Protocol 2.0 
Based on new in vitro experiments suggesting that P218 inhibits all 
stages of intra-hepatocytic development and the encouraging 
preliminary clinical data obtained so far for Cohort 2, the Sponsor 
believes that proof of pharmacology has been achieved. Therefore, the 
Sponsor would like to decrease the dose of P218 in Cohort 3 from 
1000 mg to 100 mg, to be administered at D1 and D3 (instead of D3 
and D5), to better estimate the minimal inhibitory exposure of P218 
required for liver activity. 
a This overview only lists general amendments to the protocol. Site- and country-specific amendments to the protocol are not included. 
 
 
 


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TABLE OF CONTENTS 
Title Page ........................................................................................................................... 1 
Signatures .......................................................................................................................... 2 
PROTOCOL HISTORY .................................................................................................. 4 
Table of Contents .............................................................................................................. 5 
PROTOCOL AMENDMENT 1: SUMMARY OF CHANGES ................................... 9 
Protocol Synopsis ............................................................................................................ 13 
Time and Events Schedule ............................................................................................. 25 
List of Abbreviations and Definitions of Terms .......................................................... 30 
Study Administrative Structure and Investigators ..................................................... 33 
1. 
Introduction ............................................................................................................ 34 
1.1 
Malaria Background Information ....................................................................... 34 
1.2 
P218 .................................................................................................................... 34 
1.3 
Plasmodium falciparum Sporozoites Challenge Model (PfSPZ Challenge) ...... 35 
1.4 
Rationale for the Study ....................................................................................... 36 
1.5 
Risk Benefit Analysis ......................................................................................... 36 
1.5.1 
Potential Risks ...................................................................................... 36 
1.5.2 
Potential Benefits ................................................................................. 39 
1.5.3 
Conclusion ............................................................................................ 39 
2. 
Study Objectives and Endpoints ........................................................................... 40 
2.1 
Objectives ........................................................................................................... 40 
2.1.1 
Primary Objective ................................................................................ 40 
2.1.2 
Secondary Objectives ........................................................................... 40 
2.2 
Endpoints ............................................................................................................ 40 
2.2.1 
Primary Endpoints ................................................................................ 40 
2.2.2 
Secondary Endpoints ............................................................................ 41 
3. 
Study Design ............................................................................................................ 42 
3.1 
Overview of Study Design ................................................................................. 42 
3.2 
Discussion of Study Design................................................................................ 44 
4. 
Selection of Study Population ................................................................................ 51 
4.1 
Inclusion Criteria ................................................................................................ 51 
4.2 
Exclusion Criteria ............................................................................................... 52 
4.3 
Additional Constraints ........................................................................................ 55 
5. 
Treatment(s) ............................................................................................................ 56 
5.1 
Physical Description of the IMP......................................................................... 56 
5.1.1 
P218/placebo ........................................................................................ 56 
5.1.2 
PfSPZ Challenge .................................................................................. 56 
5.2 
Antimalarial Rescue Medication ........................................................................ 57 
5.3 
Packaging and Labeling ..................................................................................... 58 
5.3.1 
P218/placebo ........................................................................................ 58 
5.3.2 
PfSPZ Challenge .................................................................................. 59 


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5.4 
Storage and Drug Accountability ....................................................................... 59 
5.4.1 
P218/placebo ........................................................................................ 59 
5.4.2 
PfSPZ Challenge Agent ....................................................................... 60 
5.5 
Randomization and Blinding .............................................................................. 60 
5.6 
Dose and Administration .................................................................................... 61 
5.6.1 
P218/placebo ........................................................................................ 61 
5.6.2 
PfSPZ Challenge .................................................................................. 61 
5.7 
Treatment Compliance ....................................................................................... 61 
5.8 
Safety Review Team........................................................................................... 62 
5.8.1 
For Progression From Cohort 1 to Cohort 2 ........................................ 62 
5.8.2 
For Progression From Cohort 2 to Cohort 3 ........................................ 64 
5.8.3 
Final SRT Review at Study End .......................................................... 64 
6. 
Prior and Concomitant Therapy ........................................................................... 65 
6.1 
Permitted Concomitant Therapies ...................................................................... 65 
6.2 
Prohibited Concomitant Therapies ..................................................................... 65 
7. 
Assessments ............................................................................................................. 66 
7.1 
Timing of Assessments....................................................................................... 66 
7.1.1 
Screening Period .................................................................................. 66 
7.1.2 
Treatment Period .................................................................................. 67 
7.1.3 
Follow-up Period .................................................................................. 68 
7.1.4 
Unscheduled Visits ............................................................................... 68 
7.2 
Pharmacokinetic Evaluations ............................................................................. 69 
7.2.1 
Sample Collection and Handling .......................................................... 69 
7.2.2 
Bioanalyses ........................................................................................... 69 
7.2.3 
Pharmacokinetic Parameters ................................................................ 69 
7.3 
Efficacy Evaluations ........................................................................................... 70 
7.3.1 
Parasitaemia ......................................................................................... 70 
7.3.2 
Malaria Clinical Score .......................................................................... 71 
7.3.3 
PK/PD ................................................................................................... 71 
7.4 
Safety Evaluations .............................................................................................. 71 
7.4.1 
Adverse Events ..................................................................................... 71 
7.4.2 
Clinical Laboratory Tests ..................................................................... 72 
7.4.3 
Vital Signs ............................................................................................ 73 
7.4.4 
Electrocardiogram ................................................................................ 73 
7.4.5 
Physical Examination ........................................................................... 73 
7.4.6 
Beck Depression Inventory .................................................................. 74 
7.5 
Total Volume of Blood Sampling ...................................................................... 74 
7.6 
Appropriateness of Measurements ..................................................................... 74 
8. 
Study Termination/Completion ............................................................................. 75 
8.1 
Study Completion ............................................................................................... 75 
8.2 
Removal of Subjects From Therapy or Study .................................................... 75 
8.3 
Stopping Rules or Discontinuation Criteria ....................................................... 76 
8.4 
Traceability of Subjects ...................................................................................... 76 
9. 
Statistical Methods.................................................................................................. 77 
9.1 
Statistical Analysis ............................................................................................. 77 
9.1.1 
Planned Analyses ................................................................................. 77 


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9.1.2 
Analysis Populations ............................................................................ 77 
9.1.3 
Initial Characteristics Data of the Subject Sample ............................... 77 
9.1.4 
Pharmacokinetic Data .......................................................................... 78 
9.1.5 
Efficacy Data ........................................................................................ 78 
9.1.6 
Safety Data ........................................................................................... 78 
9.2 
Determination of Sample Size ............................................................................ 80 
10. Adverse Event Reporting ....................................................................................... 81 
10.1 
Definitions .......................................................................................................... 81 
10.2 
Intensity of Adverse Events................................................................................ 86 
10.3 
Causality Assessment ......................................................................................... 86 
10.4 
Action Taken Regarding the IMP....................................................................... 87 
10.5 
Outcome ............................................................................................................. 87 
10.6 
Recording of Adverse Events ............................................................................. 87 
10.7 
Reporting of Serious Adverse Events to PrimeVigilance Ltd. ........................... 88 
10.8 
Pregnancy ........................................................................................................... 88 
10.9 
Reporting of Serious Adverse Events to Competent Authorities/Ethics 
Committees ......................................................................................................... 88 
11. Ethical Aspects ........................................................................................................ 90 
11.1 
Study-Specific Design Considerations ............................................................... 90 
11.2 
Regulatory Ethics Compliance ........................................................................... 90 
11.2.1 
Investigator Responsibilities ................................................................ 90 
11.2.2 
Independent Ethics Committee or Institutional Review Board 
(IEC/IRB) ............................................................................................. 90 
11.2.3 
Informed Consent ................................................................................. 92 
11.2.4 
Privacy of Personal Data ...................................................................... 92 
12. Administrative Requirements ............................................................................... 94 
12.1 
Protocol Amendments ........................................................................................ 94 
12.2 
Subject Identification, Enrolment and Screening Logs ...................................... 94 
12.3 
Source Documentation ....................................................................................... 94 
12.4 
Case Report Form Completion ........................................................................... 95 
12.5 
Monitoring .......................................................................................................... 95 
12.6 
Data Management ............................................................................................... 95 
12.7 
Data Quality Assurance ...................................................................................... 96 
12.8 
On-Site Audits .................................................................................................... 96 
12.9 
Study Termination .............................................................................................. 97 
12.10 
Record Retention ................................................................................................ 97 
12.11 
Use of Information and Publication ................................................................... 97 
12.12 
Registration of Clinical Studies and Disclosure of Results ................................ 99 
12.13 
Confidentiality .................................................................................................... 99 
13. References .............................................................................................................. 100 
Attachment 1: Example of Clinical Score For Malaria ............................................ 102 
Attachment 2: Beck Depression Inventory................................................................. 103 
Attachment 3: Normal Ranges for Vital Signs and ECG ......................................... 106 
 


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List of Tables 
Table 1: 
Simulation of P218 and its Major Metabolites PK Parameters in Plasma After 
the Administration of Two Single Doses of 1000 mg of P218 Administered 
48 Hours Apart Using a PopPK Model ......................................................... 47 
Table 2: 
Simulation of P218 and its Major Metabolites PK Parameters in Plasma After 
the Administration of Two Single Doses of 100 mg of P218 Administered 
48 Hours Apart Using a PopPK Model ......................................................... 49 
Table 3: 
Group Toxicity Rules for Progression From Cohort 1 to Cohort 2. .............. 63 
 
List of Figures 
Figure 1: 
Schematic Overview of the Study Design for Cohort 1 ................................ 42 
Figure 2: 
Schematic Overview of the Study Design for Cohorts 2 and 3 ..................... 44 
Figure 3: 
Incubation of P. falciparum infected hepatocytes with 100nM P218 at 
indicated time intervals (figure on the left), and % of remaining infected 
hepatocytes per time interval incubation (figure on the right). ...................... 45 
Figure 4: 
Activity window of P218 at different time intervals during infection and 
maturation of P. falciparum (NF175) infected hepatocytes. ......................... 45 
Figure 5: 
Simulations of the P218 plasma concentration over time following the oral 
administration of two single doses of 1000 mg of P218 when administered 
48 hours apart on Day 1 and Day 3 using a Population PK model. .............. 46 
Figure 6: 
Population PK simulations of 1000 cohorts of 9 patients each with an 
administration of 2 single doses of 100 mg P218 at 100 mg administered 
48 hours apart................................................................................................. 48 
 
 


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PROTOCOL AMENDMENT 1: SUMMARY OF CHANGES 
Overall Reason for Amending the Protocol: This amendment was created to make 
adaptations to Cohort 3. 
To date, two cohorts have been successfully completed.  
The primary objective of Cohort 1 is to assess safety and tolerability of two single doses 
of 1000 mg administered 48 hours apart in healthy volunteers (D1 and D3). 1000 mg 
P218 is the highest dose tested to date in clinical trials. At the completion of Cohort 1, 
the SRT reviewed the safety/tolerability and PK data of Cohort 1 and unanimously 
agreed that there were no concerns or unexpected findings regarding the safety or PK 
data for Cohort 1 and the study should proceed to Cohort 2. 
The primary objective of Cohort 2 is to assess the chemoprotective activity of P218 in 
non-immune healthy volunteers after the P. falciparum sporozoite challenge agent has 
been administered through direct venous inoculation. Two single doses of 1000 mg P218 
were administered 48 hours apart (on D1 and D3), as for Cohort 1, in order to interfere 
with the liver stage of the parasite. The cohort included 3 placebo and 9 active 
treatments. The cohort is still blinded, yet 3 subjects had breakthrough of parasitaemia at 
between Days 8 and 12, and 9 subjects did not have results which met the definition of 
positive PCR parasitemia up to Day 28. Hence, it seems there is no breakthrough in 
subjects treated with P218 if it is assumed that the three subjects with positive 
parasitaemia received the placebo, leading to the conclusion that P218 has 
chemoprotective activity. 
Based on new in vitro experiments suggesting that P218 inhibits all stages of 
intra-hepatocytic development and the encouraging preliminary clinical data obtained so 
far for Cohort 2, the Sponsor believes that proof of pharmacology has been achieved. 
Therefore, the Sponsor would like to decrease the dose of P218 in Cohort 3 from 
1000 mg to 100 mg, to be administered at D1 and D3 (instead of D3 and D5), to better 
estimate the minimal inhibitory exposure of P218 required for liver activity.  
Changes are summarised below together with a rationale for each change. 


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1. Change of Study Design 
Rationale: 
In order to better estimate the minimal inhibitory exposure, the dose in Cohort 3 was 
de-escalated from 1000 mg to 100 mg and days of administration were changed from D3 and 
D5 to D1 and D3. The cohort will consist of two sequential subgroups, each with 6 subjects. In 
each subgroup, at least 1 subject will receive placebo and the remaining subjects will receive 
two 100 mg doses of P218 on D1 and D3, i.e. at the same times as Cohort 2. A secondary 
objective has been added to reflect the above mentioned objective. 
Applicable 
Section(s) 
Description of Changes 
Synopsis 
A secondary objective and a secondary endpoint were added. 
The overview of study design was described for Cohorts 2 and 3 
together, and adapted for Cohort 3 according to the rationale. 
The text ‘50 mg capsules of P218’ was added to the description of the 
IMP (P218/Placebo), Dose, Mode of Administration. 
The study/Treatment Duration was adapted. 
A section was added for the PK/PD analysis. 
The PK/PD population was added. 
Determination of Sample Size was amended. 
Time and Events 
Schedule 
The Time and Events Schedule for Cohort 3 was deleted. The Time and 
Events Schedule for Cohort 2 was adapted to describe Cohorts 2 and 3 
together. 
Section 2.1.2 
A secondary objective was added. 
Section 2.2 
A secondary endpoint was added. 
Section 3.1 
The overview of study design is described for Cohorts 2 and 3 together, 
and adapted for Cohort 3 according to the rationale. 
Section 3.2 
The rationale for dose selection was updated. 
Section 5 
The text ‘2x50 mg capsules of P218’ was added and timing of snacks, 
lunch and dinner after the study drug administration was amended. 
Section 7.1 
Timing of Cohort 3 was aligned with the timing of Cohort 2. 
Section 7.3.3 
This section was added for the PK/PD analysis. 
Section 9.1.2 
The PK/PD population was added (and ‘PD’ to the abbreviation 
list). 
Section 9.2 
Determination of Sample Size was amended. 
 


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2. Practical Aspects 
Rationale: 
Practical Aspects 
Applicable 
Section(s) 
Description of Changes 
Time and Events 
Schedule 
A footnote was added for all cohorts that the assessment for serum folate 
on D-1 can be done at either D-3 or D-1, upon Investigator’s decision. 
 
3. Administrative Change 
Rationale: 
Administrative Change 
Applicable 
Section(s) 
Description of Changes 
Study 
Administrative 
Structure and 
Investigators 
Charles Stoyanov was replaced by Nicola Kerr as Clinical Operations 
Lead. 
 
4. Clarifications  
Rationale: 
Clarifications 
Applicable 
Section(s) 
Description of Changes 
Synopsis 
The description of the antimalarial rescue medication was clarified: 
treatment success, defined as one negative qPCR outcome for asexual 
parasites, means that 0 parasites per mL were detected 
In the description of the malaria clinical score, it was specified that if the 
PCR results for P. falciparum are between 0 and < 250 asexual parasites 
per mL (i.e. ‘negative’ was deleted here) at the time of the onset of the 
event, the usual AE/SAE reporting procedures and criteria will apply, 
and the event will not be classified as an inoculum-related event. For 
completeness, a positive P. falciparum PCR was defined as 
≥ 250 asexual parasites per mL. 
Section 5.2 
Section 7.3.2 
Time and Events 
Schedule 
A footnote was deleted for Cohort 1 at 48 hours and for Cohorts 2 and 3 
at 50 hours, as this footnote only applies to safety lab assessments prior 
to first IMP administration. 
 


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5. Typographical Corrections 
Rationale: 
Typographical Corrections 
Applicable 
Section(s) 
Description of Changes 
Synopsis 
Exclusion criterion 22 was aligned with body of the protocol. 
 
‘ski’ was corrected to ‘skin’ in the description of physical examinations. 
Table of Contents 
The footer was corrected. 
Section 7.4.5 
‘ski’ was corrected to ‘skin’ 
Attachment 1 
A more applicable example of clinical score card for malaria was 
inserted. The total score and corresponding text was deleted as this will 
not be used as a threshold for commencement with IMP in this study. 
 


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PROTOCOL SYNOPSIS 
PROTOCOL SYNOPSIS 
Study Title 
A single centre, randomised, double-blind, placebo-controlled, Phase Ib study to 
evaluate the safety, tolerability and chemoprotective antimalarial activity of P218 
against controlled human malaria infection with Plasmodium falciparum 
sporozoite challenge in non-immune healthy adult volunteers 
Product 
P218 
Clinical Phase 
Ib 
Protocol Number 
MMV_P218_17_01 
Indication 
Malaria infection 
EudraCT Number 
2018-003004-39 
 
Sponsor 
Medicines for Malaria Venture (MMV) 
Sponsor Medical Director 
Farouk Chughlay, MD 
Sponsor Clinical Lead 
Myriam El Gaaloul, PharmD 
Clinical Centre 
SGS Life Sciences, Clinical Pharmacology Unit, Lange 
Beeldekensstraat 267, 2060 Antwerpen, Belgium 
 
Objectives: 
For Cohort 1, the primary objective is to assess the safety and tolerability of two single doses of 1000 mg 
P218 administered 48 hours apart in healthy adult volunteers. 
For Cohorts 2 and 3, the primary objective is to assess the chemoprotective activity of P218 in 
Plasmodium falciparum (P. falciparum) controlled human malaria infection (CHMI) in non-immune 
healthy volunteers after P. falciparum sporozoites (PfSPZ) Challenge through direct venous inoculation 
(DVI). 
Secondary objectives are: 
- 
To assess the pharmacokinetic (PK) profile of P218, and in Cohort 1 only also of its main 
metabolites, up to 8 days after first P218 administration to healthy adult volunteers; 
- 
To establish the pharmacokinetic/pharmacodynamic (PK/PD) relationship between P218 plasma 
concentration and its chemoprotective activity using blood stage parasitaemia as a surrogate in 
non-immune healthy volunteers in a CHMI PfSPZ Challenge model; 
- 
To assess the safety and tolerability of P218 in non-immune healthy volunteers in a CHMI PfSPZ 
Challenge model (Cohorts 2 and 3); 
- 
To assess the safety and tolerability of PfSPZ Challenge in non-immune healthy volunteers 
before and after P218 administration during CHMI (Cohorts 2 and 3). 
There is no formal hypothesis testing as this is an exploratory study. 
Endpoints: 
For Cohort 1, the primary endpoint is the incidence, severity and relationship to P218 of observed or 
self-reported treatment-emergent adverse events (TEAEs) during the 9-day observation period without 
PfSPZ Challenge. 
For Cohorts 2 and 3, the primary endpoint is the cohort-specific, geometric mean time to parasitaemia 
based in each case on the time elapsed between PfSPZ Challenge DVI and first quantitative polymerase 
chain reaction (qPCR) outcome equal or greater than 250 asexual parasites per mL, with a maximum of 
28 days in the absence of parasitaemia. 
Secondary endpoints are: 
- 
Estimation of the following PK parameters for P218, and in Cohort 1 only, also for its major 
metabolites (P218-OH, P218-beta-acyl-glucuronide, P218-beta-acyl-glucuronide-OH), over 


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REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 20-mar-2019 (Final 2.0) 
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PROTOCOL SYNOPSIS 
8 days after first investigational medicinal product (IMP) administration using non 
compartmental methods:  
o 
Area under the plasma concentration-time curve during the dosing interval (AUCτ) = AUC 
during the first 48 hours after dosing (AUC0-48h) after each administration (i.e. AUC0-48h and 
AUC48-96h);  
o 
AUC from 48 hours after dosing to infinity (AUC48h-inf), calculated from AUC48h-t + (Ct/λz), 
where Ct is the last observed quantifiable concentration and λz the first order terminal rate 
constant;  
o 
AUC calculated between 48 hours after dosing and last quantifiable concentration 
(AUC48h-last); 
o 
Total plasma clearance (CL/F) and apparent volume of distribution (Vz/F) after the second 
administration (not for metabolites); 
o 
Observed maximum plasma concentration (Cmax) and the time to reach the maximum 
concentration after drug administration (tmax) after each administration; 
o 
The terminal elimination half-life (t1/2) after the second administration; 
o 
The accumulation ratio (Rac), calculated as AUC48-96h/AUC0-48h; 
o 
Metabolic ratio of AUCτ and AUC48h-inf for P218 β-acyl glucuronide, P218 OH and P218-OH 
β-acyl glucuronide over parent P218 (Cohort 1 only). 
- 
The minimal inhibitory concentration of P218 needed for chemoprotective activity will be 
predicted from the P218 PK/PD model; 
- 
The incidence, severity and relationship to P218 of observed or self-reported, TEAEs during the 
35-day observation period with PfSPZ Challenge (Cohorts 2 and 3 only); 
- 
The incidence and severity of observed (i.e. Malaria signs and symptoms graded by the Malaria 
clinical score) or self-reported inoculum-related events and adverse events (AEs) considered 
PfSPZ Challenge-related (Cohorts 2 and 3 only);  
- 
The Malaria clinical score at the time of introduction of rescue therapy (Cohorts 2 and 3 only); 
- 
Changes from baseline in folate levels, haematology, clinical chemistry and urinalysis 
parameters, vital signs and electrocardiogram (ECG) parameters. 
Overview of Study Design: 
This is a single centre, randomised, double-blind, placebo-controlled Phase Ib study. Thirty-two healthy 
men and women aged 18 to 45 years will be enrolled in 3 cohorts of 8, 12 and 12 subjects. A subject may 
be enrolled in one cohort only and will be randomised in a 3:1 ratio, to receive two consecutive 
administrations of either P218 or placebo. Enrolment in cohorts will proceed sequentially, to facilitate 
review of Cohort 1 and Cohort 2 data by a Safety Review Team (SRT) before populating Cohort 2 and 
Cohort 3, respectively. 
Cohort 1 
Cohort 1 will consist of 2 subgroups of subjects, to be enrolled sequentially: subgroup 1 will be composed 
of 2 subjects: one to receive two 1000 mg doses of P218 48 hours apart and one to receive placebo; 
subgroup 2 will be composed of 6 subjects: five to receive two 1000 mg doses of P218 48 hours apart and 
one to receive placebo. Subjects in subgroup 2 will not be treated until 24 hours after second IMP 
administration in the last subject of subgroup 1 and only upon decision of the PI after review of available 
safety data of subgroup 1. 
Subjects will be admitted to the clinical unit in the morning of Day -1 and will be confined to the unit for 
3 days thereafter (until Day 4, i.e. 36 hours after second IMP administration), for close safety monitoring 
and PK assessments. First administration of 1000 mg of P218 or placebo will take place on Day 1. Second 
administration of 1000 mg of P218 or placebo will take place 48 hours later, on Day 3. After discharge 
from the clinical unit on Day 4, subjects will be followed up with daily ambulatory visits to the clinical 
unit up to Day 9. 
Progression to Cohort 2 will be assessed by an SRT, who will review safety and tolerability after data up 
to Day 9 for Cohort 1 are available. 
Cohorts 2 and 3 
Cohort 2 will consist of three subgroups of subjects, to be enrolled sequentially: subgroup 1 will be 
composed of 2 subjects: one to receive two 1000 mg doses of P218 48 hours apart and one to receive 
placebo; subgroups 2 and 3 will be composed of 5 subjects each: four to receive two 1000 mg doses of 
P218 48 hours apart and one to receive placebo. Subjects in subgroup 2 will not be treated until 24 hours 


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REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 20-mar-2019 (Final 2.0) 
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PROTOCOL SYNOPSIS 
after second IMP administration in the last subject of subgroup 1. In subgroup 2 and subgroup 3, subjects 
will only be inoculated upon decision of the PI after review of available safety data of the previous 
subgroup, i.e. subgroup 1 and subgroup 2, respectively. 
Cohort 3 will consist of two subgroups, each with 6 subjects, to be enrolled sequentially. Treatment will 
be allocated in a ratio of 3 active to 1 placebo. In each subgroup, at least 1 subject will receive placebo 
and the remaining subjects will receive two 100 mg doses of P218 48 hours apart. Subjects in subgroup 2 
will not be inoculated until 24 hours after second IMP administration in the last subject of subgroup 1. 
Subjects will be admitted to the clinical unit in the morning of Day -1 and will be confined to the unit until 
12 days post the PfSPZ Challenge on Day 1 (i.e. until Day 13), for close safety monitoring and PK 
assessments. Each subject will be administered 3,200 P. falciparum sporozoites by DVI. First 
administration of P218 or placebo will take place 2 hours after PfSPZ Challenge inoculation. Second 
administration of P218 or placebo will take place 48 hours after first administration of P218or placebo, on 
Day 3.  
Safety, parasitaemia and Malaria signs and symptoms (Malaria clinical score) will be assessed as of 
Day 7, i.e. during confinement in the unit until Day 13 and on daily ambulatory visits to the clinical unit 
as of Day 14, until development of positive parasitaemia or until Day 28 otherwise. If positive 
parasitaemia is confirmed, the subject will receive rescue therapy and will continue to be monitored daily 
at the clinical unit until treatment success. Upon treatment success, daily visits to the clinical unit are 
stopped, except for subjects that first need to complete the 3-day rescue treatment regimen and associated 
assessments. All subjects will be assessed again for parasitaemia at the end-of-study (EOS) visit on 
Day 35. Subjects not developing positive parasitaemia until Day 28 will receive rescue therapy on that 
day. Instead of daily monitoring at the clinical unit until treatment success, these subjects will only be 
assessed again for parasitaemia at the EOS visit on Day 35. All subjects that receive rescue therapy will be 
asked non leading questions to determine the occurrence of any AEs approximately two weeks after 
initiation of the rescue treatment, either during a planned study visit or by phone in case there is no 
planned study visit at that time. 
Antimalarial rescue therapy may be initiated whenever deemed necessary by the Investigators, e.g. if there 
is a concern regarding the safety of a study subject or if a study subject decides to withdraw from the 
study. Therapy may be amended according to the treating physician if the patient does not respond to 
treatment or the condition worsens. 
Progression to Cohort 3 will be assessed by the SRT, who will review safety, parasitaemia and Malaria 
signs and symptoms after data up to Day 35 for Cohort 2 are available, or after successful completion of 
the last rescue treatment, whichever is later. 
Study Population: 
Approximately 32 subjects are planned to be enrolled in one of 3 cohorts of 8, 12 and 12 subjects. A subject 
may be enrolled in one cohort only. Subjects will be randomised within each cohort in a 3:1 ratio to receive 
two consecutive administrations of either P218 or placebo. 
Eligibility Criteria: 
Inclusion Criteria: 
1. 
Informed Consent Form signed voluntarily before any study-related procedure is performed, 
indicating that the subject understands the purpose of and procedures required for the study and 
is willing to participate in the study, including administration of rescue treatment. 
2. 
Male or female, between 18 and 45 years old (extremes included) at screening. 
3. 
Body weight of at least 50 kg and a body mass index (BMI) of 19 to 30 kg/m2 (extremes 
included).  
4. 
Good general health without clinically relevant medical illness, physical exam findings including 
vital signs, and laboratory abnormalities as determined by the investigator. 
5. 
Willing to adhere to the prohibitions and restrictions specified in this protocol, including 
willingness to stay confined to the inpatient unit for required duration and willingness to avoid to 
travel outside of Benelux during the study period. 
6. 
Female subjects should fulfil one of the following criteria: 
a. 
At least 1 year post-menopausal (amenorrhea >12 months and follicle stimulating hormone 
(FSH) >30 mIU/mL) prior to screening; 
b. 
Surgically sterile (bilateral oophorectomy, hysterectomy or tubal ligation); 


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REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 20-mar-2019 (Final 2.0) 
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PROTOCOL SYNOPSIS 
c. 
Will use contraceptives as outlined in inclusion criteria 7 and 8. 
7. 
Female subjects of childbearing potential must agree to the use of a highly effective method of 
birth control from screening visit to until 40 days after the last dose of IMP (covering a full 
menstrual cycle of 30 days starting after 5 half-lives of last dose of IMP). 
Note: Highly effective birth control methods include: combined (estrogen and progestogen containing) 
oral/intravaginal/transdermal hormonal contraception associated with inhibition of ovulation, progestogen-
only oral/injectable/implantable hormonal contraception associated with inhibition of ovulation, intrauterine 
device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner or sexual 
abstinence. 
8. 
Male subjects who are sexually active with a female partner of childbearing potential must agree 
to the use of an effective method of birth control from the day of the first IMP dose until 
100 days thereafter (covering a full sperm cycle of 90 days starting after 5 half-lives of last dose 
of IMP). 
Note: Medically acceptable methods of contraception that may be used by the subject and/or partner include 
sterilization and vasectomy or a double barrier option combining oral contraceptive, contraceptive vaginal 
ring, contraceptive injection, intrauterine device or etonogestrel implant. 
9. 
Female subject has a negative pregnancy test at screening and upon admission in the clinical unit. 
Note: Pregnancy testing will consist of a serum β-human chorionic gonadotropin (β-HCG) test at screening 
and urine β-HCG tests at other visits, in all women. 
Inclusion Criteria - CHMI specific: 
10. Different ways of being reachable 24/7 (e.g. by mobile phone, regular phone or electronic mail) 
during the whole study period. 
Exclusion Criteria: 
1. 
Nursing (lactating) women. 
2. 
Participation in any other clinical drug or vaccine study within 30 days (or five half-lives for 
drugs) preceding the first dose of IMP (whichever is longer), or plans to participate in other 
investigational drug or vaccine research during the study period. 
3. 
Blood product donation to any blood bank during the 8 weeks (whole blood) or 4 weeks (plasma 
and platelets) prior to admission in the clinical unit. 
4. 
ECG outside normal range and deemed clinically relevant by the investigator. Examples of 
clinically significant ECG abnormalities for this study include: 
a. 
PR-interval >220 ms; 
b. 
QRS-complex >120 ms; 
c. 
QT interval corrected according to Bazett’s formula (QTcB) or QT interval corrected 
according to Fridericia’s formula (QTcF) >450 ms; 
d. 
Pathologic Q wave; 
e. 
Significant ST-T wave changes; 
f. 
Left or right ventricular hypertrophy; 
g. 
Non-sinus rhythm except isolated premature atrial contractions and ventricular extrasystole 
<2 per 10 s ECG lead; 
h. 
Incomplete left bundle branch block, or complete or intermittent right or left bundle branch 
block; 
i. 
Second or third degree A-V heart block. 
5. 
Seropositive human immunodeficiency virus (HIV) (antibody and antigen), hepatitis B virus 
(HBV) (hepatitis B surface antigen [HBsAg]) or hepatitis C virus (HCV) (antibody) tests.  
6. 
History or presence of diagnosed food or known drug allergies (including but not limited to 
allergy to any of the antimalarial rescue medications to be used in the study), or history of 
anaphylaxis or other severe allergic reactions. 
Note: Subjects with seasonal allergies/hay fever, house dust mite or allergy to animals that are untreated and 
asymptomatic at the time of dosing can be enrolled in the study. 
7. 
History of convulsion or severe head trauma. 
Note: A medical history of a single febrile convulsion during childhood is not an exclusion criteria. 
8. 
History of serious psychiatric condition that may affect participation in the study or preclude 
compliance with the protocol, including but not limited to past or present psychoses, disorders 
requiring lithium, a history of attempted or planned suicide, more than one previous episode of 
major depression, any previous single episode of major depression lasting for or requiring 
treatment for more than 6 months, or any episode of major depression during the 5 years 
preceding screening. 


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REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 20-mar-2019 (Final 2.0) 
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Note: The Beck Depression Inventory will be used as an objective tool for the assessment of depression at 
screening. In addition to the conditions listed above, subjects with a score of 20 or more on the Beck 
Depression Inventory and/or a response of 1, 2 or 3 for item 9 of this inventory (related to suicidal ideation) 
will not be eligible for participation. Subjects with a Beck score of 17 to 19 may be enrolled at the discretion 
of the Investigator if they do not have a history of the psychiatric conditions mentioned in this criterion and 
their mental state is not considered to pose additional risk to the health of the volunteer or to the execution 
of the study and interpretation of the data gathered. 
9. 
A medical, occupational or family problem as a result of alcohol or illicit drug abuse during the 
past 12 months or current alcohol or illicit drug abuse or addiction (positive alcohol breath test or 
positive drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine or 
opiates at screening or upon check-in at the clinical unit). 
Note: Excessive use of alcohol is an intake of >21 units per week for males and >14 units per week for 
females where one alcohol unit is defined as 10 mL or 8 g of pure alcohol. A single unit is equal to one 
25-mL (single) measure of whisky (alcohol by volume [ABV] 40%), or a third of a pint of beer (190 mL; 
ABV 5-6%) or half a standard (175 mL) glass of wine (ABV 12%). 
10. 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. 
11. Use of any prescription drugs, herbal supplements (e.g. St John’s Wort) or over the counter 
medication within 7 days or five half-lives (whichever is longer) prior to the first IMP 
administration, or an anticipated requirement for the use of these during the course of the study. 
Note: If necessary, the incidental use of non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol 
(2g/day, 10 gr/week), vitamins and topical treatments may be acceptable after approval by the study 
Sponsor and will be documented in the eSource system. The use of nutritional supplements during this time 
that are not believed to have the potential to affect subject safety nor the overall results of the study, may be 
permitted on a case-by-case basis following approval by the Sponsor in consultation with the Investigator. 
12. Any surgical or medical condition possibly affecting drug absorption (e.g. cholecystectomy, 
gastrectomy, bowel disease), distribution, metabolism or excretion. 
13. Any history of gallbladder disease, including cholecystitis and/or cholelithiasis. 
14. History of megaloblastic anaemia or folate deficiency. 
15. Personnel (e.g. investigator, sub-investigator, research assistant, pharmacist, study coordinator or 
anyone mentioned in the delegation log) directly involved in the conduct of the study. 
16. Any condition that in the opinion of the investigator would jeopardize the safety or rights of a 
person participating in the trial or would render the person unable to comply with the protocol. 
Exclusion Criteria - CHMI specific: 
17. Glucose-6-phosphate dehydrogenase (G6PD) deficiency (due to possible hemolysis induced by 
primaquine treatment at study end in G6PD deficient subjects). 
18. Personal history of malaria. 
19. Volunteer has travelled to or lived in a malaria-endemic area for more than 4 weeks during the 
12 months prior to first IMP administration, or spent any time in an endemic area during the 
4 weeks prior to first IMP administration. 
20. Plans to travel to malaria-endemic region during the study period up to last follow-up visit. 
21. Previous participation in any malaria vaccine or CHMI study. 
22. Falling in moderate or higher risk category for a fatal or non-fatal cardiovascular event within 
10 years (≥5%) determined by a validated risk estimation system e.g. SCORE. 
23. Use of medications known to interact with atovaquone-proguanil (Malarone®), 
artemether-lumefatrine (Riamet®) or primaquine (Primaquine®) such as cimetidine, 
metoclopramide or antacids, or an anticipated requirement for the use of these at any point during 
the study period. 
24. Use of systemic antibiotics with known antimalarial activity within 30 days (or 5 half-lives 
whichever is longer) of first IMP administration (e.g. trimethoprim sulfamethoxazole, 
doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones or azithromycin) or an 
anticipated requirement for the use of these during the study period. 
25. Receipt of blood or blood-derived products (including immunoglobulin) within 3 months prior to 
screening. Receipt of packed red blood cells given for an emergent indication in an otherwise 
healthy person, and not required as ongoing treatment is not exclusionary (for example packed 
red blood cells emergently given during an elective surgery). 


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REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 20-mar-2019 (Final 2.0) 
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PROTOCOL SYNOPSIS 
Note: In case of an out-of-range clinical laboratory test, vital sign or ECG value that will determine a 
subject’s eligibility, or in case of a positive drug screen, a retest or expert evaluation can be requested. 
Results of any retest must be available prior to inoculation. The result of the retest will be considered for 
subject eligibility at the investigator’s discretion. Subjects can be rescreened at the discretion of the 
investigator. 
IMP (P218/Placebo), Dose, Mode of Administration: 
P218 capsules for oral administration will be supplied by the Sponsor. Each capsule will contain 50 mg or 
250 mg P218. 
To preserve blinding, placebo capsules will be matched to the drug product with regard to appearance and 
taste. They are contained in the same packaging as the drug product. 
On each scheduled dosing, subjects will take simultaneously 4 capsules (either placebo or a total of 
1000 mg P218) p.o in Cohorts 1 and 2 or 2 capsules (either placebo or a total of 100 mg P218) p.o. in 
Cohort 3. Subjects will be asked to take the study drugs under the supervision of the clinical staff. Study 
drug administration will be done with 240 mL of non-carbonated water and in a fasted state (overnight 
fast for at least 8 hours; intake of water will be allowed until 1 hour before the administration of the study 
drugs). After intake of the study drugs, the subjects will be asked to maintain an upright position for at 
least 15 minutes. Thereafter, they will be asked to remain seated in bed for 2 hours. Fasting conditions 
will be maintained for 2 hours, including drinking water that will be allowed from 2 hour post dose 
onwards (ad libitum but approximately 1500mL/24 hours). 
PfSPZ Challenge, Dose, Mode of Administration: 
The PfSPZ Challenge consists of aseptic, cryopreserved P. falciparum sporozoites used for CHMI trials 
and is produced and provided by the biotechnology company, Sanaria (USA). Each cryovial contains 
15,000 or 50,000 sporozoites. 
The PfSPZ Challenge (3,200 P. falciparum sporozoites per subject) will be administered intravenously by 
DVI. The study staff administering the PfSPZ Challenge will wear gloves and eye protection. Advanced 
life support drugs and resuscitation equipment will be immediately available in the event of any subjects 
experiencing an anaphylactic reaction to the challenge. 


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REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 20-mar-2019 (Final 2.0) 
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PROTOCOL SYNOPSIS 
Antimalarial Rescue Medication: 
The clinical unit will be responsible for acquiring the anti-malarial drugs, Riamet®, Malarone® and 
Primaquine®: 
- 
Subject will be prescribed with Riamet® (20 mg artemeter and 120 mg lumefantrine) to ensure 
parasite clearance prior to the end-of-study evaluation. Tablets for oral use will be taken over 
3 days. The first dose should be taken as soon as possible and should be followed by five further 
doses approximately 8, 24, 36, 48 and 60 hours after the first dose. Drug administration should be 
immediately followed by a meal or drinks rich in fat (e.g. milk). 
- 
If an intolerance or contraindication to Riamet® develops, Malarone® (250 mg atovaquone and 
100 mg proguanil hydrochloride; tablets for oral use) will be administered for 3 consecutive days. 
- 
To ensure complete clearance of gametocytes (a low probability event in this study due to early 
treatment at low parasitemia levels), subjects will receive a single dose of Primaquine® (26.4 mg 
primaquine phosphate equivalent to 15 mg primaquine base; tablets for oral use, registered 
product in Canada) on the first day of rescue treatment or on Day 28 together with rescue 
treatment, for subjects who do not develop positive parasitaemia until this day. 
The PfSPZ Challenge product consists of a strain P. falciparum sporozoites used for CHMI trials that is 
known to be sensitive to the rescue treatment described above. 
Rescue treatment will be administered and monitored on the occasion of daily ambulatory visits to the 
clinical unit. The required anti-malarial drug intakes 36 and 60 hours after the first dose, can be done at 
home. Subjects will be notified by a study nurse via phone/text message/e-mail when it is time for dosing 
and must confirm study drug intake. Thick blood smear (TBS) microscopy and qPCR assessments of 
parasitaemia will be carried out daily until treatment success (defined as one negative qPCR outcome for 
asexual parasites, i.e. 0 parasites per mL, confirmed by TBS microscopy). Upon treatment success, daily 
visits to the clinical unit are stopped, except for subjects that first need to complete the 3-day rescue 
treatment regimen and associated assessments. All subjects will be assessed for parasitaemia at the EOS 
visit on Day 35.  
In subjects who do not develop positive parasitaemia until Day 28 of the study, rescue treatment will be 
initiated on Day 28. Instead of daily qPCR, TBS and Troponin I assessments until treatment success, for 
these subjects only a final qPCR will be performed at the EOS visit on Day 35.  
All subjects that receive rescue therapy will be asked non leading questions to determine the occurrence of 
any AEs approximately two weeks after initiation of the rescue treatment, either during a planned study 
visit or by phone in case there is no planned study visit at that time. 
All subjects must consent to rescue treatment. Even in case of withdrawal from the study, all challenged 
subjects are to receive rescue treatment as soon as possible, including all appropriate visits and 
assessments, and phone call as required. 
Study/Treatment Duration: 
In Cohort 1, each subject will be in the study for approximately 1 month and 1 week (37 days) maximum, 
including a screening period of up to 28 days and a follow-up period until 9 days after first IMP 
administration on Day 1. IMP will be administered twice; on Days 1 and 3. 
In Cohorts 2 and 3, each subject will be in the study for approximately 2.5 months (73 days) maximum, 
including a screening period of up to 28 days, a follow-up period until 35 days after PfSPZ DVI and a 
possible follow-up call approximately 2 weeks after start of rescue treatment, i.e. at 45 days after PfSPZ 
DVI at the latest. IMP will be administered twice; on Days 1 and 3.  
Assessments: 
Pharmacokinetics 
Plasma samples for determination of P218 concentration, and concentration of its major metabolites P218 
β-acyl-glucuronide, P218-OH β-acyl-glucuronide and possibly P218 OH in Cohort 1 only, will be 
analysed by Swiss BioQuant laboratory on behalf of MMV using a validated high performance liquid 
chromatography tandem mass spectrometry (HPLC/MS/MS) method at scheduled time points.  
Pharmacokinetic calculations will be performed by SGS-Life Sciences using Phoenix WinNonLin 8.0 or 
higher (Pharsight Corporation, Palo Alto, CA, USA). 


MMV 
REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 20-mar-2019 (Final 2.0) 
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PROTOCOL SYNOPSIS 
The following parameters, where appropriate, will be determined for P218, and in Cohort 1 only also for 
its major metabolites (P218-OH, P218-beta-acyl-glucuronide, P218-beta-acyl-glucuronide-OH) using 
individual concentration data in plasma, according to the definitions and methods of calculation below: 
- 
AUCτ = AUC0-48h after each administration (i.e. AUC0-48h and AUC48-96h);  
- 
AUC48h-inf, calculated from AUC48h-t + (Ct/λz);  
- 
AUC48h-last; 
- 
CL/F and Vz/F after the second administration (not for metabolites); 
- 
Cmax and tmax after each administration; 
- 
t1/2 after the second administration; 
- 
Rac, calculated as AUC48-96h/AUC0-48h; 
- 
Metabolic ratio of AUCτ and AUC48h-inf for P218 β-acyl glucuronide, P218 OH and P218-OH β-
acyl glucuronide over parent P218 (Cohort 1 only). 
Additional pharmacokinetic parameters may be calculated as appropriate. 
Efficacy 
Parasitaemia 
The assessment of malaria parasitology by TBS and qPCR will be as follows: 
- 
Parasite density, expressed as the number of parasites per microliter of blood will be measured 
using the routine diagnostic TBS microscopy method for parasite count employed by the centre 
of excellence for tropical medicine (ITM) as per relevant standard operating procedure and 
Laboratory Manual. The reading will be considered positive if 2 unambiguous malaria structures 
are seen in at least 0.5µl of blood and the observation is confirmed by a second expert malaria 
microscopist.  
- 
varATS (the acidic terminal segment in Plasmodium var genes) targeted qPCR assay of parasite 
load will be performed in accordance with the ITM standard operating procedure and the 
Laboratory Manual. Method validation and external quality assessment (EQA) of the outcomes 
will be carried out at the Department of Laboratory Medicine, School of Medicine, University of 
Washington (Dr. Sean Murphy) using 18S rRNA targeted qRT-PCR methodology described in a 
dedicated Validation Plan. Given the higher sensitivity of qPCR compared to microscopy, this 
method will be used to confirm aparasitaemia after definitive antimalarial therapy for all subjects. 
A subject will be considered cured following completion of the course of rescue antimalarial 
therapy and after qPCR results are obtained with values below the limit of detection.  
The results of the TBS microscopy and qPCR at the ITM will be available in approximately 24 hours. 
Malaria Clinical Score 
An inoculum-related event is a sign or symptom associated with malaria infection (confirmed by a 
positive P. falciparum PCR [defined for the purpose of this study as ≥ 250 asexual parasites per mL] at the 
onset of the event) that is of expected intensity, frequency and duration for the individual subject in the 
context of this study. 
Prevention of expected signs and symptoms associated with malaria infection form part of the efficacy 
evaluation of the study. If the presence of P. falciparum malaria is confirmed by positive PCR at the time 
of onset of these signs/symptoms and if, in the Investigator's opinion, the signs/symptoms are of the 
expected intensity, frequency and duration for the individual subject in the context of this study, then the 
events will be classified as inoculum-related events and reported as such in the final clinical study report. 
Inoculum-related events meeting the classification criteria for SAEs or AEs of special interest should be 
subjected to standard expedited reporting procedures of these events. 
The following malaria signs/symptoms will not be classified as inoculum-related events: 
- 
If the PCR results for P. falciparum are between 0 and < 250 asexual parasites per mL at the time 
of the onset of the event, usual AE/SAE reporting procedures and criteria will apply, and the 
event will not be classified as an inoculum-related event. 
- 
Observed malaria symptoms or signs that are of greater intensity, frequency or duration than 
would be expected in the context of this study, will be regarded as medically important events 
and must be reported promptly (i.e. in an expedited manner) to the Sponsor using an SAE report 
form, and will not be classified as inoculum-related events. 


MMV 
REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 20-mar-2019 (Final 2.0) 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Final classification of signs and symptoms as inoculum-related event or AE will occur after PCR results 
are available. 
Safety 
Adverse Events 
Adverse events will be monitored continuously from informed consent until the last study-related activity. 
At regular intervals during the study, subjects will be asked non-leading questions to determine the 
occurrence of any AEs. All AEs reported spontaneously during the course of the study will be recorded as 
well. 
Clinical Laboratory Tests 
Blood samples will be collected by venipuncture or via indwelling cannula. Biochemistry and 
haematology testing will be performed on these samples, as well as immunology testing (hepatitis B 
surface antigen [HbsAg], anti-hepatitis C virus [HCV] antibody and human immunodeficiency virus 
[HIV] antibody and antigen) on the sample from screening. In all female subjects, also serum β-HCG 
assessment at screening and urine β-HCG assessments on Day-1 and at the EOS visit will be performed. 
Follicle stimulating hormone (FSH) will be measured at screening in all women. 
All blood samples for safety assessments, except the ones taken during rescue treatment for Troponin I 
measurements only, should be taken in a fasted state (overnight fast for at least 8 hours for unbiased 
glucose determination).  
Standard laboratory tests will be performed by ZNA Middelheim. 
The following biochemistry and haematology tests will be performed on the safety blood samples:  
- 
Biochemistry: sodium, potassium, chloride, bicarbonate, urate, inorganic phosphate, creatinine, 
albumin, glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase (ALP), gamma glutamylaminotransferase (GGT), lactate dehydrogenase (LDH), 
total and direct bilirubin, total serum proteins, blood urea nitrogen (BUN), C reactive protein 
(CRP), creatine phosphokinase (CPK) and troponin I (Cohorts 2 and 3 only);  
- 
Haematology: haemoglobin, haematocrit, red blood cell (RBC) count, mean corpuscular 
haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), mean corpuscular 
volume (MCV), white blood cell (WBC) count, platelet count, reticulocytes, neutrophils, 
eosinophils, basophils, lymphocytes and monocytes; 
- 
Coagulation: prothrombin time (PT), international normalized ratio (INR), activated partial 
thromboplastin time (aPTT). 
Serum folate will be measured at scheduled time points. 
G6PD enzyme test will be performed at screening. 
A midstream urine sample will be collected for urinalysis by dipstick for glucose, protein, nitrite, pH and 
occult blood. Microscopic examination for WBC, RBC and casts will be performed 
A urine drug screen (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine and opiates) 
and an alcohol breath test will be performed at scheduled time points. 
The Investigator must review the laboratory report, document this review and record any change occurring 
during the study he/she considers to be clinically relevant in the eSource system. Laboratory values 
outside the normal range will be flagged and their clinical relevance will be assessed by the Investigator. 
Samples that remain after protocol-specific assessments have been performed may be used for further 
exploratory work on pharmacokinetics, metabolites, plasma protein binding, protein analysis and 
biochemistry. No human DNA or RNA analysis will be performed. 
Vital Signs 
Vital sign parameters will be assessed after 5 minutes in supine position at scheduled time points. The 
vital sign parameters that will be assessed are supine systolic and diastolic blood pressure (SBP and DBP, 
respectively), pulse rate and body temperature (sublingual). In Cohort 1, orthostatic changes to BP and 
pulse rate will also be assessed at screening: Subjects will be requested to stand after completion of the 
supine measurements and blood pressure and pulse rate will be recorded after 2 minutes in the standing 
position. 


MMV 
REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 20-mar-2019 (Final 2.0) 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
These parameters will be measured using a completely automated device consisting of an inflatable cuff 
and an oscillatory detection system. All values will be registered on a built-in recorder so that 
measurements are observer-independent. 
Any change from baseline in vital sign values occurring during the study that is considered to be clinically 
relevant by the Investigator should be recorded. 
Electrocardiogram 
Twelve-lead ECGs recordings will be will be recorded after 10 minutes in supine position at scheduled 
time points.  
All recordings will be performed once, except at screening and before the first and second IMP 
administration when they will be performed in triplicates at approximately 1-minute intervals. Paper speed 
will be 25 mm/s, so that the different ECG intervals can be measured manually.  
Between Day 10 and 28, one record will be performed on the first day of rescue treatment only. 
The interpretations of the ECGs will be performed by the Investigator or his/her designee at the clinical 
unit. Any change from baseline ECG occurring during the study that is considered to be clinically relevant 
by the Investigator should be recorded. 
Physical Examination 
Physical examination will be performed at scheduled time points. 
Height is to be measured barefoot and at screening only. Body weight to be measured at scheduled time 
points. To obtain the actual body weight, subjects must be weighed lightly clothed at screening.  
Any change in physical examination occurring during the study that is considered to be clinically relevant 
by the Investigator should be recorded. 
After screening, a targeted, symptom-driven physical examination will be performed focused on changes 
since the previous examination, but will always include at least: general appearance, skin, 
heart/circulation, chest, lungs, abdomen and brief neurological examination. 
Beck Depression Inventory 
The Beck depression inventory is performed at screening only. 
The questionnaire is scored by the subject. The inventory completed by the subject will be 
reviewed/checked for completeness and the total score calculated by the study personnel. 
Statistical Methods: 
All statistical analysis will be performed by SGS Life Sciences, using SAS® (SAS Institute Inc., Cary, 
NC, USA; version 9.4 or higher) software for statistical computations. 
The standard descriptive statistics for continuous variables are the number of subjects (N), mean, standard 
deviation (SD), median, first and third quartiles, minimum and maximum values. The standard descriptive 
statistics for categorical variables are the number of subjects in the category and the proportion expressed 
as a percentage. 
Fasting placebo data from the Cohorts 1, 2 and 3 will be pooled while IMP treatments per cohort are 
considered as two different treatment groups.  
Sample size 
Thirty-two subjects will be enrolled in 3 cohorts of 8, 12 and 12 subjects. In agreement with the Sponsor, 
additional subjects may be recruited in each cohort, to replace discontinuations for non-safety reasons and 
achieve cohort sizes of 8 and 12.  
This is an exploratory study thus no sample size calculation is performed. However, if the nine treated 
subjects each in Cohort 2 and 3 do not develop positive parasitaemia (qPCR ≥ 250 asexual parasites per 
mL) after IMP administration and until Day 28, it may be concluded that the protection rate for P218 is 
0.72 (72%) with a 95% probability (lower limit of exact, one sided test, 95%, CI 0.72). This holds true for 
both Cohort 2 and Cohort 3. 
Planned Analyses 
The primary objective of this analysis is the assessment of the chemoprotective activity of P218 in P. 
falciparum CHMI in non-immune healthy volunteers after PfSPZ Challenge through DVI.  


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REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 20-mar-2019 (Final 2.0) 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
No interim analysis will be performed. 
All statistical methods shall be detailed in a Statistical Analysis Plan (SAP) that will be finalized before 
database lock. 
Analysis Populations 
The following populations will be considered for analysis: 
- 
Intent-to-treat (ITT) population, defined as all randomised subjects who received at least one 
dose of IMP and who received the PfSPZ challenge inoculation, analysed as randomised; 
- 
Safety (SAF) population, defined as all subjects who received at least one dose of IMP, analysed 
as treated; 
- 
Pharmacokinetic (PK) population, defined as all subjects who have received at least 1 dose of 
IMP and had measurable concentrations of parent and/or metabolites; 
- 
Efficacy population, defined as all subjects in the safety population who received PfSPZ 
Challenge by DVI; 
- 
PK/PD population, defined as all subjects belonging to both the PK and the efficacy population. 
The ITT population will be used for the analysis of demographics and efficacy, the pharmacokinetic 
population will be used for the pharmacokinetic statistical analysis, the efficacy population for the 
efficacy statistical analysis and the safety population will be used for safety/tolerability analysis. 
Initial Characteristics Data of the Subject Sample 
For all randomised and treated subjects, descriptive statistics will be provided per treatment group for 
demographic (e.g. age, height, weight, BMI, race, gender) and other initial subject characteristics (alcohol 
and drug screening tests, pregnancy test, orthostatic changes to blood pressure and pulse rate [Cohort 1 
only], G6PD enzyme test, serology, medical and social history, concomitant diseases, Beck Depression 
Inventory).  
Prior and concomitant medications will be coded using the World Health Organization (WHO)_DRUG 
Dictionary. 
Pharmacokinetic Data 
Pharmacokinetic concentrations will be summarized by treatment group, day and scheduled sampling 
times by using number of subjects with data, arithmetic mean, standard deviation, coefficient of variation, 
median, minimum and maximum. 
For PK parameters, descriptive statistics will be included with in addition geometric mean and geometric 
coefficient of variance (CV%); tmax will be summarized by using number of subjects with data, median, 
minimum and maximum. 
Individual and mean concentrations versus time figures will be presented. 
Efficacy Data 
Parasitaemia 
Primary endpoint: The duration from PfSPZ challenge DVI to positive parasitaemia will be analysed 
using descriptive statistics, including the geometric mean and corresponding two-sided 90% confidence 
intervals. In the absence of positive parasitaemia, the duration will be set to a maximum of 28 days. 
The number and proportion of subjects with presence of positive parasitaemia between inoculation with 
PfSPZ and Day 28 (or the administation of rescue medication) will be summarized by a responder analysis 
per treatment group. Corresponding two-sided 90% Exact Clopper-Pearson confidence limits will be 
presented as well.  
Malaria Clinical Score 
For the malaria clinical score that will be administered by the PI or study physician, actual values and 
changes from baseline will be evaluated by means of descriptive statistics. Additionally, expected signs 
and symptoms will be summarized by score. 
PK/PD 
A model-based analysis is foreseen to characterise the PK/PD relationship between P218 plasma 
concentrations and blood stage asexual parasitaemia. Details of the modelling analysis will be described in 
the modelling analysis plan (MAP). 


MMV 
REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 20-mar-2019 (Final 2.0) 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Safety Data 
Safety parameters will be tabulated and analysed descriptively. 
Adverse Events 
The original terms entered in the eSource system by Investigators to identify AEs will be fully described 
and coded according to the Medical Dictionary for Regulatory Activities (MedDRA). 
The reported AEs will be allocated to phases based on their start date. All AEs will be listed. For Cohort 1 
all AEs with onset after first IMP treatment will be summarized by treatment group. For Cohorts 2 and 3 
all AEs with onset after PfSPZ challenge DVI will be summarised by treatment group. Summaries will be 
made per MedDRA primary system organ class, MedDRA preferred term, severity, with the number and 
percentage of subjects and the number of events. Similar summaries will be prepared for AEs considered 
to be related to IMP and AEs considered to be related to the PfSPZ challenge DVI, for serious AEs and 
AEs of special interest. 
Special attention will be paid to those subjects who died, discontinued IMP due to an AE, or experienced 
a severe or serious AE. Summaries, listings and narratives may be provided, as appropriate. 
Clinical Laboratory Tests 
Serum folate, continuous biochemistry and hematology laboratory tests will be evaluated by means of 
descriptive statistics on the actual values, at each assessment time point and by treatment group. Changes 
from baseline will also be summarized using descriptive statistics by assessment time point and by 
treatment group. 
Relative changes in clinical laboratory test values compared to values at baseline will be evaluated in 
accordance with the normal ranges of the clinical laboratory (below, within or above normal range). The 
percentage of subjects with clinical laboratory test abnormalities will be summarized by treatment group. 
The number and percentage of subjects with liver enzyme elevations after IMP administration as defined 
below will be summarised: 
- 
ALT or AST >3 x Upper Limit of Normal (ULN); 
- 
ALT or AST >5 x ULN; 
- 
ALT or AST >8 x ULN; 
- 
ALT or AST >3 x ULN and bilirubin >2 x ULN at the same time point, together with a 
conjugated bilirubin fraction> 35% (Potential Hy’s law cases). 
A listing of subjects with any clinical laboratory test result outside the reference ranges will be provided. 
Vital Signs 
Vital signs parameters will be assessed after 5 minutes in supine position at scheduled time points. Pulse 
rate, systolic blood pressure, diastolic blood pressure and body temperature will be evaluated by means of 
descriptive statistics (actual values and changes from baseline).  
The percentage of subjects with vital signs abnormalities will be summarized by treatment group in a 
cross-tabulation of post-baseline versus baseline abnormalities to the normal ranges. 
Electrocardiogram 
12-lead ECG recordings will be performed after subjects remained in a supine position for at least 
10 minutes. All recordings will be performed once, except at the screening and before the first and second 
IMP administration when they will be performed in triplicates.  
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 by 
means of descriptive statistics at each assessment time point and by treatment group.  
The percentage of subjects with ECG abnormalities will be summarized by treatment group in a 
cross-tabulation of post-baseline versus baseline abnormalities to the normal ranges.This cross-tabulation 
will include categorical assessment on actual values and changes from baseline of QTcB and QTcF 
prolongation. 
Physical Examination 
Abnormal findings in physical examination will be listed. 


MMV 
REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 
20-mar-2019 (Final 2.0) 
CONFIDENTIAL 
25 
TIME AND EVENTS SCHEDULE 
Cohort 1 
Description 
SCR 
Treatment and follow-up 
EOS 
Study Day -28 
to -2 
-1a 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Timepoint (h) in 
relation to 1st IMP 
administration 
 
0 
0b 
1 
2b 
4 
6 
10 
24 
36 
48 
48.5 
49 
49.5 
50 
52 
54 
58 
72 
84 
96c 
120c 
144c 
168c 
192c 
Ambulatory visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Confinement in 
clinical unitd 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consento 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and social 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beck depression 
inventory 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisationp 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol & drug 
screene 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height & weightf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Physical examinationg 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Vital signsh 
X 
X 
X 
X 
X 
 
 
X 
X 
 
X 
 
 
 
X 
 
 
X 
X 
X 
 
X 
 
 
X 
12-lead ECGi 
X 
X 
Xi 
 
 
 
 
 
X 
 
Xi 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Serologyj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testk 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
IMP administrationl 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology, 
chemistry & 
urinalysisq 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Serum folate 
X 
Xr 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Coagulation 
parametersm 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
PK blood samplen 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
X 
X 
X 
X 
X 
Previous medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


MMV 
REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 
20-mar-2019 (Final 2.0) 
CONFIDENTIAL 
26 
Description 
SCR 
Treatment and follow-up 
EOS 
Study Day -28 
to -2 
-1a 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Timepoint (h) in 
relation to 1st IMP 
administration 
 
0 
0b 
1 
2b 
4 
6 
10 
24 
36 
48 
48.5 
49 
49.5 
50 
52 
54 
58 
72 
84 
96c 
120c 
144c 
168c 
192c 
Concomitant 
medications 
 
X-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
AEs 
 
X-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
SAE reporting 
X----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
AE: adverse event, ECG: electrocardiogram, EOS: end of study, IMP: investigational medicinal product, PK: pharmacokinetic, SAE: serious adverse event, SCR: screening 
a. Assessments begin as of subject confinement in the clinical unit and must be completed and outcomes must be available before IMP administration. 
b. The assessments indicated must be completed and outcomes must be available before IMP administration. Predose PK sample should be taken within 1 hour before IMP 
administration. 
c. The assessments indicated will be performed daily during ambulatory visits to the clinical unit. 
d. Subjects will be admitted to the clinical unit in the morning of Day -1 and will remain in confinement until Day 4, i.e. 36 hours after second IMP administration. 
e. Alcohol breath test and urine dipstick screening for drug abuse. 
f. Height to be measured at screening only; body weight to be measured at screening, upon admission to the clinical unit on Day-1, upon discharge from the clinical unit on Day 4 and 
at the EOS visit on Day 9. 
g. Full physical examination will be conducted at screening and at the EOS visit on Day 9. Targeted (symptom-driven) physical examination will be conducted on all other occasions. 
Symptom-driven physical examination will be conducted at any time during follow-up, if indicated. 
h. Vital signs (blood pressure, pulse and body temperature) will be measured after remaining 5 minutes in a supine position. At screening, orthostatic changes to blood pressure and 
pulse rate will also be assessed: subjects will be requested to stand after completion of the supine measurements and blood pressure and pulse rate will be recorded after 2 min in the 
standing position. 
i. 12-lead ECGs recordings will be performed after subjects have remained in a supine position for at least 10 minutes. All recordings will be performed once, except at the screening 
and before the first and second IMP administration when they will be performed in triplicates. 
j. Serological testing for human immunodeficiency virus (HIV) antibody and antigen, hepatitis B surface antigen (HbsAg) and anti-hepatitis C virus (HCV) antibody, to determine 
eligibility for the trial. 
k. Pregnancy testing consists of serum β-human chorionic gonadotropin (β-HCG) assessment at screening and urine β-HCG assessments on Day-1 and at the EOS visit. 
l. In each instance, the subject will receive a single oral dose of 1000 mg P218 or placebo after fasting at least 8 hours (see Section 4.3).  
m. International Normalised Ratio (INR), prothrombin time (PT) and activated partial thromboplastin time (aPTT). 
n. On Day 4, the subject will be discharged from the clinical unit only after the PK sample at 84 hours is drawn. 
o. No study-related procedure is to be performed before voluntarily signing of the informed consent form. 
p. Randomisation will be performed before first IMP administration. 
q. Laboratory tests will be performed after fasting for at least 8 hours. 
r. This assessment can be done at either D-3 or D-1, upon Investigator’s decision. 


MMV 
REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 
20-mar-2019 (Final 2.0) 
CONFIDENTIAL 
27 
Cohorts 2 and 3 
Description 
SCR 
Challenge, treatment and follow-up 
EOS 
visit 
EOS
u 
Study Day -28 
to -2 -1a 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 14-
28c 
35 
45 
max 
Timepoint (h) in 
relation to PfSPZ 
Challenge 
 
0 
0b 2b 2.5 
3 
3.5 
4 
6 
8 
12 
24 
36 
50 50.5 51 51.5 52 54 
56 
60 
72 
84 
96 120 144 168 192 216 240 264 288 
 
 
 
Ambulatory visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Confinement in 
clinical unitd 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consente 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and social 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beck depression 
inventory 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisationt 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol & drug 
screenf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height & weightg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Physical 
examinationh 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Xh 
 
 
X 
 
Xh 
 
 
X 
Xh 
X 
 
Vital signsi 
X 
X 
X 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Xi 
X 
 
12-lead ECGj 
X 
X 
Xj Xj 
 
 
 
X 
 
 
X 
X 
 
Xj 
 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Xj 
X 
 
G6PD deficiency 
enzyme test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serologyk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testl 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


MMV 
REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 
20-mar-2019 (Final 2.0) 
CONFIDENTIAL 
28 
Description 
SCR 
Challenge, treatment and follow-up 
EOS 
visit 
EOS
u 
Study Day -28 
to -2 -1a 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 14-
28c 
35 
45 
max 
Timepoint (h) in 
relation to PfSPZ 
Challenge 
 
0 
0b 2b 2.5 
3 
3.5 
4 
6 
8 
12 
24 
36 
50 50.5 51 51.5 52 54 
56 
60 
72 
84 
96 120 144 168 192 216 240 264 288 
 
 
 
DVI of PfSPZ 
Challenge 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP 
administrationm 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Malaria clinical 
scoren 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Haematology, 
chemistry & 
urinalysiso 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Xo 
X 
 
Serum folate 
X 
Xv 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Xo 
X 
 
Coagulation 
parametersp 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
PK blood sample 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Rescue therapyq 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
TBSr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
qPCR for 
parasitess 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Previous 
medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
AEs 
 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
SAE reporting 
X-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
AE: adverse event, DVI: direct venous inoculation, ECG: electrocardiogram, EOS: end of study, G6PD: glucose-6-phosphate dehydrogenase, IMP: investigational medicinal product, 
PfSPZ: Plasmodium falciparum sporozoites, PK: pharmacokinetic, qPCR: quantitative polymerase chain reaction, SAE: serious adverse event, SCR: screening, TBS: thick blood smear 
a. Assessments begin as of subject confinement in the clinical unit and must be completed and safety assessment outcomes must be available before PfSPZ Challenge DVI on Day 1. 
b. On Day 1, assessments begin as of 3 hours before challenge. The assessments indicated must be completed and safety assessment outcomes must be available before PfSPZ 
inoculation or before IMP administration. Predose PK sample should be taken within 1 hour before IMP administration. 
c. The assessments indicated will be performed daily during ambulatory visits to the clinical unit. 
d. Subjects will be admitted to the clinical unit in the morning of Day -1 and will remain in confinement until Day 13, i.e. 12 days post PfSPZ Challenge. 
e. No study-related procedure is to be performed before voluntarily signing of the informed consent form. 
f. Alcohol breath test and urine dipstick screening for drug abuse. 
g. Height to be measured at screening only; body weight to be measured at screening, upon admission to the clinical unit on Day-1, upon discharge from the clinical unit on Day 13 and 
at the EOS visit on Day 35. 


MMV 
REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 
20-mar-2019 (Final 2.0) 
CONFIDENTIAL 
29 
h. Full physical examination will be conducted at screening, at Days -1, 2, 4, 8 and 13, and at the EOS visit on Day 35. Targeted (symptom-driven) physical examination will be 
conducted on Days 5, 10, 15, 20 and 25, and at the start of rescue treatment. Symptom-driven physical examination will be conducted at any time during follow-up, if indicated. 
i. Vital signs (blood pressure, pulse and body temperature) will be measured after remaining 5 minutes in a supine position. During the period between Day 14 and 28, vital signs will 
be measured on Days 15, 20 and 25 and on the first day of rescue treatment only.  
j. 12-lead ECGs recordings will be performed after subjects have remained in a supine position for at least 10 minutes. All recordings will be performed once, except at the screening 
and before the first and second IMP administration when they will be performed in triplicates. During the period between Day 14 and 28, one record will be performed on the first 
day of rescue treatment only. 
k. Serological testing for HIV antibody and antigen, HbsAg and anti-HCV antibody, to determine eligibility for the trial.  
l. Pregnancy testing consists of serum β-HCG assessment at screening and urine β-HCG assessments on Day-1 and at the EOS visit. 
m. In each instance, the subject will receive a single oral dose of 1000 mg P218 or placebo (Cohort 2) or a single oral dose of 100 mg P218 or placebo (Cohort 3) after fasting 8 hours at 
least (see Section 4.3). The initial dose at Day 1 must not be given prior to 2 hours post-inoculation. 
n. Malaria clinical score for malaria signs and symptoms is assessed on Day 1, in the 3 hours before PfSPZ Challenge, and daily from Day 7 to the day subject is positive for 
parasitaemia and at the EOS visit at Day 35. Daily assessments will take place during rescue treatment. For subjects that not develop positive parasitaemia until Day 28, after Day 28, 
assessments will take place only at the EOS visit at Day 35. 
o. During the period between Day 14 and Day 28, haematology, clinical chemistry and urinalysis laboratory tests will be performed and serum folate measured after fasting for at least 
8 hours on Days 14, 21 and 28, and additionally one day after the subject turned positive for parasitaemia, if not coincident with one of these scheduled timepoints. Troponin I will be 
measured at screening, baseline prior to inoculation and on Days 2 and 3 of rescue treatment (see Section 5.2). 
p. INR, PT and aPTT. 
q. Every subject will receive a three-day course of antimalarial rescue medication as soon as positive for parasitaemia or on Day 28 in subjects who do not develop positive parasitaemia 
throughout the follow-up period (see Section 5.2). On the first day of rescue treatment, the subject will also receive a single oral dose of Primaquine® to ensure complete clearance of 
gametocytes.  
r. Blood samples for the assessment of parasitaemia by TBS microscopy will be drawn daily from Day 7 to Day 28. In subjects who develop parasitaemia and receive rescue treatment, 
TBS microscopy will be performed daily for confirmation of the qPCR outcomes until treatment completion and success (see Section 5.2 for definition), and at the EOS visit on 
Day 35. In subjects who do not develop positive parasitaemia until Day 28 of the study, rescue treatment will be initiated on Day 28. Instead of daily qPCR and TBS assessments 
until treatment success, for these subjects only a final qPCR will be performed at the EOS visit on Day 35. 
s. Blood samples for the assessment of parasitaemia by qPCR will be drawn at the following timepoints: immediately before PfSPZ Challenge DVI and daily from Day 7 to Day 28. In 
subjects who develop parasitaemia and receive rescue treatment, qPCR will be performed daily until treatment completion and one negative outcome is obtained, and at the EOS visit 
on Day 35. In subjects who do not develop positive parasitaemia until Day 28 of the study, rescue treatment will be initiated on Day 28. Instead of daily qPCR and TBS assessments 
until treatment completion and success, for these subjects only a final qPCR will be performed at the EOS visit on Day 35. 
t. Randomisation will be performed before first IMP administration. 
u. All subjects that receive rescue therapy will be asked non leading questions to determine the occurrence of any AEs approximately two weeks after initiation of the rescue treatment, 
either during a planned study visit or by phone in case there is no planned study visit at that time. If this time point is after the EOS visit on Day 35, the moment of the phone call will 
be considered the EOS and not Day 35. 
v. This assessment can be done at either D-3 or D-1, upon Investigator’s decision. 
 
 


MMV 
REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 20-mar-2019 (Final 2.0) 
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30 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
List of Abbreviations 
β-HCG 
β-human chorionic gonadotropin  
λz 
First order terminal rate constant 
ABV 
alcohol by volume 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
API 
Active pharmaceutical ingredient 
aPTT 
activated partial thromboplastin time  
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUC0-inf 
Area under the plasma concentration-time curve from time zero to 
infinity 
AUC0-last 
Area under the plasma concentration-time curve from time zero to the 
last quantifiable concentration  
AUC48h-inf 
Area under the plasma concentration-time curve from 48 hours after 
dosing to infinity 
AUC48h-last 
Area under the plasma concentration-time curve calculated between 
48 hours after dosing and last quantifiable concentration 
AUCτ 
Area under the plasma concentration-time curve during the dosing 
interval 
AUC0-48h 
Area under the plasma concentration-time curve during the first 
48 hours after dosing 
AUCx-yh 
Area under the plasma concentration-time curve from time x to y 
hours post-dose 
AUCinf 
Area under the plasma concentration-time curve from time zero to 
infinity  
BMI 
Body mass index 
BSC 
Biosafety cabinet 
CHMI 
Controlled human malaria infection 
CL/F 
Total plasma clearance 
Cmax 
Observed maximum plasma concentration 
Ct 
Last observed quantifiable concentration 
DVI 
Direct venous inoculation 
DBP 
Diastolic blood pressure 
DHFR 
dihydrofolate reductase 
DNA 
Deoxyribonucleic acid 
DVI 
Direct venous injection  
ECG 
Electrocardiogram 
ED90 
effective dose for 90% of the animals 
EOS 
End-of-study 
FIH 
first-in-human 
FSH 
Follicle stimulating hormone 
G6PD 
Glucose-6-phosphate dehydrogenase 


MMV 
REVISED CLINICAL STUDY PROTOCOL - MMV_P218_17_01 20-mar-2019 (Final 2.0) 
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31 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HSA 
Human serum albumin 
IB 
Investigator’s Brochure  
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
INR 
international normalized ratio  
IRB 
Institutional Review Board 
ITM 
centre of excellence for tropical medicine 
ITT 
Intent-to-treat 
LPLV 
Last Patient Last Visit 
MCH 
Mean corpuscular hemoglobin 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimal inhibitory concentration  
MHRA 
Medicines and Healthcare products Regulatory Agency  
MPC 
Minimal parasiticidal concentration 
NSAID 
non-steroidal anti-inflammatory drug 
PBS 
Phosphate buffered saline 
P. falciparum 
Plasmodium falciparum 
PD 
Pharmacodynamic(s) 
Pf 
P. falciparum 
PfSPZ 
P. falciparum sporozoites 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PopPK 
population pharmacokinetics  
PT 
Prothrombin time 
qPCR 
quantitative polymerase chain reaction 
QTcB 
QT interval corrected according to Bazett’s formula  
QTcF 
QT interval corrected according to Fridericia’s formula 
Rac 
Accumulation ratio  
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SPZ 
Sporozoites 
SRT 
Safety Review Team 
t½ 
Terminal elimination half-life 
TBS 
Thick blood smear 
TEAE 
Treatment-emergent adverse event 
tmax 
Time to reach the maximum concentration after drug administration  
ULN 
Upper Limit of Normal 


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Vz/F 
Apparent volume of distribution 
WBC 
White blood cell 
WHO 
World Health Organization 
 
Definitions of Terms 
BMI 
Weight in kilogram divided by the square of height in meters 
QTcB 
QT interval corrected according to Bazett’s formula:  
QTcB (ms)=QT (ms)/RR1/2 where RR=(60/heart rate)*1000 
QTcF 
QT interval corrected according to Fridericia’s formula:  
QTcF (ms)=QT (ms)/RR1/3 where RR=(60/heart rate)*1000 
Positive 
parasitaemia 
Defined as qPCR outcome equal or greater than 250 asexual parasites 
per mL. The presence of asexual parasites will be confirmed by thick 
blood smear (TBS) microscopy. 
 


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STUDY ADMINISTRATIVE STRUCTURE AND 
INVESTIGATORS 
SPONSOR 
Medicines for Malaria Venture (MMV) 
ICC – Building G 
20, route de Pré-Bois 
P O Box 1826 
1215 Geneva 15 
Switzerland 
Medical Director: Farouk Chughlay 
Clinical Lead: Myriam El Gaaloul 
Clinical Operations Lead: Nicola Kerr 
CLINICAL CENTRE 
SGS Life Sciences, Clinical Pharmacology 
Unit 
Lange Beeldekensstraat 267 
2060 Antwerpen 
Belgium 
Tel: +32 (0)3 217 25 60 
Fax: +32 (0)3 217 25 81 
Principal Investigator: Pieter-Jan Berghmans 
CLINICAL LABORATORY 
ZNA Klinisch Laboratorium 
Campus Middelheim 
Lindendreef 1 
2020 Antwerpen 
Belgium 
BIOANALYTICAL LABORATORY 
Swiss BioQuant AG 
Kägenstrasse 18 
4153 Reinach 
Switzerland 
PHARMACOVIGILANCE 
PrimeVigilance Ltd. (Head office) 
1 Occam Court 
Surrey Research Park 
Guildford, Surrey GU2 7HJ 
United Kingdom 
CLINICAL MONITORING 
Biologic LLP 
Enville House 
Hedgerley Hill 
Hedgerley, Bucks SL2 3RL 
United Kingdom 
MEDICAL MONITORING 
 
ICON Clinical Research 
Heinrich-Hertz Str. 26  
63225 Langen 
Germany 


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1. INTRODUCTION 
1.1 
MALARIA BACKGROUND INFORMATION 
Malaria is the second most prevalent infectious disease in the world and threatens half of 
the world’s human population. In 2016, the World Health Organization (WHO) reported 
216 million new cases of malaria worldwide and 445,000 deaths [21]. Children <5 years 
of age accounted for 70% of deaths in 2015. The majority of these deaths were due to 
infection with Plasmodium falciparum (P. falciparum) [20]. 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 P. 
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 owing to increasing resistance to the 
current antimalarial therapies, new therapies are required as both stand-alone and partner 
therapies to address a growing unmet medical need. 
1.2 
P218 
P218 is a selective inhibitor of Plasmodium dihydrofolate reductase (DHFR), an enzyme 
catalysing the reduction of folates to tetrahydrofolates, which are essential for DNA 
biosynthesis in the malarial parasite [22]. DHFR inhibitors, selective to the Plasmodium 
DHFR not targeting the distinct 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. Its usage for malaria 
treatment was stopped worldwide following emergence and spread of resistance. 
However, it is still WHO-recommended for prophylactic use solely or in combination as 
seasonal malaria chemoprevention (SMC) in West Africa and as Intermittent Preventive 
Treatment during Pregnancy (IPTp) and in Infants (IPTi) in malaria endemic areas where 
benefits are still expected. 
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 has potential value as chemoprotective agent against P. falciparum malaria as it 
showed strong activity in vitro on P. yoelii, P. berghei and P. falciparum liver 
sporozoites with a 50% inhibitory concentration (IC50) of 2.14, 2.0 and 0.94 nM, 
respectively. The P218 in vitro inhibitory activity on P. falciparum DHFR was 
comparable to, or greater than pyrimethamine.  
Based on these encouraging data, P218 is primarily considered for malaria 
chemoprotection. 
A first in human (FIH) study was conducted in the UK (MMV_P218_15_01/C16009). It 
was a double-blind, randomised, placebo-controlled, ascending-dose study with Part A 
(single ascending doses of 10 mg to 1000 mg) and Part B (food effect assessment). There 
were no serious adverse events (SAEs) or severe adverse events in subjects who received 
a single oral dose of up to 1000 mg P218. The highest single dose tested (1000 mg) was 


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considered safe and well tolerated and was associated with mean maximum observed 
plasma concentration (Cmax) and area under the plasma concentration-time curve from 
time zero to infinity (AUC0-inf) values of 8.64 μg/ml and 17.8 μg∙h/ml, respectively. This 
provides an exposure margin of 4.0-fold to the protocol-defined stopping criteria of 
71.9 μg∙h/ml based on total cumulative AUC from time 0 to 336 hours post dose 
(AUC0-336h) observed in the most sensitive species (dog). The single oral dose of 
1000 mg of P218 was associated with a mean elimination half-life of 19.6 h which is too 
short to allow for weekly or monthly oral dosing in a chemoprotection setting. 
Antimalarial efficacy against the blood stage P. falciparum has also been evaluated in a 
validated mouse model (Humanized SCID mouse) with established effective dose for 
90% of the animals (ED90) of 1.6 mg/kg/day and derived minimal parasiticidal 
concentration (MPC) and minimal inhibitory concentration (MIC) of 4.4 ng/ml and 
1.3 ng/ml, respectively. A human dose that could maintain blood concentrations above 
MIC was identified as a target minimal efficacious dose for chemoprotection against 
P. falciparum malaria. Using this approach and observed human pharmacokinetics (PK) 
in the completed FIH study, it is likely that using the currently available oral formulation 
of P218, a single human dose of 1000 mg would be needed to maintain in human 
subjects P218 plasma concentrations above the target mouse blood MIC for 48 hours.  
During conduct of the FIH study, two acyl glucuronides previously identified in 
preclinical species were also observed in healthy subjects. Given that the structure and in 
particular, the site of conjugation are identical between both acyl glucuronides of P218, it 
is considered appropriate to assess safety in terms of total acyl glucuronide burden rather 
than each one independently [19]. In agreement with the Medicines and Healthcare 
products Regulatory Agency (MHRA), 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 total human AUC being the sum of human AUC of each 
molecule. The observed P218 β-acyl glucuronides total human AUC0-inf at the 1000 mg 
dose was 54.4 μg∙h/ml which remains below the highest tolerated, estimated cumulative 
glucuronides AUCs in the 14-day Good Laboratory Practice (GLP) toxicology study in 
dog (74.6 μg∙h/ml) and the study in rat (62.5 μg∙h/ml). 
Please refer to the current Investigator’s Brochure (IB) for more detailed information on 
P218 [6]. 
1.3 
PLASMODIUM FALCIPARUM SPOROZOITES CHALLENGE MODEL 
(PFSPZ CHALLENGE) 
P. falciparum sporozoites challenge model (PfSPZ Challenge) consists of aseptic, 
purified, live, infectious, cryopreserved P. falciparum (Pf) sporozoites (SPZ) (PfSPZ 
Challenge) obtained from Anopheles stephensi mosquitoes reared under aseptic 
conditions and infected with P. falciparum sporozoites of either the NF54 strain or 7G8 
clone. The PfSPZ Challenge product was developed to infect volunteers by controlled 
human malaria infection (CHMI) to assess the efficacy of antimalarial drugs and 
vaccines and the effects of naturally acquired immunity and innate resistance. PfSPZ 
Challenge is administered by trained clinical study staff with a needle and syringe as 
directed by the protocol.  


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Malaria Challenge has been safely used in multiple clinical trials in the United States, 
Europe, Australia and Africa via the intradermal (ID), intravenous (IV) and 
intramuscular (IM) routes [4, 5, 9, 10, 12, 15, 16, 17, 18]. As of 17 April 2018, 
913 volunteers have received 1407 doses of PfSPZ Challenge (NF54) and 34 volunteers 
have received 34 doses of PfSPZ Challenge (7G8). Extensive safety and efficacy data are 
available [7]. In addition, PfSPZ Challenge has been safely administered to volunteers in 
combination with antimalarial drugs. Currently, the validated inoculation method for 
drug and vaccine evaluation consists of direct venous injection (DVI) with an inoculum 
size of 3,200 sporozoites which has been shown to induce subclinical malaria in 100% of 
inoculated healthy volunteers [11]. 
Please refer to the current IB for more detailed information on the PfSPZ Challenge [7]. 
1.4 
RATIONALE FOR THE STUDY 
The present study will investigate P218 as possible chemoprotective agent against 
P falciparum in a standardised and validated CHMI model using DVI of aseptic, 
purified, cryopreserved, vialed P. falciparum sporozoites (PfSPZ Challenge).  
If the P218 activity against P. falciparum infection is clinically demonstrated in this 
study, a long acting injectable depot formulation will be considered, allowing for 
slow-blood-release of P218 over at least one week and preferably, over one month 
following single injection [1]. 
1.5 
RISK BENEFIT ANALYSIS 
1.5.1 
Potential Risks 
To date, P218 has been administered as a single dose to 50 healthy human subjects. The 
pharmacokinetic, safety and tolerability data from these subjects suggest a favourable 
tolerability and safety profile. This is supported by the pharmacological and toxicological 
profile of P218 observed in preclinical studies.  
Potential Risks Based on Non-Clinical Studies 
The gastrointestinal (GI) toxicity (erosion, epithelial hyperplasia, inflammation and a 
mucosal inflammatory infiltrate of the caecum) observed in nonclinical studies (14-day 
repeated dose in rats and dogs) was largely reversible after 14 days off-dose, although 
slight ulceration, epithelial hyperplasia, dilated glands, inflammation and a mucosal 
inflammatory infiltrate of the caecum persisted in female animals.  
Co-administration of folate in rats completely abolished the histopathological effects 
observed on the GI tract. The mechanism for the GI toxicity has been established to be 
caused by folate depletion and is consistent with the pathology observed after treatment 
with other DHFR inhibitors. Based on reported GI toxicity in clinical trials conducted 
with pyrimethamine, a marketed DHFR inhibitor for malaria, the following adverse 
events could be reported in human subjects after P218 administration: anorexia, nausea, 
vomiting and less commonly leucopoenia, thrombocytopenia and megaloblastic anaemia 
(due to folate depletion). 


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Gall bladder pathology (epithelial dysplasia and/or apoptosis, and inflammation) was 
observed in 14-day repeated dose study in dogs. These microscopic findings were found 
to be reversible in males and partially reversible in females. 
Administration of P218 to rats or dogs results in exposure to all human metabolites. 
Exposure to P218-OH is quantitatively lower in humans than the 10% threshold accepted 
under Metabolites in Safety Testing (MIST) guidance to require further evaluation and is 
therefore considered qualified. 
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. 
Given that the structure and in particular the site of conjugation is identical between both 
acyl glucuronides of P218 and in agreement with the MHRA, it is considered appropriate 
to assess safety in terms of total acyl glucuronide burden rather than considering each 
one independently [19]. This approach allows compensating partly for the likely high 
variation in specific acyl glucuronides of parent drug and metabolites across species 
where variation across Phase 1 and Phase 2 metabolite enzymes will be magnified. These 
include oxidative and uridine 5’-diphospho-glucuronic transferases (UDPGTs) 
responsible for formation of glucuronides, but also hydrolytic enzymes (esterases) which 
will influence degradation.  
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 AUC from time zero to the last quantifiable concentration (AUC0-last) being 
the sum of the human AUC0-last 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. For more information, please 
refer to the IB [6].  
Potential Risks Based on Clinical Data 
To date P218 was administered in one Phase 1 study performed in the UK. The FIH 
study (MMV_P218_15_01) included a total of 64 adult male and female (women of 
non-childbearing potential [WONCBP]) healthy subjects. In Part A, 42 subjects received 
P218 at singles doses of 10 mg (n=6), 30 mg (n=6), 100 mg (n=6), 250 mg (n=6), 
500 mg (n=6), 750 mg (n=6) or 1000 mg (n=6) and 14 subjects received placebo (two 
each per dose level). In Part B, four subjects received a single dose of 250 mg P218 when 
fasted in Period 1 and fed in Period 2, four other subjects received 250 mg P218 when 
fed in Period 1 and fasted in Period 2. Subjects were administered P218 as a capsule for 
oral administration.  
Overall, in this clinical study, there were no significant abnormalities on laboratory 
parameters including hepatic transaminases, vital signs, electrocardiograms (ECGs) or 
physical examination and there were only five drug related treatment-emergent adverse 
events (TEAEs) in Part A (and none in any fasted subjects in Part B). These findings 
indicate that P218 was safe and well tolerated when administered, fasted, in single doses 
of up to 1000 mg. There did not appear to be any effect on the tolerability profile of P218 
when administered as a single dose in the fed state on the basis of this study. 


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P218 was rapidly absorbed with Cmax values achieved between 30 minutes and 2 hours 
post dose. Plasma concentrations of P218 decline in a bi-exponential manner with P218 
half-life values ranging from 3.1 to 6.7 hours at the two lowest doses (10 and 30 mg) and 
increase up to 8.9-19.6 hours at doses up to 1000 mg. P218 parent and metabolite 
exposure values as assessed by Cmax and AUC0-inf, increase in a dose-proportional 
manner between 100 and 1000 mg. Co-administration of P218 with food reduced Cmax 
(35%) and delayed absorption (1 hour) but with no significant impact on AUC. 
Potential Risks Associated With PfSPZ Challenge 
Subjects receiving the PfSPZ DVI will be exposed to additional risks, including the 
development of malaria symptoms as well as adverse effects of the approved rescue 
medication (Riamet® or Malarone® and Primaquin®) to be prescribed as curative therapy 
for parasite clearance prior to the end of the study. 
The CHMI PfSPZ challenge model with the DVI technique is a well-validated method 
for obtaining informative data on the clinical activity of novel antimalarial compounds. It 
has replaced the traditional method of CHMI by the bite of mosquitos to measure vaccine 
and drug efficacy. In a series of clinical trials, inoculation of PfSPZ Challenge was found 
to be safe and well tolerated with the optimal dose established as 3200 PfSPZ 
administered by DVI.  
Risks to subjects in this Phase IB study will be minimized in the following ways: 
- 
Sentinel dosing of subjects in Cohort 1 (Please refer to Section 3.1); 
- 
Progression to consecutive study cohorts only after evaluation of data from 
previous cohorts and approval from Safety Review Team (SRT) (Please refer to 
Section 5.8); 
- 
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; 
- 
The dose of PfSPZ inoculum and route of administration has previously been 
shown to be safe and well-tolerated in healthy human subjects;  
- 
Regular and intense monitoring to ensure the safety and well-being of the study 
subjects will include the following: 
o Admission to the clinical unit in the morning of Day -1, i.e. from at least 
8 hours before first investigational medicinal product (IMP) 
administration or for Cohorts 2 and 3 before PfSPZ Challenge until 
12 days post PfSPZ Challenge; 
o Vital signs (blood pressure, heart rate, body temperature); 
o 12-lead ECGs; 
o Safety laboratory assessments of clinical chemistry and haematological 
blood parameters performed at scheduled time points and repeated, if 
necessary, to ensure appropriate follow-up of any clinically relevant 
abnormality; 
o Daily parasitaemia assessments by both quantitative polymerase chain 
reaction (qPCR) and Thick Blood Smear (TBS) techniques from Day 7 


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post inoculation until the subject is positive for parasitaemia or until 
follow-up to Day 35 post inoculation is completed; 
o Objective/directed evaluation of Malaria signs and symptoms through a 
clinical score. 
- 
All subjects in Cohorts 2 and 3 will be prescribed curative therapy for malaria 
for radical clearance during or at the end of the study; 
- 
The total volume of blood drawn from each subject will not exceed 450 ml in 
any given 30-day period. This volume includes allowance for unscheduled 
safety laboratory assessments that may be required at the discretion of the 
Principal Investigator (PI) or MMV to ensure subjects safety;  
- 
In addition to the PI or his representative, the site has access to an expert 
medical malariologist to help in making clinical decisions as necessary, 
including in the rare event that hospitalization is required, which will be done at 
the Antwerp University Hospital (UZA). SAEs will be treated according to their 
nature at a specialist inpatient facility.  
1.5.2 
Potential Benefits 
P218 will be given to healthy subjects purely for research and development purposes and 
those subjects receiving P218 will experience no medical benefit except for a general 
health examination.  
Benefits of the study are society-based and related to possible future antimalarial 
therapies. Taking into consideration the proposed risk-management plan as described, the 
risk to subjects participating in this study is considered to be minimal and acceptable. 
1.5.3 
Conclusion 
No benefit is expected for individual subjects participating in this study. Benefits of the 
study are society-based and related to possible future antimalarial therapies. Taking into 
consideration the proposed risk-management plan as described, the risk to subjects 
participating in this study is considered to be minimal and acceptable. 
 


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2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 
OBJECTIVES 
2.1.1 
Primary Objective 
2.1.1.1 
COHORT 1 
The primary objective of this cohort is to assess the safety and tolerability of two single 
doses of 1000 mg P218 administered 48 hours apart in healthy adult volunteers. 
2.1.1.2 
COHORTS 2 AND 3 
The primary objective of these cohorts is to assess the chemoprotective activity of P218 
in P. falciparum CHMI in non-immune healthy volunteers after PfSPZ Challenge 
through DVI. 
2.1.2 
Secondary Objectives 
Secondary objectives are: 
- 
To assess the PK profile of P218, and in Cohort 1 only also of its main 
metabolites, up to 8 days after the first P218 administration to healthy adult 
volunteers;  
- 
To establish the pharmacokinetic/pharmacodynamic (PK/PD) relationship 
between P218 plasma concentration and its chemoprotective activity using 
blood stage parasitaemia as a surrogate in non-immune healthy volunteers in a 
CHMI PfSPZ Challenge model; 
- 
To assess the safety and tolerability of P218 in non-immune healthy volunteers 
in a CHMI PfSPZ Challenge model (Cohorts 2 and 3); 
- 
To assess the safety and tolerability of PfSPZ Challenge in non-immune healthy 
volunteers before and after P218 administration during CHMI (Cohorts 2 and 3). 
There is no formal hypothesis testing as this is an exploratory study. 
2.2 
ENDPOINTS 
2.2.1 
Primary Endpoints 
2.2.1.1 
COHORT 1 
The primary endpoint of this cohort is the incidence, severity and relationship to P218 of 
observed or self-reported TEAEs during the 9-day observation period without PfSPZ 
Challenge. 
2.2.1.2 
COHORTS 2 AND 3 
The primary endpoint of these cohorts is the cohort-specific, geometric mean time to 
parasitaemia based in each case on the time elapsed between PfSPZ Challenge DVI and 
first qPCR outcome equal or greater than 250 asexual parasites per mL, with a maximum 
of 28 days in the absence of parasitaemia. 


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2.2.2 
Secondary Endpoints 
Secondary endpoints are: 
- 
Estimation of the following PK parameters for P218, and in Cohort 1 only, also 
for its major metabolites (P218-OH, P218-beta-acyl-glucuronide, 
P218-beta-acyl-glucuronide-OH), over 8 days after first IMP administration using 
non-compartmental methods:  
o Area under the plasma concentration-time curve during the dosing interval 
(AUCτ) = AUC during the first 48 hours after dosing (AUC0-48h) after each 
administration (i.e. AUC0-48h and AUC48-96h);  
o AUC from 48 hours after dosing to infinity (AUC48h-inf), calculated from 
AUC48h-t + (Ct/λz), where Ct is the last observed quantifiable 
concentration and λz the first order terminal rate constant;  
o AUC calculated between 48 hours after dosing and last quantifiable 
concentration (AUC48h-last); 
o Total plasma clearance (CL/F) and apparent volume of distribution (Vz/F) 
after the second administration (not for metabolites); 
o Cmax and the time to reach the maximum concentration after drug 
administration (tmax) after each administration; 
o The terminal elimination half-life (t1/2) after the second administration; 
o The accumulation ratio (Rac), calculated as AUC48-96h/AUC0-48h; 
o Metabolic ratio of AUCτ and AUC48h-inf for P218 β-acyl glucuronide, 
P218-OH and P218-OH β-acyl glucuronide over parent P218 (Cohort 1 
only). 
- 
The minimal inhibitory concentration of P218 needed for chemoprotective 
activity will be predicted from the P218 PK/PD model; 
- 
The incidence, severity and relationship to P218 of observed or self-reported, 
TEAEs during the 35-day observation period with PfSPZ Challenge (Cohorts 2 
and 3 only); 
- 
The incidence and severity of observed (i.e. Malaria signs and symptoms graded 
by the Malaria clinical score; see Attachment 1) or self-reported inoculum-related 
events and adverse events (AEs) considered PfSPZ Challenge-related (Cohorts 2 
and 3 only);  
- 
The Malaria clinical score at the time of introduction of rescue therapy (Cohorts 2 
and 3 only); 
- 
Changes from baseline in folate levels, haematology, clinical chemistry and 
urinalysis parameters, vital signs and ECG parameters. 


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3. STUDY DESIGN 
3.1 
OVERVIEW OF STUDY DESIGN 
This is a single centre, randomised, double-blind, placebo-controlled Phase Ib study. 
Thirty-two healthy men and women aged 18 to 45 years will be enrolled in 3 cohorts of 
8, 12 and 12 subjects. A subject may be enrolled in one cohort only and will be 
randomised in a 3:1 ratio, to receive two consecutive administrations of either P218 or 
placebo. Enrolment in cohorts will proceed sequentially, to facilitate review of Cohort 1 
and Cohort 2 data by an SRT before populating Cohort 2 and Cohort 3, respectively. 
Cohort 1 
Cohort 1 will consist of 2 subgroups of subjects, to be enrolled sequentially: subgroup 1 
will be composed of 2 subjects: one to receive two 1000 mg doses of P218 48 hours apart 
and one to receive placebo; subgroup 2 will be composed of 6 subjects: five to receive 
two 1000 mg doses of P218 48 hours apart and one to receive placebo. Subjects in 
subgroup 2 will not be treated until 24 hours after second IMP administration in the last 
subject of subgroup 1 and only upon decision of the PI after review of available safety 
data of subgroup 1. 
Subjects will be admitted to the clinical unit in the morning of Day -1 and will be 
confined to the unit for 3 days thereafter (until Day 4, i.e. 36 hours after second IMP 
administration), for close safety monitoring and PK assessments. First administration of 
1000 mg of P218 or placebo will take place on Day 1. Second administration of 1000 mg 
of P218 or placebo will take place 48 hours later, on Day 3. After discharge from the 
clinical unit on Day 4, subjects will be followed up with daily ambulatory visits to the 
clinical unit up to Day 9. 
A schematic overview of the study design of Cohort 1 is shown in Figure 1. The 
assessments performed are summarized per visit in the Time and Events Schedule. 
Figure 1: 
Schematic Overview of the Study Design for Cohort 1 
 
Progression to Cohort 2 will be assessed by an SRT, who will review safety and 
tolerability after data up to Day 9 for Cohort 1 are available (see Section 5.8.1).  


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Cohorts 2 and 3 
Cohort 2 will consist of three subgroups of subjects, to be enrolled sequentially: 
subgroup 1 will be composed of 2 subjects: one to receive two 1000 mg doses of P218 
48 hours apart and one to receive placebo; subgroups 2 and 3 will be composed of 
5 subjects each: four to receive two 1000 mg doses of P218 48 hours apart and one to 
receive placebo. Subjects in subgroup 2 will not be inoculated until 24 hours after second 
IMP administration in the last subject of subgroup 1. In subgroup 2 and subgroup 3, 
subjects will only be inoculated upon decision of the PI after review of available safety 
data of the previous subgroup, i.e. subgroup 1 and subgroup 2, respectively. 
Cohort 3 will consist of two subgroups, each with 6 subjects, to be enrolled sequentially. 
Treatment will be allocated in a ratio of 3 active to 1 placebo. In each subgroup, at least 
1 subject will receive placebo and the remaining subjects will receive two 100 mg doses 
of P218 48 hours apart. Subjects in subgroup 2 will not be inoculated until 24 hours after 
second IMP administration in the last subject of subgroup 1. 
Subjects will be admitted to the clinical unit in the morning of Day -1 and will be 
confined to the unit until 12 days post the PfSPZ Challenge on Day 1 (i.e. until Day 13), 
for close safety monitoring and PK assessments. Each subject will be administered 
3,200 P. falciparum sporozoites by DVI. First administration of P218 or placebo will 
take place 2 hours after PfSPZ Challenge inoculation. Second administration of P218 or 
placebo will take place 48 hours after first administration of P218 or placebo, on Day 3.  
Safety, parasitaemia (see Section 2.2.1 for definition) and Malaria signs and symptoms 
(Malaria clinical score; see Attachment 1) will be assessed as of Day 7, i.e. during 
confinement in the unit until Day 13 and on daily ambulatory visits to the clinical unit as 
of Day 14, until development of positive parasitaemia or until Day 28 otherwise. If 
positive parasitaemia is confirmed, the subject will receive rescue therapy (see 
Section 5.2) and will continue to be monitored daily at the clinical unit until treatment 
success. Upon treatment success, daily visits to the clinical unit are stopped, except for 
subjects that first need to complete the 3-day rescue treatment regimen and associated 
assessments. All subjects will be assessed again for parasitaemia at the end-of-study 
(EOS) visit on Day 35. Subjects not developing positive parasitaemia until Day 28 will 
receive rescue therapy on that day. Instead of daily monitoring at the clinical unit until 
treatment success, these subjects will only be assessed again for parasitaemia at the EOS 
visit on Day 35. All subjects that receive rescue therapy will be asked non-leading 
questions to determine the occurrence of any AEs approximately two weeks after 
initiation of the rescue treatment, either during a planned study visit or by phone in case 
there is no planned study visit at that time. 
Antimalarial rescue therapy (see Section 5.2) may be initiated whenever deemed 
necessary by the Investigators, e.g. if there is a concern regarding the safety of a study 
subject or if a study subject decides to withdraw from the study. Therapy may be 
amended according to the treating physician if the patient does not respond to treatment 
or the condition worsens. 
A schematic overview of the study design of Cohorts 2 and 3 is shown in Figure 2. The 
assessments performed are summarized per visit in the Time and Events Schedule. 


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Figure 2: 
Schematic Overview of the Study Design for Cohorts 2 and 3 
 
Progression to Cohort 3 will be assessed by the SRT, who will review safety, 
parasitaemia and Malaria signs and symptoms after data up to Day 35 for Cohort 2 are 
available, or after successful completion of the last rescue treatment, whichever is later 
(see Section 5.8.2).  
3.2 
DISCUSSION OF STUDY DESIGN 
Dose Selection 
Based on an in vitro experiment, P218 was expected to be active against P. falciparum 
infected hepatocytes from 48 hours onwards after incubation (Figure 3).  


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Figure 3: 
Incubation of P. falciparum infected hepatocytes with 100nM P218 at indicated time 
intervals (figure on the left), and % of remaining infected hepatocytes per time interval 
incubation (figure on the right). 
In new in vitro experiments, the activity window of P218 was re-evaluated in 
P. falciparum (NF175) infected hepatocytes. The results depicted in Figure 4 suggest that 
P218 inhibits all stages of intra-hepatocytic development, from 3 hours onwards, post 
addition of sporozoites to the primary liver cells. 
 
Figure 4: 
Activity window of P218 at different time intervals during infection and maturation of 
P. falciparum (NF175) infected hepatocytes. 
In the completed FIH study with P218 conducted in the UK 
(MMV_P218_15_01/C16009), the highest dose tested was 1000 mg. The highest dose 
tested was considered safe and well tolerated and was associated with mean Cmax and 
AUC0-inf values of 8.64 μg/ml and 17.8 μg∙h/ml, respectively. That provided an exposure 
margin of 4.0-fold to the protocol defined stopping criteria of 71.9 μg∙h/ml based on total 
cumulative AUC0-336h observed in the most sensitive species (dog). The single oral dose 
of 1000 mg of P218 was associated with a mean elimination half-life of 19.6 h, which is 
too short to allow for weekly or monthly oral dosing in a chemo-protection setting. Thus, 


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if proof of pharmacology is achieved in this human malaria challenge model, i.e. P218 
activity against P. falciparum infection is clinically demonstrated, a long acting 
injectable depot formulation will be considered, allowing for slow-blood-release of P218 
over at least one week and preferably, over one month following single injection [1]. 
Antimalarial efficacy against the blood stage P. falciparum has also been evaluated in a 
validated mouse model (Humanized SCID mouse) with established ED90 dose of 
1.6 mg/kg/day and derived MPC and MIC of 4.4 ng/ml and 1.3 ng/ml, respectively. A 
human dose that could maintain blood concentrations above MIC was identified as a 
target minimal efficacious dose for chemo-protection against P. falciparum malaria. 
Using this approach and observed human PK in the completed FIH study, it was 
concluded that using the currently available oral formulation of P218, a human dose of 
1000 mg would be needed to maintain in human subjects P218 plasma concentrations 
above the target mouse blood MIC. Based on P218 PopPK model simulations, two single 
doses of 1000 mg of P218 administered 48 hours apart would be needed in order to 
maintain P218 plasma concentrations above the target mouse blood MIC for a sufficient 
period of time during the P. falciparum liver stage to properly address the P218 
chemoprotection against P. falciparum malaria proof of pharmacology (Figure 5) [14]. 
 
Figure 5: 
Simulations of the P218 plasma concentration over time following the oral 
administration of two single doses of 1000 mg of P218 when administered 48 hours 
apart on Day 1 and Day 3 using a Population PK model. 
For the evaluation of the administration of two single doses of 1000 mg of P218 
administered 48 hours apart, PopPK simulations predict that no accumulation of the 


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parent and major metabolites will occur and similar exposures to those associated with a 
1000 mg single dose of P218 will be achieved (Table 1).  
Table 1: 
Simulation of P218 and its Major Metabolites PK Parameters in Plasma After the 
Administration of Two Single Doses of 1000 mg of P218 Administered 48 Hours Apart 
Using a PopPK Model 
Moiety 
Parameter 
Median 
90% C.I. 
P218 
AUC0-48h (ug/L.h) 
15708 
[10997; 22495] 
 
AUC48-96h (ug/L.h) 
15798 
[11082; 22599] 
 
AUC48-96h/AUC0-48h 
1.00 
[1.00; 1.01] 
 
AUC48h-inf (ug/L.h) 
15978 
[11170; 22790] 
P218 β acyl 
glucuronide 
AUC0-48h (ug/L.h) 
28101 
[16680; 47373] 
AUC48-96h (ug/L.h) 
28257 
[16805; 47585] 
 
AUC48-96h/AUC0-48h 
1.00 
[1.00; 1.01] 
 
AUC48h-inf (ug/L.h) 
28510 
[16957; 48064] 
 
AUC0-48h/AUC0-48h,P218 
1.80 
[1.22; 2.60] 
 
AUCinf/AUCinf,P218 
1.80 
[1.22; 2.60] 
P218-OH β acyl 
glucuronide 
AUC0-48h (ug/L.h) 
24061 
[14118; 40130] 
AUC48-96h (ug/L.h) 
24294 
[14266; 40507] 
AUC48-96h/AUC0-48h 
1.01 
[1.00; 1.02] 
 
AUC48h-inf (ug/L.h) 
24755 
[14546; 41210] 
 
AUC0-48h/AUC0-48h,P218 
1.54 
[1.02; 2.24] 
 
AUCinf/AUCinf,P218 
1.55 
[1.03; 2.25] 
P218-OH 
AUC0-48h (ug/L.h) 
1520 
[937; 2490] 
 
AUC48-96h (ug/L.h) 
1557 
[961; 2540] 
 
AUC48-96h/ AUC0-48h 
1.02 
[1.02; 1.03] 
 
AUC48h-inf (ug/L.h) 
1611 
[990; 2625] 
 
AUC0-48h/AUC0-48h,P218 
0.10 
[0.07; 0.14] 
 
AUCinf/AUCinf,P218 
0.10 
[0.07; 0.14] 
Cmax values are available in the PopPK report [14]. 
For P218 AUC cap: 71.9 µg•h/mL. 
Therefore, the administration of two single doses of 1000 mg of P218 administered 
48 hours apart was considered a safe dosing regimen of P218 to be evaluated in this 
clinical trial. However, since P218 oral single doses were assessed in the FIH study, the 
safety, tolerability and PK profile of 2 consecutive doses of 1000 mg of P218 
administered 48 hours apart under fasted conditions will be characterized in Cohort 1. 
Then, for the second cohort of healthy men and women evaluating P218 as possible 
chemo-protective agent against P. falciparum, the most relevant dosing regimen with the 
currently available oral formulation was PfSPZ inoculation on Day 1 and administration 
of a 1000 mg oral dose of P218 under fasted conditions on Day 1 and Day 3. 
Preliminary Cohort 2 data show that 3 subjects had breakthrough parasitaemia between 
Days 8 and 12, and 9 subjects had no positive parasitaemia, as assessed by PCR 
monitoring, up to Day 28. Although data are still blinded, these results suggest that there 
is no breakthrough in subjects treated with P218, if one assumes that the three subjects 
with positive parasitaemia received placebo, leading to conclude that P218 has 
chemoprotective activity. The new in vitro results are in good alignment with what was 
observed in Cohort 2. 
Based on P218 PopPK model simulations, two single doses of 100 mg of P218 
administered 48 hours apart on D1 and D3 would allow to better document the lowest 
efficacious exposure of P218. As shown in Figure 6, this regimen would maintain P218 


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plasma concentrations above the target mouse blood MIC for 24 hours after each P218 
administration. This PK profile is expected to be associated with positive PCR in some 
subjects treated with active drug which will support a better estimation of the minimal 
inhibitory exposure of P218 required for liver activity.  
 
Figure 6: 
Population PK simulations of 1000 cohorts of 9 patients each with an administration of 
2 single doses of 100 mg P218 at 100 mg administered 48 hours apart. 


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Table 2: 
Simulation of P218 and its Major Metabolites PK Parameters in Plasma After the 
Administration of Two Single Doses of 100 mg of P218 Administered 48 Hours Apart 
Using a PopPK Model 
Moiety 
Parameter 
Median 
90% C.I. 
P218 
AUC0-48h (ng/mL.h) 
1556 
[1085; 2240] 
 
AUC48-96h (ng/mL.h) 
1565 
[1090; 2251] 
 
AUC48h-last (ng/mL.h) 
1578 
[1098; 2270] 
 
AUC48h-inf (ng/mL.h) 
1581 
[1099; 2273] 
 
AUCinf (ng/mL.h) 
3135 
[2187; 4516] 
 
Cmax D1 (ng/mL) 
742 
[429; 1195] 
 
Tmax D1 (h) 
1 
[0.5; 2.4] 
 
Cmax D3 (ng/mL) 
743 
[430; 1195] 
 
Tmax D3 (h) 
49 
[48.5; 50.4] 
P218 β acyl 
glucuronide 
AUC0-48h (ng/mL.h) 
153 
[93; 249] 
AUC48-96h (ng/mL.h) 
157 
[95; 255] 
 
AUC48h-last (ng/mL.h) 
162 
[98; 262] 
 
AUC48h-inf (ng/mL.h) 
162 
[99; 262] 
 
AUCinf (ng/mL.h) 
315 
[192; 512] 
 
Cmax D1 (ng/mL) 
32 
[19; 54] 
 
Tmax D1 (h) 
2.2 
[1.8; 3.2] 
 
Cmax D3 (ng/mL) 
33 
[19; 54] 
 
Tmax D3 (h) 
50.2 
[49.8; 51.2] 
P218-OH β acyl 
glucuronide 
AUC0-48h (ng/mL.h) 
2416 
[1420; 4031] 
AUC48-96h (ng/mL.h) 
2442 
[1434; 4075] 
AUC48h-last (ng/mL.h) 
2480 
[1458; 4140] 
 
AUC48h-inf (ng/mL.h) 
2484 
[1459; 4145] 
 
AUCinf (ng/mL.h) 
4899 
[2878; 8180] 
 
Cmax D1 (ng/mL) 
810 
[434; 1465] 
 
Tmax D1 (h) 
1.3 
[0.9; 2.6] 
 
Cmax D3 (ng/mL) 
811 
[434; 1467] 
 
Tmax D3 (h) 
49.3 
[48.9; 50.6] 
P218-OH 
AUC0-48h (ng/mL.h) 
2797 
[1618; 4710] 
 
AUC48-96h (ng/mL.h) 
2813 
[1631; 4736] 
 
AUC48h-last (ng/mL.h) 
2836 
[1648; 4778] 
 
AUC48h-inf (ng/mL.h) 
2840 
[1651; 4787] 
 
AUCinf (ng/mL.h) 
5637 
[3269; 9484] 
 
Cmax D1 (ng/mL) 
1191 
[648; 2064] 
 
Tmax D1 (h) 
1.2 
[0.8; 2.5] 
 
Cmax D3 (ng/mL) 
1192 
[649; 2064] 
 
Tmax D3 (h) 
49.2 
[48.8; 50.5] 
Therefore, for the third cohort of healthy men and women evaluating P218 as possible 
chemo-protective agent against P. falciparum, the most relevant dosing regimen with the 
currently available oral formulation was PfSPZ inoculation on Day 1 and administration 
of a 100 mg oral dose of P218 under fasted conditions on Day 1 and Day 3. 
Placebo Control 
Placebo control will be used to establish the frequency and magnitude of changes in 
clinical endpoints that may occur in the absence of active treatment. Note that this is also 
used to confirm “infectivity” of the PfSPZ inoculation, i.e. sort of internal validation of 
the inoculum (for a situation where all the subjects treated with P218 would be protected, 
one could question the “infectivity” of the inoculum). 


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Randomization and Blinding 
Randomisation will be used to avoid bias in the assignment of subjects to treatment, to 
increase the likelihood that known and unknown subject attributes (e.g. demographic and 
baseline characteristics) are evenly balanced across cohorts and treatment groups, and to 
enhance the validity of statistical comparisons across cohorts and treatment groups. 
Blinded treatment will be used to reduce potential bias during data collection and 
evaluation of clinical endpoints. 


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4. SELECTION OF STUDY POPULATION 
Screening for eligible subjects will be performed within approximately 4 weeks prior to 
randomisation and up to Day -2. 
Approximately 32 subjects are planned to be enrolled in one of 3 cohorts of 8, 12 and 
12 subjects. A subject may be enrolled in one cohort only. Subjects will be randomised 
within each cohort in a 3:1 ratio to receive two consecutive administrations of either 
P218 or placebo. 
For details on the sample size calculation, please refer to Section 9.2. 
4.1 
INCLUSION CRITERIA 
Subjects meeting all of the following criteria are eligible to participate in this study: 
1. Informed Consent Form signed voluntarily before any study-related procedure is 
performed, indicating that the subject understands the purpose of and procedures 
required for the study and is willing to participate in the study, including 
administration of rescue treatment. 
2. Male or female, between 18 and 45 years old (extremes included) at screening. 
3. Body weight of at least 50 kg and a body mass index (BMI) of 19 to 30 kg/m2 
(extremes included).  
4. Good general health without clinically relevant medical illness, physical exam 
findings including vital signs, and laboratory abnormalities as determined by the 
investigator. 
5. Willing to adhere to the prohibitions and restrictions (see Section 4.3) specified in 
this protocol, including willingness to stay confined to the inpatient unit for 
required duration and willingness to avoid to travel outside of Benelux during the 
study period. 
6. Female subjects should fulfil one of the following criteria: 
a. At least 1 year post-menopausal (amenorrhea >12 months and 
follicle-stimulating hormone (FSH) >30 mIU/mL) prior to screening; 
b. Surgically sterile (bilateral oophorectomy, hysterectomy or tubal ligation); 
c. Will use contraceptives as outlined in inclusion criteria 7 and 8. 
7. Female subjects of childbearing potential must agree to the use of a highly 
effective method of birth control from screening visit to until 40 days after the 
last dose of IMP (covering a full menstrual cycle of 30 days starting after 5 half-
lives of last dose of IMP). 
Note: Highly effective birth control methods include: combined (estrogen and progestogen 
containing) oral/intravaginal/transdermal hormonal contraception associated with inhibition of 
ovulation, progestogen-only oral/injectable/implantable hormonal contraception associated with 
inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal 
occlusion, vasectomised partner or sexual abstinence. 
8. Male subjects who are sexually active with a female partner of childbearing 
potential must agree to the use of an effective method of birth control from the 
day of the first IMP dose until 100 days thereafter (covering a full sperm cycle of 
90 days starting after 5 half-lives of last dose of IMP). 
Note: Medically acceptable methods of contraception that may be used by the subject and/or 
partner include sterilization and vasectomy or a double barrier option combining oral 


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contraceptive, contraceptive vaginal ring, contraceptive injection, intrauterine device or 
etonogestrel implant. 
9. Female subject has a negative pregnancy test at screening and upon admission in 
the clinical unit. 
Note: Pregnancy testing will consist of a serum β-human chorionic gonadotropin (β-HCG) test at 
screening and urine β-HCG tests at other visits, in all women. 
Inclusion Criteria - CHMI specific: 
10. Different ways of being reachable 24/7 (e.g. by mobile phone, regular phone or 
electronic mail) during the whole study period. 
4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria are excluded from participation in this 
study: 
1. Nursing (lactating) women. 
2. Participation in any other clinical drug or vaccine study within 30 days (or five 
half-lives for drugs) preceding the first dose of IMP (whichever is longer), or 
plans to participate in other investigational drug or vaccine research during the 
study period. 
3. Blood product donation to any blood bank during the 8 weeks (whole blood) or 
4 weeks (plasma and platelets) prior to admission in the clinical unit. 
4. ECG outside normal range and deemed clinically relevant by the investigator. 
Examples of clinically significant ECG abnormalities for this study include: 
a. PR-interval >220 ms; 
b. QRS-complex >120 ms; 
c. QT interval corrected according to Bazett’s formula (QTcB) or QT interval 
corrected according to Fridericia’s formula [3] (QTcF) >450 ms; 
d. Pathologic Q wave; 
e. Significant ST-T wave changes; 
f. Left or right ventricular hypertrophy; 
g. Non-sinus rhythm except isolated premature atrial contractions and 
ventricular extrasystole <2 per 10 s ECG lead; 
h. Incomplete left bundle branch block, or complete or intermittent right or left 
bundle branch block; 
i. Second or third degree A-V heart block. 
5. Seropositive human immunodeficiency virus (HIV) (antibody and antigen), 
hepatitis B virus (HBV) (hepatitis B surface antigen [HBsAg]) or hepatitis C 
virus (HCV) (antibody) tests.  
6. History or presence of diagnosed food or known drug allergies (including but not 
limited to allergy to any of the antimalarial rescue medications to be used in the 
study, see Section 5.2), or history of anaphylaxis or other severe allergic 
reactions. 
Note: Subjects with seasonal allergies/hay fever, house dust mite or allergy to animals that are 
untreated and asymptomatic at the time of dosing can be enrolled in the study. 
7. History of convulsion or severe head trauma. 
Note: A medical history of a single febrile convulsion during childhood is not an exclusion criteria. 


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8. History of serious psychiatric condition that may affect participation in the study 
or preclude compliance with the protocol, including but not limited to past or 
present psychoses, disorders requiring lithium, a history of attempted or planned 
suicide, more than one previous episode of major depression, any previous single 
episode of major depression lasting for or requiring treatment for more than 
6 months, or any episode of major depression during the 5 years preceding 
screening. 
Note: The Beck Depression Inventory (Attachment 2) will be used as an objective tool for the 
assessment of depression at screening. In addition to the conditions listed above, subjects with a 
score of 20 or more on the Beck Depression Inventory and/or a response of 1, 2 or 3 for item 9 of 
this inventory (related to suicidal ideation) will not be eligible for participation. Subjects with a 
Beck score of 17 to 19 may be enrolled at the discretion of the Investigator if they do not have a 
history of the psychiatric conditions mentioned in this criterion and their mental state is not 
considered to pose additional risk to the health of the volunteer or to the execution of the study 
and interpretation of the data gathered. 
9. A medical, occupational or family problem as a result of alcohol or illicit drug 
abuse during the past 12 months or current alcohol or illicit drug abuse or 
addiction (positive alcohol breath test or positive drug screen for amphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine or opiates at screening or 
upon check-in at the clinical unit). 
Note: Excessive use of alcohol is an intake of >21 units per week for males and >14 units per 
week for females where one alcohol unit is defined as 10 mL or 8 g of pure alcohol. A single unit 
is equal to one 25-mL (single) measure of whisky (alcohol by volume [ABV] 40%), or a third of a 
pint of beer (190 mL; ABV 5-6%) or half a standard (175 mL) glass of wine (ABV 12%). 
10. 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. 
11. Use of any prescription drugs, herbal supplements (e.g. St John’s Wort) or 
over-the-counter medication within 7 days or five half-lives (whichever is longer) 
prior to the first IMP administration, or an anticipated requirement for the use of 
these during the course of the study (See Section 6.2). 
Note: If necessary, the incidental use of non-steroidal anti-inflammatory drugs (NSAIDs), 
paracetamol (2g/day, 10 gr/week), vitamins and topical treatments may be acceptable after 
approval by the study Sponsor and will be documented in the eSource system. The use of 
nutritional supplements during this time that are not believed to have the potential to affect subject 
safety nor the overall results of the study, may be permitted on a case-by-case basis following 
approval by the Sponsor in consultation with the Investigator. 
12. Any surgical or medical condition possibly affecting drug absorption (e.g. 
cholecystectomy, gastrectomy, bowel disease), distribution, metabolism or 
excretion. 
13. Any history of gallbladder disease, including cholecystitis and/or cholelithiasis. 
14. History of megaloblastic anaemia or folate deficiency. 


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15. Personnel (e.g. investigator, sub-investigator, research assistant, pharmacist, study 
coordinator or anyone mentioned in the delegation log) directly involved in the 
conduct of the study. 
16. Any condition that in the opinion of the investigator would jeopardize the safety 
or rights of a person participating in the trial or would render the person unable to 
comply with the protocol. 
Exclusion Criteria - CHMI specific: 
17. Glucose-6-phosphate dehydrogenase (G6PD) deficiency (due to possible 
hemolysis induced by primaquine treatment at study end in G6PD deficient 
subjects). 
18. Personal history of malaria. 
19. Volunteer has travelled to or lived in a malaria-endemic area for more than 
4 weeks during the 12 months prior to first IMP administration, or spent any time 
in an endemic area during the 4 weeks prior to first IMP administration. 
20. Plans to travel to malaria-endemic region during the study period up to last 
follow-up visit. 
21. Previous participation in any malaria vaccine or CHMI study. 
22. Falling in moderate or higher risk category for a fatal or non-fatal cardiovascular 
event within 10 years (≥5%) determined by a validated risk estimation system e.g. 
SCORE [13]. 
23. Use of medications known to interact with atovaquone-proguanil (Malarone®), 
artemether-lumefatrine (Riamet®) or primaquine (Primaquine®) such as 
cimetidine, metoclopramide or antacids, or an anticipated requirement for the use 
of these at any point during the study period (see Section 6.2). 
24. Use of systemic antibiotics with known antimalarial activity within 30 days (or 
5 half-lives whichever is longer) of first IMP administration (e.g. 
trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, 
erythromycin, fluoroquinolones or azithromycin) or an anticipated requirement 
for the use of these during the study period (see Section 6.2). 
25. Receipt of blood or blood-derived products (including immunoglobulin) within 
3 months prior to screening. Receipt of packed red blood cells given for an 
emergent indication in an otherwise healthy person, and not required as ongoing 
treatment is not exclusionary (for example packed red blood cells emergently 
given during an elective surgery). 
Note: In case of an out-of-range clinical laboratory test, vital sign or ECG value that will determine a 
subject’s eligibility, or in case of a positive drug screen, a retest or expert evaluation can be requested. 
Results of any retest must be available prior to inoculation. The result of the retest will be considered 
for subject eligibility at the investigator’s discretion. Subjects can be rescreened at the discretion of the 
investigator. 


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4.3 
ADDITIONAL CONSTRAINTS 
Subjects will have to comply with the following restrictions: 
Meals and Dietary 
1. Safety clinical laboratory blood tests will be performed after fasting for at least 
8 hours. 
2. IMP will be administered after fasting for at least 8 hours. Water is restricted 
from 1 hour predose and is allowed ad libitum as of 2 hours post dose. Snacks are 
allowed from 2 hours post dose and a meal can be taken 4 hours after dosing.  
3. During confinement in the clinical unit, no food intake in addition to the standard 
meals and snacks provided by the study personnel will be allowed. 
4. Subjects will abstain from xanthine-containing food or beverages (e.g. coffee, tea, 
cola, chocolate) from 24 hours prior to screening and 24 hours prior to the first 
IMP administration until collection of the last PK sample.  
5. Subjects will abstain from energy drinks containing taurine or glucuronolactone 
from 24 hours prior to screening and from 24 hours prior to the first IMP 
administration until collection of the last PK sample.  
6. Subjects will abstain from drinking alcohol from 24 hours prior to screening and 
24 hours prior to the first IMP administration until collection of the last 
PK sample.  
7. Subjects will abstain from eating or drinking grapefruit or grapefruit-related citrus 
fruits (e.g. Seville oranges, pomelos) from 30 days prior to the first IMP 
administration and for the whole duration of the study. 
8. Ban of transplantation until successful rescue. 
Activity 
9. Subjects will be confined from Day -1 in the morning to Day 4 (i.e. 36 hours after 
second IMP administration) in Cohort 1 and from Day -1 in the morning to 
12 days post the PfSPZ Challenge on Day 1 in Cohorts 2 and 3, unless they are 
withdrawn from the study.  
10. Authorization to leave the clinical unit will be given by the Investigator. 
11. Subjects will abstain from smoking a tobacco product or marijuana from 24 hours 
prior to the first IMP administration until end of confinement. 
12. Subjects will abstain from any strenuous activity (e.g. weight lifting, aerobics, 
football, endurance training sessions) or unaccustomed physical exercise from 
48 hours prior to screening and from 48 hours prior to the first IMP 
administration until collection of the last PK sample. 
Other 
13. Information on prohibited therapies can be found in Section 6.2. 
 


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5. TREATMENT(S) 
Manufacturing, packaging and labelling of P218/placebo (IMP) and PfSPZ Challenge 
incoculum will be done under the responsibility of the Sponsor and the biotechnology 
company Sanaria (USA) [6,7], respectively. 
5.1 
PHYSICAL DESCRIPTION OF THE IMP 
5.1.1 
P218/placebo 
P218 and placebo capsules are prepared in accordance with Good Manufacturing 
Practice (GMP) and supplied by the Sponsor as bulk to the pharmacy of the clinical unit, 
including batch certificates, as: 
- 
P218, 50 mg and 250 mg capsules for oral administration; 
- 
Placebo to match P218 capsules for oral administration. 
Blinded treatment regimens for each subject will be prepared at the pharmacy of the 
clinical unit. Please refer to the Dispensing Protocol for further details. 
Due to the favourable physicochemical properties of P218, the active pharmaceutical 
ingredient (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 50 mg or 250 mg of P218. 
P218 capsules (50 mg 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 IB [6] and in the Investigational Medicinal Product 
Dossier (IMPD) [8]. 
Placebo capsules will be used for the purpose of the clinical trial. To preserve blinding, 
placebo capsules will be matched to the drug product with regard to appearance and 
taste. They are contained in the same packaging as the drug product. 
5.1.2 
PfSPZ Challenge 
The PfSPZ Challenge consists of aseptic, cryopreserved P. falciparum sporozoites used 
for CHMI trials and is produced by the biotechnology company, Sanaria (USA) [7]. 
In brief, the manufacturing process includes the production, under traditional 
environmental condition, of eggs from a colony of A. stephensi mosquitos housed in a 
controlled environmental chamber. Surface disinfection of the eggs is performed by 
exposure to chemical agents in a Class II biosafety cabinet (BSC). Thereafter, all 
materials and product are handled using aseptic methods to ensure that contaminating 
microorganisms are not introduced to, and carried through, the process. 
Surface-disinfected eggs are inoculated into sterile, vented flasks containing aseptic 
growth medium. The eggs hatch and develop into pupae, which are transferred to an 
adult mosquito container from which the adult mosquitoes emerge.  
These adult mosquitos, which have been raised under aseptic conditions, are fed 
P. falciparum gametocyte-infected blood in a BSC in a high-security insectary in 
Rockville, Maryland, USA. The P. falciparum gametocyte-infected blood is produced 


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from cultures of the P. falciparum strain NF54, derived from a master cell bank of the 
well characterised P. falciparum strain NF 54. Infected adult mosquitos are maintained 
under aseptic conditions until P. falciparum sporozoites migrate to the salivary glands. 
The salivary glands from the P. falciparum sporozoite infected mosquitos are removed 
by hand dissection and then triturated to release the P. falciparum sporozoites.  
The sporozoites are purified, counted, and at a specified concentration, cryopreserved. 
Cryopreservation commences with the addition of cryoprotective additives to the purified 
sporozoites to produce the PfSPZ Challenge product. 
The diluent for PfSPZ Challenge is composed of phosphate buffered saline (PBS) and 
human serum albumin (HSA). Vials of PBS and HSA will be shipped to the clinical unit, 
where diluent composed of PBS and HSA is prepared according to a local Standard 
Operational Procedure, as described in the Laboratory Manual of Sanaria (Storage, 
Preparation and Administration of PfSPZ Challenge).  
PBS that is manufactured in compliance with GMP and according to upstream processing 
specifications is purchased by Sanaria. Every lot of PBS is supplied with a batch 
certification that is reviewed and approved upon receipt of Sanaria. The PBS is stored at 
ambient temperature in a controlled room.  
HSA (25%), approved for parenteral, intravenous administration to humans, is purchased 
by Sanaria. Every lot of HSA is supplied with a Certificate of Analysis that is reviewed 
and approved upon receipt of Sanaria. HSA vials are stored at ambient temperature in a 
controlled room. 
The PfSPZ Challenge is stored in liquid nitrogen vapour phase at -140°C to -196°C until 
it is shipped to the clinical study unit. Shipment is in compliance with U.S. Food and 
Drug Administration (FDA), U.S. Department of Transportation and United Nations 
transport guidelines for shipping bio-hazardous materials on dry ice and liquid or vapour 
phase nitrogen.  
5.2 
ANTIMALARIAL RESCUE MEDICATION  
The clinical unit will be responsible for acquiring the anti-malarial drugs, Riamet®, 
Malarone® and Primaquine®: 
- 
Subject will be prescribed with Riamet® (20 mg artemeter and 120 mg 
lumefantrine) to ensure parasite clearance prior to the end-of-study evaluation. 
Tablets for oral use will be taken over 3 days. The first dose should be taken as 
soon as possible and should be followed by five further doses approximately 8, 
24, 36, 48 and 60 hours after the first dose. Drug administration should be 
immediately followed by a meal or drinks rich in fat (e.g. milk). 
- 
If an intolerance or contraindication to Riamet® develops, Malarone® (250 mg 
atovaquone and 100 mg proguanil hydrochloride; tablets for oral use) will be 
administered for 3 consecutive days. 
- 
To ensure complete clearance of gametocytes (a low probability event in this 
study due to early treatment at low parasitemia levels), subjects will receive a 
single dose of Primaquine® (26.4 mg primaquine phosphate equivalent to 15 mg 
primaquine base; tablets for oral use, registered product in Canada) on the first 
day of rescue treatment or on Day 28 together with the rescue treatment, for 
subjects who do not develop positive parasitaemia until this day. 


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The PfSPZ Challenge product consists of a strain P. falciparum sporozoites used for 
CHMI trials that is known to be sensitive to the rescue treatment described above [7]. 
Rescue treatment will be administered and monitored on the occasion of daily 
ambulatory visits to the clinical unit. The required anti-malarial drug intakes 36 and 
60 hours after the first dose, can be done at home. Subjects will be notified by a study 
nurse via phone/text message/e-mail when it is time for dosing and must confirm study 
drug intake. On commencement of antimalarial rescue medication, and in addition to the 
assessments described in Section 7 and the Time and Events Schedule, subjects will 
report to the clinical unit to enable the following assessments to be performed, where X0 
is the time prior to the first dose of treatment, X24 is after 1 day of treatment, X48 is after 
2 days of treatment and X72 is after completion of the rescue treatment: 
- 
Blood sampling for the following parameters (only for subjects who develop 
asexual parasitaemia): 
o Malaria parasitaemia by qPCR (X0, X24, X48 and X72 and EOS visit); 
o Malaria parasitaemia by TBS (X0, X24, X48 and X72 and EOS visit); 
o Troponin I (X48 and X72) (see Section 7.4.2) 
- 
Questioning regarding signs and symptoms of malaria and calculation of a 
malaria clinical symptom score (at all time points for subject who were treated 
for positive parasitaemia only). 
- 
Recording of adverse events and concomitant medications (all time points). 
TBS microscopy and qPCR assessments of parasitaemia will be carried out daily until 
treatment success (defined as one negative qPCR outcome for asexual parasites, i.e. 
0 parasites per mL, confirmed by TBS microscopy). Upon treatment success, daily visits 
to the clinical unit are stopped, except for subjects that first need to complete the 3-day 
rescue treatment regimen and associated assessments. All subjects will be assessed again 
for parasitaemia at the EOS visit on Day 35.  
In subjects who do not develop positive parasitaemia until Day 28 of the study, rescue 
treatment will be initiated on Day 28. Instead of daily qPCR, TBS and Troponin I 
assessments until treatment success, for these subjects only a final qPCR will be 
performed at the EOS visit on Day 35. Antimalarial rescue medication intakes can be 
done at home. Subjects will be notified by a study nurse via phone/text message/e-mail 
when it is time for dosing and must confirm study drug intake. 
All subjects that receive rescue therapy will be asked non leading questions to determine 
the occurrence of any AEs approximately two weeks after initiation of the rescue 
treatment, either during a planned study visit or by phone in case there is no planned 
study visit at that time. 
All subjects must consent to rescue treatment. Even in case of withdrawal from the study, 
all challenged subjects are to receive rescue treatment as soon as possible, including all 
appropriate visits and assessments, and phone call as required (see above). 
5.3 
PACKAGING AND LABELING 
5.3.1 
P218/placebo  
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 unit. 


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The labelling of the IMPs will be in compliance with 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 Belgian health authorities according to the 
submission requirements. 
5.3.2 
PfSPZ Challenge 
The PfSPZ Challenge product is dispensed into screw-cap vials containing 15,000 or 
50,000 sporozoites in a 20 µL aliquot. PfSPZ Challenge is stored in liquid nitrogen 
vapour phase at -140°C to -196°C. 
Transfer of PfSPZ Challenge from its storage site to the clinical unit will follow local 
Standard Operational Procedure, as described in the Laboratory Manual of Sanaria.  
At the clinical unit, the liquid nitrogen vapour phase container will be monitored. Receipt 
of the PfSPZ Challenge will be documented on a tracking log by study staff. 
5.4 
STORAGE AND DRUG ACCOUNTABILITY 
5.4.1 
P218/placebo  
The Investigator (or his/her designee) is responsible for the safe storage of all study drugs 
assigned to the clinical unit, in a locked, secure storage facility with access limited to 
those individuals authorized to dispense the study drugs, and maintained within the 
appropriate ranges of temperature. All study drugs must be stored as specified at delivery 
and in the original packaging.  
Study drugs must be stored at ambient temperature (15-30°C or 59-86°F), away from 
light. 
Regular temperature logging of the study drug storage room at the clinical unit should be 
performed. In case a deviation in storage conditions should occur, the clinical unit must 
not further dispense the affected study drug and notify the Sponsor. 
The Investigator is responsible for ensuring that all study drugs received at the clinical 
unit are inventoried and accounted for throughout the study. 
Study drugs should be dispensed under the supervision of the Investigator, a qualified 
member of the clinical staff, or by a hospital/clinic pharmacist. The Investigator must 
maintain accurate records demonstrating date and amount of drugs supplied to whom and 
by who. Study drugs will be supplied only to subjects participating in the study. 
The Sponsor’s designated site monitor will periodically check the supplies of study drugs 
held by the Investigator or pharmacist to ensure accountability and appropriate storage 
conditions of all study drugs used. 
Unused study drugs must be available for verification by the site monitor during on-site 
monitoring visits. 
After the last visit of the last subject in the study (LPLV), any unused study drug will be 
returned to the Sponsor, or destroyed at the clinical unit with the Sponsor’s written 
permission (in this case a certificate of destruction will be provided and filed in the Trial 
Master File [TMF]). 


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5.4.2 
PfSPZ Challenge Agent 
PfSPZ Challenge is stored in liquid nitrogen vapour phase at -140°C to -196°C. See also 
Section 5.3.2. 
5.5 
RANDOMIZATION AND BLINDING 
At screening, subjects receive a unique screening number using the letter S and a number 
ranging from 001 to 999. Subjects who are rescreened will be assigned a new screening 
number. 
Subjects will be assigned to 1 of 3 cohorts. Within each cohort, they will be randomised 
in a 3:1 ratio to receive two consecutive administrations of either P218 or placebo. 
Allocation of each subject to a given treatment will be described in a randomisation list 
prepared prior to study start by SGS Life Sciences Secure Data Office using SAS® 
software (SAS Institute Inc., Cary, NC, USA). 
The randomisation will be balanced using randomly permuted blocks across the 
treatment groups. 
Based on this randomisation code, the study drug will be packaged and labeled. 
Medication code numbers will be preprinted on the study drug labels and assigned as 
subjects qualify for the study and are randomly assigned to treatment. 
In agreement with the Sponsor, additional subjects may be recruited in each cohort, to 
replace discontinuations for non-safety reasons and achieve cohort sizes of 12. 
Replacement subjects will receive the number of the subject to be replaced, increased by 
100, and will be administered the same treatment.  
Blinding will be achieved with placebo identical in appearance. 
The randomisation list will be retained by SGS Life Sciences Secure Data Office until the 
end of the study (database lock). One copy of the randomisation list will be sent in a sealed 
envelope to the site pharmacist before the start of the study. Another copy will also be sent 
before the start of the study in a sealed envelope to the bioanalytical laboratory responsible 
for plasma drug determination.  
An individual disclosure envelope will be supplied to the Investigator for each subject (or 
randomisation number) and will contain the medication assignment for that subject. The 
Investigator will keep the treatment code envelopes in a locked, secure storage facility. A 
treatment code envelope can only be opened in an emergency situation where the 
Investigator considers it essential to know what treatment the subject was receiving. The 
medical monitor shall be notified promptly if a treatment code envelope is opened. It is 
recommended that the Investigator contacts the Sponsor before opening an envelope, if 
possible. The Investigator must document the date, time, and reason for the unblinding in 
the eSource system. If the code is broken by the Investigator or by someone of his/her 
clinical staff, the subject must be withdrawn from the study and must be followed as 
appropriate. If the code is broken by the Sponsor for safety reporting purposes, the subject 
may remain in the study. 
Upon completion of the study, the monitor needs to check the completeness and status of 
the envelopes and once this is done the monitor can retrieve the envelopes and have them 
destroyed. 


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5.6 
DOSE AND ADMINISTRATION 
5.6.1 
P218/placebo 
A rationale for the dose of study drug selected in this study is provided in Section 3.2. 
On each scheduled dosing (see Time and Events Schedule), subjects will take 
simultaneously 4 capsules (either placebo or a total of 1000 mg P218) p.o. in Cohorts 1 
and 2 or 2 capsules (either placebo or a total of 100 mg P218) p.o. in Cohort 3 after at 
least 8-hour fasting. After administration, a minimum of 2 hours of fasting will be 
required. 
Subjects will be asked to take the study drugs as indicated in the Time and Events 
Schedule under the supervision of the clinical staff. Study drug administration will be 
done with 240 mL of non-carbonated water and in a fasted state (overnight fast for at 
least 8 hours; intake of water will be allowed until 1 hour before the administration of the 
study drugs). After intake of the study drugs, the subjects will be asked to maintain an 
upright position for at least 15 minutes. Thereafter, they will be asked to remain seated in 
bed for 2 hours. 
Fasting conditions will be maintained for 2 hours, including drinking water that will be 
allowed from 2 hour post dose onwards (ad libitum but approximately 
1500mL/24 hours). 
For Cohort 1, a standardized snack, lunch, snack, dinner and snack will be served at 
approximately 2, 4, 8, 10 and 12 hours, respectively, after the administration of study 
drugs. For Cohorts 2 and 3, a standardized snack, lunch, dinner and snack will be served 
at approximately 2, 4, 8 and 10 hours, respectively, after the administration of study 
drugs.  
Any deviation from the treatment regimen defined in the protocol must be documented in 
the eSource system. 
5.6.2 
PfSPZ Challenge 
Immediately prior to use, PfSPZ Challenge in cryovials (each of which contains 15,000 
or 50,000 sporozoites), will be thawed individually by partial submersion of the vials for 
30 seconds in a 37°C ± 1°C water bath. Designated, trained study staff will then prepare, 
dilute (if necessary) and dispense the PfSPZ Challenge to clinical staff at the clinical unit 
according to local standard Operational Procedures and as described in the Laboratory 
Manual of Sanaria. 
The PfSPZ Challenge (3,200 P. falciparum sporozoites per subject) will be administered 
intravenously by DVI. The study staff administering the PfSPZ Challenge will wear 
gloves and eye protection. Advanced life support drugs and resuscitation equipment will 
be immediately available in the event of any subjects experiencing an anaphylactic 
reaction to the challenge. 
5.7 
TREATMENT COMPLIANCE 
To ensure treatment compliance, all study drug intakes (P218/placebo and PfSPZ 
Challenge) will be supervised by the Investigator or his/her designee. 


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5.8 
SAFETY REVIEW TEAM 
The SRT will review safety data during the study. The required data will be detailed in a 
separate study specific Safety Management Plan and will be sent to the SRT at least 
48 hours prior to an SRT meeting.  
Initially the data will be reviewed blinded, but if it is considered necessary by the SRT 
due to a safety concern, either individual subjects or the entire cohort may be unblinded 
to the SRT to enable their decision-making. Before breaking the code, the potential 
decisions and actions should be determined and documented. 
The decision of the SRT to progress or not to the next cohort will be taken in consensus 
between the members of the SRC. 
5.8.1 
For Progression From Cohort 1 to Cohort 2 
For progression from Cohort 1 to Cohort 2, the SRT members will include at least the PI 
and the MMV Medical Director (or their delegates). The MMV Project Director or 
further internal or external experts such as a clinical lead, a pharmacokineticist and/or a 
statistician may be consulted by the SRT as necessary. 
The SRT will meet after data up to Day 9 for Cohort 1 are available to review safety and 
tolerability in Cohort 1 and determine whether progression to Cohort 2 is indicated.  
Specific guidelines for toxicity rules that need to be taken into account in taking the 
decision to proceed or not with Cohort 2 are provided in Section 5.8.1.2. If no concerns 
are identified during SRT review, progression to Cohort 2 will take place.  
5.8.1.1 
DATA REQUIREMENTS FOR PROGRESSION FROM COHORT 1 TO COHORT 2 
A minimum of 168 hours post dose safety data from a minimum of 6 subjects (of which a 
minimum of 4 will have received the active compound) from Cohort 1 will be required 
for progression of the study to Cohort 2. 
Assessments of safety will be determined from AEs, vital sign parameters (temperature, 
blood pressure and heart rate), 12-lead ECGs and clinical laboratory parameters 
(hematology, coagulation, biochemistry and urinalysis). Assessments will also be 
determined from other relevant clinical tests conducted on a case-by-case basis or other 
exploratory samples, additional data that may be available at the time of review. 
5.8.1.2 
TOXICITY RULES  
For the purpose of this protocol, toxicity means clinically significant and at least possibly 
drug-related AE(s). An overview of rules to guide progression to Cohort 2 based on 
observed toxicities in Cohort 1 is provided in Table 3. 


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Table 3: 
Group Toxicity Rules for Progression From Cohort 1 to Cohort 2. 
 
Number of 
subjects 
Toxicity Rules for progression to Cohort 2 
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 Cohort 2 on hold 
until results of full dosing 
regimen of Cohort 1 are 
available, to which toxicity rules 
will be applied. Progression can 
then proceed, unless the data 
meet suspension rules in which 
case a substantial amendment is 
required.  
 
≥3 
≥4 
Yes 
Progression to Cohort 2 requires 
substantial amendment. 
 
N/A 
1 
No 
Progression to Cohort 2 on hold 
until results of full dosing 
regimen of Cohort 1 are 
available, to which toxicity rules 
will be applied. Progression can 
then proceed, unless the data 
meet suspension rules in which 
case a substantial amendment is 
required. 
 
N/A 
≥2 
No 
Progression to Cohort 2  
requires substantial amendment. 
3 
Severe 
Not serious 
N/A 
1 
Yes 
Progression to Cohort 2 on hold 
until results of full dosing 
regimen of Cohort 1 are 
available, to which toxicity rules 
will be applied. Progression can 
then proceed, unless the data 
meet suspension rules in which 
case a substantial amendment is 
required. 
 
N/A 
≥2 
Yes 
Progression to Cohort 2 requires 
substantial amendment. 
 
N/A 
≥1 
No 
3 
Severe 
Serious 
N/A 
≥1 
N/A 
4 or 5 
Life-
threatening or 
death -related 
Serious 
N/A 
≥1 
N/A 
Study suspended. 
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. 


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5.8.2 
For Progression From Cohort 2 to Cohort 3 
For Cohort 2, the SRT members will include at least the PI, the MMV Medical Director 
and an infectious diseases physician with expertise in malaria (or their delegates). The 
MMV Project Director or further internal or external experts such as a clinical lead, a 
pharmacokineticist and/or a statistician may be consulted by the SRT as necessary. 
The SRT will review safety, parasitaemia and malaria signs and symptoms data during 
the study. The SRT will meet after the completion of all Day 35 assessments in Cohort 2 
or after successful completion of the last rescue treatment, whichever is later, to review 
safety, parasitaemia and malaria signs and symptoms data in Cohort 2 and determine 
whether progression to Cohort 3 is indicated. If no safety concerns are identified during 
SRT review, progression to Cohort 3 will take place. Initiation of Cohort 3 will be put on 
hold and further review will be conducted by the SRT, if any of the following are 
observed in Cohort 2: 
- 
PfSPZ Challenge-related or IMP-related SAE, or 
- 
Any other critical PfSPZ Challenge-related finding that may place subjects at 
risk in subsequent subgroups (in the next cohort or within the same cohort), or 
- 
Two or more IMP-related severe (Grade 3 or higher), same organ class adverse 
events. 
If after data review the SRT confirms that any of the above has been met and relationship 
with the PfSPZ and/or the IMP is definitively established, progression to Cohort 3 can be 
either stopped or authorized at a lower dosage regimen (de-escalation possible based on 
safety observations). 
5.8.3 
Final SRT Review at Study End 
The SRT will also meet at the end of the study when data from Cohort 3 are available for 
a final assessment in order to review the study results and share feedback on possible 
safety signals/events.  
Throughout the study, the SRT can be convened at the request of any member should 
they have cause for concern regarding subject safety in relation to the challenge agent, 
where no other cause can be attributed. In the event that it is not possible to quickly 
convene the SRT for a review of the data, or not all the data are available, the study will 
be interrupted or temporarily halted, at the discretion of the PI or Sponsor, at any time. 
 


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6. PRIOR AND CONCOMITANT THERAPY 
All therapies (prescriptions and over-the-counter medications, including herbal 
preparations/treatments) other than the IMP and antimalarial rescue medication, 
administered from informed consent until the last study visit must be recorded in the 
source documents and in the concomitant therapy section of the eSource system (name of 
the drug, dosage, route and dates of administration). 
Medications taken during the 28 days prior to first IMP administration will be recorded 
in the eSource system as previous medications. Medications taken after this time will be 
recorded as concomitant medications. 
Female subjects of childbearing potential and non-vasectomized male subjects having a 
female partner of childbearing potential must agree to the use of an effective method of 
contraception throughout the study, as outlined in Section 4.1. The use of oral, injectable 
and implantable hormonal contraceptives is to be recorded in the eSource system. 
6.1 
PERMITTED CONCOMITANT THERAPIES 
Subjects will abstain from using any medications (prescription or over-the-counter) or 
herbal remedies 7 days prior to first administration of the IMP as described in the 
exclusion criteria of this protocol (see Section 4.2). If necessary, the incidental use of 
NSAIDs, paracetamol (2g/day, 10 gr/week), vitamins, topical treatments, and the use of 
nutritional supplements may be acceptable after approval by the study Sponsor. 
Except for the IMP, antimalarial rescue medication and medication considered essential 
to treat AEs, all medications (prescription and non-prescription), herbal remedies and 
nutritional supplements should be avoided from the time of first IMP administration until 
after Day 28 or completion of the course of antimalarial rescue medication (whichever is 
later). Incidental and limited use of medications not believed to affect subject safety nor 
the overall results of the study, may be permitted on a case-by-case basis following 
approval by the Sponsor in consultation with the Investigator as described in the 
exclusion criteria of this protocol (see Section 4.2). 
Due to possible liver stress and alanine aminotransferase (ALT) over aspartate 
aminotransferase (AST) elevations after malaria inoculation, ibuprofen (at doses of up to 
1.8 g/day) is the preferred treatment over paracetamol for possible emergent malaria 
symptoms. 
6.2 
PROHIBITED CONCOMITANT THERAPIES 
The following medications are prohibited during the study: 
- 
Drugs with known antimalarial activity (trimethoprim sulfamethoxazole, 
tetracycline, doxycycline, erythromycin, clarithromycin, azithromycin, 
clindamycin, rifampicin, or newer quinolones, benzodiazepines, flunarizine, 
fluoxetine, methotrexate, chloroquine and hydroxychloroquine); 
- 
Drugs known to cause drug-drug interactions with artemether-lumefantrine 
(Riamet®), atovaquone-proguanil (Malarone®) or primaquine (Primaquine®), 
including but not limited to cimetidine, metoclopramide or antacids; 
- 
Any drug susceptible to interact with BCRP (cyclosporine, elacridar, 
eltrombopag, gefitinib). 


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7. 
ASSESSMENTS 
7.1 
TIMING OF ASSESSMENTS 
An overview of the timing of PfSPZ DVI challenge, treatment and assessments is given 
in the Time and Events Schedule. 
If assessments are planned at the same time point in the study, the order of assessments 
should be as follows: 
1. 12-lead ECG recordings; 
2. Vital signs measurements; 
3. Blood sampling; 
4. Other assessments. 
The following time-related windows for PK sampling, body temperature, blood pressure, 
pulse rate, ECG, haematology, blood chemistry and urinalysis assessments will be 
acceptable based on logistical and operational considerations: 
- 
Pre-IMP and pre-inoculation observations within 3 hours prior to 
dosing/inoculation; 
- 
± 5 min from 0.5 to 4 hours post dose (inclusive); 
- 
± 15 min from >4 to 12 hours post dose;  
- 
± 30 min >12 to <24 hours post dose (inclusive); 
- 
± 60 min for 24 hours post dose; 
- 
± 10% deviation from theoretical post dose times for >24 hours to <120 hours 
post dose; 
- 
a deviation of ± 1 day for further days. 
All assessments scheduled for a particular time point should be performed within these 
windows. 
Any deviations from the above-mentioned window periods will be documented as 
protocol non-compliances and will be evaluated for significance at the data review 
meeting prior to database lock. 
Adverse events and the intake of concomitant medication(s) will be monitored 
continuously from informed consent until the last study-related activity. 
7.1.1 
Screening Period 
Screening 
Screening for eligible and consenting subjects will be performed within approximately 
4 weeks prior to randomisation. 
Subjects will be given a full explanation of the nature of the study and written informed 
consent (approved by the local ethics committee) will be obtained according to local 
requirements before any study-related assessment will be carried out. 
At screening, subjects will be asked to attend the clinical unit to have assessments 
performed as indicated in the Time and Events Schedule.  


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All results from the screening procedure needed to evaluate eligibility, including the 
clinical laboratory results, must be available prior to the first administration of the IMP 
on Day 1 for Cohort 1 and prior to PfSPZ Challenge DVI on Day 1 for Cohorts 2 and 3. 
Any abnormal assessment at the screening visit will be assessed according to its clinical 
relevance, and if found relevant, the subject will not be included in the study. 
Unscheduled visits may be planned to assess, confirm and follow-up on out-of-range 
clinical laboratory test, vital sign or ECG values that determine a subject’s eligibility, or 
in case of a positive urine drug screen. The result of the retest will be considered for 
subject eligibility. Findings made during unscheduled visits should be reported in the 
eSource system. 
7.1.2 
Treatment Period 
Day -1 
Subjects will be enrolled in one of the 3 cohorts. Subjects will be admitted to the clinical 
unit in the morning of Day -1. Subjects in Cohort 1 will remain at the clinical unit until 
Day 4, i.e. 36 hours after second IMP administration. Subjects in Cohorts 2 and 3 will 
remain at the clinical unit until Day 13, i.e. 12 days post PfSPZ Challenge. 
Eligibility of the subjects will be confirmed and assessments will be performed as 
indicated in the Time and Events Schedule. 
Dinner will be served and no food intake will be allowed thereafter until 2 hours after the 
first administration of the IMP on the following day (Day 1). Intake of water will be 
allowed until 1 hour before the first administration of IMP. Fasting conditions will be 
maintained for 2 hours, including drinking water that will be allowed from 2 hours post 
dose onwards (ad libitum but approximately 1500mL/24 hours). 
Day 1 
On Day 1, subjects in Cohorts 2 and 3 will be administered 3,200 P. falciparum 
sporozoites by DVI.  
Subjects in all cohorts will be randomised in a 3:1 ratio, to receive two consecutive 
administrations of either P218 or placebo.  
Subjects in Cohort 1 will receive a first dose of IMP; and so do the subjects in Cohorts 2 
and 3, 2 hours after PfSPZ Challenge inoculation. For Cohorts 2 and 3, this initial dose at 
Day 1 must not be given prior to 2 hours post-inoculation. 
Predose procedures will be performed as indicated in the Time and Events Schedule, as 
close to the time of IMP administration as possible and surely within 3 hours before 
dosing. Predose PK samples should be taken within 1 hour before IMP administration. 
After the predose procedures, the subjects will be asked to ingest the first dose of study 
drugs according to the procedure described in Section 5.6, followed by repeated blood 
sampling and other assessments as outlined in the Time and Events Schedule. 
Day 2 
Dinner will be served and no food intake will be allowed thereafter until 2 hours after the 
administration of the IMP on the following day (Day 3). Intake of water will be allowed 
until 1 hour before administration of IMP. Fasting conditions will be maintained for 


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2 hours, including drinking water that will be allowed from 2 hours post dose onwards 
(ad libitum but approximately 1500mL/24 hours). 
Day 3 
Subjects in all cohorts will receive a second dose of IMP on Day 3, i.e. 48 hours after 
first IMP administration.  
Predose procedures will be performed as indicated in the Time and Events Schedule, as 
close to the time of IMP administration as possible and surely within 3 hours before 
dosing. Predose PK samples should be taken within 1 hour before IMP administration. 
After the predose procedures, the subjects will be asked to ingest the dose of study drugs 
according to the procedure described in Section 5.6, followed by repeated blood 
sampling and other assessments as outlined in the Time and Events Schedule. 
7.1.3 
Follow-up Period 
After discharge from the clinical unit on Day 4, subjects in Cohort 1 will be followed up 
with daily ambulatory visits to the clinical unit up to Day 9. After discharge from the 
clinical unit on Day 13, subjects in Cohorts 2 and 3 will be followed up with daily 
ambulatory visits to the clinical unit until development of positive parasitaemia or until 
Day 28 otherwise.  
The subjects in Cohorts 2 and 3 will receive rescue therapy (see Section 5.2) if positive 
parasitaemia is confirmed and will continue to be monitored daily at the clinical unit until 
treatment success. Upon treatment success, daily visits to the clinical unit are stopped, 
except for subjects that first need to complete the 3-day rescue treatment regimen and 
associated assessments. All subjects will be assessed again for parasitaemia at the EOS 
visit on Day 35. Subjects not developing positive parasitaemia until Day 28 will receive 
rescue therapy on that day. Instead of daily monitoring at the clinical unit until treatment 
success, these subjects will only be assessed again for parasitaemia at the EOS visit on 
Day 35.  
Assessments will be performed as indicated in the Time and Events Schedule and in 
Section 5.2).  
All subjects in Cohorts 2 and 3 will be assessed for parasitaemia at the EOS visit on 
Day 35. In order to provide some flexibility for the subjects regarding the site visit and to 
maintain the integrity of the study design, a time window of ±1 day is permitted, in case 
of time conflict or unforeseen circumstances. All subjects that receive rescue therapy will 
be asked non leading questions to determine the occurrence of any AEs approximately 
two weeks after initiation of the rescue treatment, either during a planned study visit or 
by phone in case there is no planned study visit at that time. If this time point is after the 
EOS visit on Day 35, the moment of the phone call will be considered the EOS and not 
Day 35. In order to provide some flexibility regarding the phone call and to maintain the 
integrity of the study design, a time window of ±2 days is permitted for this follow-up 
call, in case of time conflict or unforeseen circumstances.  
7.1.4 
Unscheduled Visits 
Unscheduled visits can be planned for instance: 


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- 
to obtain additional information to ensure safety to the subject. Additional blood 
and urine samples may be taken at the discretion of the Investigator.  
- 
to assess, confirm and follow-up on out-of-range clinical laboratory test, vital sign 
or ECG values that will determine a subject’s eligibility, or in case of a positive 
drug screen. The result of the retest will be considered for subject eligibility. 
Findings made during unscheduled visits should be reported in the eSource system. 
7.2 
PHARMACOKINETIC EVALUATIONS 
7.2.1 
Sample Collection and Handling 
Blood samples 
At each planned time point, a 4 mL venous blood sample will be drawn for analysis of 
P218 (and its metabolites in Cohort 1 only) in plasma, as described in the Time and 
Events Schedule. The exact date and time of blood sampling and of administration of the 
study drugs must be recorded in the eSource system. 
Every blood sample will be drawn by venipuncture or via indwelling cannula in the 
forearm into a pre-chilled EDTA vacuum tube and immediately placed in an ice bath. 
Further processing of the sample must be completed within 30 minutes.  
Detailed procedures for sample collection, shipment, processing and storage will be 
described in a laboratory manual. Briefly, the sample will be acidified with 10 µL/mL 
2M citric acid and centrifuged under refrigeration, to isolate plasma. Two aliquots of at 
least 0.5 mL will be prepared in screw-cap polypropylene tubes and immediately frozen 
on dry ice and stored at -80 °C until analysis. Shipment of aliquots to Swiss Bioquant 
must take place on dry ice – only the first aliquot of each sample will be shipped, the 
second one must remain at the clinical unit and can be shipped by request in a separate 
parcel. 
7.2.2 
Bioanalyses 
Plasma samples for determination of P218 concentration, and concentration of its major 
metabolites P218 β-acyl-glucuronide, P218-OH β-acyl-glucuronide and possibly 
P218-OH in Cohort 1 only, will be analysed by Swiss BioQuant laboratory on behalf of 
MMV using a validated high performance liquid chromatography tandem mass 
spectrometry (HPLC/MS/MS) method. Analytical methodology will be detailed in a 
separate Bioanalytical Study Plan. Outcomes of analyses will be reported in a dedicated 
Bioanalytical report which will be attached to or referred to in the Clinical Study Report 
upon completion of the study.  
No human deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) analysis will be 
performed. 
7.2.3 
Pharmacokinetic Parameters 
Pharmacokinetic calculations will be performed by SGS-Life Sciences using Phoenix 
WinNonLin 8.0 or higher (Pharsight Corporation, Palo Alto, CA, USA). 
The following parameters, where appropriate, will be determined for P218, and in 
Cohort 1 only also for its major metabolites (P218-OH, P218-beta-acyl-glucuronide, 


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P218-beta-acyl-glucuronide-OH) using individual concentration data in plasma, 
according to the definitions and methods of calculation below: 
- 
AUCτ = AUC0-48h after each administration (i.e. AUC0-48h and AUC48-96h);  
- 
AUC48h-inf, calculated from AUC48h-t + (Ct/λz);  
- 
AUC48h-last; 
- 
CL/F and Vz/F after the second administration (not for metabolites); 
- 
Cmax and tmax after each administration; 
- 
t1/2 after the second administration; 
- 
Rac, calculated as AUC48-96h/AUC0-48h; 
- 
Metabolic ratio of AUCτ and AUC48h-inf for P218 β-acyl glucuronide, P218-OH 
and P218-OH β-acyl glucuronide over parent P218 (Cohort 1 only). 
Additional pharmacokinetic parameters may be calculated as appropriate. 
7.3 
EFFICACY EVALUATIONS 
For an overview of efficacy endpoints, see Section 2.2. 
7.3.1 
Parasitaemia 
A blood sample of maximum 1.5 ml will be collected via direct venepuncture in an 
EDTA tube from each subject at time points where parasitological assessments are 
scheduled Time and Events Schedule. The assessment of malaria parasitology by TBS 
and qPCR will be as follows: 
- 
Parasite density, expressed as the number of parasites per microliter of blood will 
be measured using the routine diagnostic TBS microscopy method for parasite 
count employed by the centre of excellence for tropical medicine (ITM) as per 
relevant standard operating procedure and Laboratory Manual. The reading will 
be considered positive if 2 unambiguous malaria structures are seen in at least 
0.5µl of blood and the observation is confirmed by a second expert malaria 
microscopist.  
- 
varATS (the acidic terminal segment in Plasmodium var genes) targeted qPCR 
assay of parasite load will be performed in accordance with the ITM standard 
operating procedure and the Laboratory Manual. Method validation and external 
quality assessment (EQA) of the outcomes will be carried out at the Department 
of Laboratory Medicine, School of Medicine, University of Washington (Dr. Sean 
Murphy) using 18S rRNA targeted qRT-PCR methodology described in a 
dedicated Validation Plan. Given the higher sensitivity of qPCR compared to 
microscopy, this method will be used to confirm aparasitaemia after definitive 
antimalarial therapy for all subjects. A subject will be considered cured following 
completion of the course of rescue antimalarial therapy and after qPCR results are 
obtained with values below the limit of detection.  
The results of the TBS microscopy and qPCR at the ITM will be available in 
approximately 24 hours.  


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7.3.2 
Malaria Clinical Score 
An inoculum-related event is a sign or symptom associated with malaria infection 
(confirmed by a positive P. falciparum PCR [defined for the purpose of this study as 
≥ 250 asexual parasites per mL] at the onset of the event) that is of expected intensity, 
frequency and duration for the individual subject in the context of this study. 
Prevention of expected signs and symptoms associated with malaria infection form part 
of the efficacy evaluation of the study and are listed in Attachment 1. If the presence of 
P. falciparum malaria is confirmed by positive PCR at the time of onset of these 
signs/symptoms and if, in the Investigator's opinion, the signs/symptoms are of the 
expected intensity, frequency and duration for the individual subject in the context of this 
study, then the events will be classified as inoculum-related events and reported as such 
in the final clinical study report. 
Inoculum-related events meeting the classification criteria for SAEs or AEs of special 
interest should be subjected to standard expedited reporting procedures of these events 
(See Section 10). 
The following malaria signs/symptoms will not be classified as inoculum-related events: 
- 
If the PCR results for P. falciparum are between 0 and < 250 asexual parasites per 
mL at the time of the onset of the event, usual AE/SAE reporting procedures and 
criteria will apply (see Section 10), and the event will not be classified as an 
inoculum-related event. 
- 
Observed malaria symptoms or signs that are of greater intensity, frequency or 
duration than would be expected in the context of this study, will be regarded as 
medically important events and must be reported promptly (i.e. in an expedited 
manner) to the Sponsor using an SAE report form (see Section 10.7), and will not 
be classified as inoculum-related events. 
Final classification of signs and symptoms as inoculum-related event or AE will occur 
after PCR results are available. 
7.3.3 
PK/PD 
A model-based analysis is foreseen to characterise the PK/PD relationship between P218 
plasma concentrations and blood stage asexual parasitaemia. Details of the modelling 
analysis will be described in the modelling analysis plan (MAP). 
7.4 
SAFETY EVALUATIONS 
The safety assessment in this study will be based on AEs, clinical laboratory tests 
including serum folate, vital signs, ECG, physical examination and Beck depression 
Inventory (screening only) as described in the following sections. 
7.4.1 
Adverse Events 
Adverse events will be monitored continuously from informed consent until the last 
study-related activity. At regular intervals during the study, subjects will be asked 
non-leading questions to determine the occurrence of any AEs. All AEs reported 
spontaneously during the course of the study will be recorded as well. 


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For detailed definitions and reporting procedures of AEs, see Section 10. 
7.4.2 
Clinical Laboratory Tests 
Blood samples will be collected by venipuncture or via indwelling cannula at the time 
points indicated in the Time and Events Schedule. Biochemistry and haematology testing 
will be performed on these samples, as well as immunology testing (HbsAg, anti-HCV 
antibody and HIV antibody and antigen) on the sample from screening. In all female 
subjects, also serum β-HCG assessment at screening and urine β-HCG assessments on 
Day-1 and at the EOS visit will be performed. FSH will be measured at screening in all 
women. 
All blood samples for safety assessments, except the ones taken during rescue treatment 
for Troponin I measurements only (see Section 5.2), should be taken in a fasted state 
(overnight fast for at least 8 hours for unbiased glucose determination).  
Standard laboratory tests will be performed by ZNA Middelheim. 
The following biochemistry and haematology tests will be performed on the safety blood 
samples:  
- 
Biochemistry: sodium, potassium, chloride, bicarbonate, urate, inorganic 
phosphate, creatinine, albumin, glucose, AST, ALT, alkaline phosphatase (ALP), 
gamma glutamylaminotransferase (GGT), lactate dehydrogenase (LDH), total and 
direct bilirubin, total serum proteins, blood urea nitrogen (BUN), C-reactive 
protein (CRP), creatine phosphokinase (CPK) and troponin I (Cohorts 2 and 3 
only);  
- 
Haematology: haemoglobin, haematocrit, red blood cell (RBC) count, mean 
corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration 
(MCHC), mean corpuscular volume (MCV), white blood cell (WBC) count, 
platelet count, reticulocytes, neutrophils, eosinophils, basophils, lymphocytes and 
monocytes; 
- 
Coagulation: prothrombin time (PT), international normalized ratio (INR), 
activated partial thromboplastin time (aPTT). 
Serum folate will be measured according to the time points in the Time and Events 
Schedule. 
G6PD enzyme test will be performed at screening. 
A midstream urine sample will be collected for urinalysis by dipstick for glucose, 
protein, nitrite, pH and occult blood. Microscopic examination for WBC, RBC and casts 
will be performed 
A urine drug screen (amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine and opiates) and an alcohol breath test will be performed at the time points 
indicated in the Time and Events Schedule. 
The Investigator must review the laboratory report, document this review and record any 
change occurring during the study he/she considers to be clinically relevant in the 
eSource system. Laboratory values outside the normal range will be flagged and their 
clinical relevance will be assessed by the Investigator. 


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Samples that remain after protocol-specific assessments have been performed may be 
used for further exploratory work on pharmacokinetics, metabolites, plasma protein 
binding, protein analysis and biochemistry. No human DNA or RNA analysis will be 
performed. 
7.4.3 
Vital Signs 
Vital sign parameters will be assessed after 5 minutes in supine position at the time 
points indicated in the Time and Events Schedule. The vital sign parameters that will be 
assessed are supine systolic and diastolic blood pressure (SBP and DBP, respectively), 
pulse rate and body temperature (sublingual). In Cohort 1, orthostatic changes to BP and 
pulse rate will also be assessed at screening: Subjects will be requested to stand after 
completion of the supine measurements and blood pressure and pulse rate will be 
recorded after 2 minutes in the standing position. 
These parameters will be measured using a completely automated device consisting of an 
inflatable cuff and an oscillatory detection system. All values will be registered on a 
built-in recorder so that measurements are observer-independent. 
Any change from baseline in vital sign values occurring during the study that is 
considered to be clinically relevant by the Investigator should be recorded in the eSource 
system. 
7.4.4 
Electrocardiogram 
Twelve-lead ECGs recordings will be will be recorded after 10 minutes in supine 
position at the time points indicated in the Time and Events Schedule.  
All recordings will be performed once, except at screening and before the first and 
second IMP administration when they will be performed in triplicates at approximately 
1-minute intervals. Paper speed will be 25 mm/s, so that the different ECG intervals can 
be measured manually.  
Between Day 10 and 28, one record will be performed on the first day of rescue 
treatment only. 
The interpretations of the ECGs will be performed by the Investigator or his/her designee 
at the clinical unit. Any change from baseline ECG occurring during the study that is 
considered to be clinically relevant by the Investigator should be recorded in the eSource 
system. 
7.4.5 
Physical Examination 
Physical examination will be performed at the time points indicated in the Time and 
Events Schedule. 
Height is to be measured barefoot and at screening only. Body weight to be measured as 
indicated in the Time and Events Schedule. To obtain the actual body weight, subjects 
must be weighed lightly clothed at screening.  
Any change in physical examination occurring during the study that is considered to be 
clinically relevant by the Investigator should be recorded in the eSource system. 


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After screening, a targeted, symptom-driven physical examination will be performed 
focused on changes since the previous examination, but will always include at least: 
general appearance, skin, heart/circulation, chest, lungs, abdomen and brief neurological 
examination. 
7.4.6 
Beck Depression Inventory 
The Beck depression inventory is performed at screening only (see Attachment 2). 
The questionnaire is scored by the subject. The inventory completed by the subject will 
be reviewed/checked for completeness and the total score calculated by the study 
personnel. 
7.5 
TOTAL VOLUME OF BLOOD SAMPLING 
The total volume of blood from any single subject will not exceed the maximum 
allowable volume of 450 mL in any given 30-day period during his/her participation in 
the study. 
If necessary, in order to obtain additional information to ensure a subject’s safety, 
additional blood samples (up to 50 mL) and/or urine samples may be taken at the 
discretion of the Investigator. 
7.6 
APPROPRIATENESS OF MEASUREMENTS 
The assessments which will be made in this study are standard, and are generally 
recognized as reliable, accurate and relevant. 


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8. STUDY TERMINATION/COMPLETION 
8.1 
STUDY COMPLETION 
A subject will be considered to have completed the study if he or she has completed the 
required EOS visit and EOS phone call.  
8.2 
REMOVAL OF SUBJECTS FROM THERAPY OR STUDY 
Subjects have the right to withdraw from the study at any time for any reason, including 
personal reasons. A subject can withdraw without giving a reason. This will not affect 
his/her future care. The Investigator should however try to find out why a subject 
withdraws from the study and document the reason for withdrawal in the source 
documents and on the in the eSource system. 
All withdrawn subjects who were inoculated with the PfSPZ challenge agent must 
receive antimalarial rescue therapy as described in Section 5.2. Subjects who fail to 
return for visits will be traced as described in Section 8.4. 
Subjects may be withdrawn in the event of: 
- 
A severe AE or SAE. 
Subjects must be withdrawn in the event of: 
- 
Withdrawal of consent; 
- 
For safety reasons, it being in the best interest of the subject that he/she be 
withdrawn, in the Investigator’s opinion or in the opinion of the SRT; 
- 
A positive pregnancy test (the subject or, in the case of a male subject, his female 
partner), or if the subject/partner is non-compliant with the contraception 
requirements (see Section 4.1); 
- 
Development of a medical condition that requires concomitant treatment with a 
prohibited therapy (see Section 6.2); 
- 
Failure of the subject to comply with the protocol requirements or to cooperate 
with the Investigator resulting in a significant risk to the subject’s safety; 
- 
Breaking of the randomisation code during administration of the IMPs, by the 
Investigator or by a member of his/her clinical staff. If the code is broken by the 
Sponsor, for safety reporting purposes, the subject may remain in the study. 
In the event of a subject being withdrawn, the monitor and Sponsor should be informed: 
in case of withdrawal due to an SAE (for details on AE reporting see Section 10), the 
Sponsor should be notified within 24 hours; in case of withdrawal for other reasons; the 
Sponsor should be notified within 2 days from the event. 
If there is a medical reason for withdrawal, the subject will remain under the supervision 
of the Investigator until satisfactory health has returned. 
Subjects who are withdrawn from the study prior to completion of the scheduled study 
procedures for any reason (AE, withdrawal of consent, etc.) should be invited to 
complete the assessments as much as possible: as long as the subject consents, all 
relevant assessments of the day on which the subject withdrew from the study should be 
completed, at least those related to safety, and the subject should come for a safety 


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follow-up visit 4 weeks after the last administration of IMP. In case of an AE, the 
appropriate follow-up will be done. 
Subjects who are withdrawn from the study for reasons other than safety may be 
replaced. This decision will be made based upon discussion and mutual agreement 
between the Sponsor and the Investigator. 
IMPs that are assigned to a subject that withdraws must not be assigned to another 
subject. 
8.3 
STOPPING RULES OR DISCONTINUATION CRITERIA 
The study will be overseen by an SRT (see Section 5.8). 
8.4 
TRACEABILITY OF SUBJECTS 
The following measures will be taken to assure traceability of subjects in Cohorts 2 and 
3: 
- 
Following scheduled, in-house confinement within the pharmacology unit or 
removal from the study, all subjects will be contacted daily until Day 28. 
- 
All subjects will commit to remaining contactable throughout the study and this 
will be recorded on the ICF. 
- 
Subjects will be required to provide current contact details (two telephone 
numbers including a mobile number and a responsible adult as an emergency 
contact) and a relevant email address. 
- 
Should a subject not be contactable by the unit, all alternative methods possible 
(e.g. sending someone to home address of subject) will be used to locate and 
communicate with the subject. 
- 
Should a subject still be uncontactable the situation will be discussed with the 
Sponsor and escalated as appropriate including alerting the regulatory authorities 
to a deviation from protocol. 


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9. STATISTICAL METHODS 
9.1 
STATISTICAL ANALYSIS 
All statistical analysis will be performed by SGS Life Sciences, using SAS® 
(SAS Institute Inc., Cary, NC, USA; version 9.4 or higher) software for statistical 
computations. 
The standard descriptive statistics for continuous variables are the number of subjects 
(N), mean, standard deviation (SD), median, first and third quartiles, minimum and 
maximum values. The standard descriptive statistics for categorical variables are the 
number of subjects in the category and the proportion expressed as a percentage. 
Fasting placebo data from the Cohorts 1, 2 and 3 will be pooled while IMP treatments 
per cohort are considered as two different treatment groups.  
9.1.1 
Planned Analyses 
The primary objective of this analysis is the assessment of the chemoprotective activity 
of P218 in P. falciparum CHMI in non-immune healthy volunteers after PfSPZ 
Challenge through DVI.  
No interim analysis will be performed. 
All statistical methods shall be detailed in a Statistical Analysis Plan (SAP) that will be 
finalized before database lock. 
9.1.2 
Analysis Populations 
The following populations will be considered for analysis: 
- 
Intent-to-treat (ITT) population, defined as all randomised subjects who received 
at least one dose of IMP and who received the PfSPZ challenge inoculation, 
analysed as randomised; 
- 
Safety (SAF) population, defined as all subjects who received at least one dose of 
IMP, analysed as treated; 
- 
Pharmacokinetic (PK) population, defined as all subjects who have received at 
least 1 dose of IMP and had measurable concentrations of parent and/or 
metabolites; 
- 
Efficacy population, defined as all subjects in the safety population who received 
PfSPZ Challenge by DVI; 
- 
PK/PD population, defined as all subjects belonging to both the PK and the 
efficacy population. 
The ITT population will be used for the analysis of demographics and efficacy, the 
pharmacokinetic population will be used for the pharmacokinetic statistical analysis, the 
efficacy population for the efficacy statistical analysis and the safety population will be 
used for safety/tolerability analysis. 
9.1.3 
Initial Characteristics Data of the Subject Sample 
For all randomised and treated subjects, descriptive statistics will be provided per 
treatment group for demographic (e.g. age, height, weight, BMI, race, gender) and other 


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initial subject characteristics (alcohol and drug screening tests, pregnancy test, orthostatic 
changes to blood pressure and pulse rate [Cohort 1 only], G6PD enzyme test, serology, 
medical and social history, concomitant diseases, Beck Depression Inventory).  
Prior and concomitant medications will be coded using the World Health Organization 
(WHO)_DRUG Dictionary. 
9.1.4 
Pharmacokinetic Data 
Pharmacokinetic concentrations will be summarized by treatment group, day and 
scheduled sampling times by using number of subjects with data, arithmetic mean, 
standard deviation, coefficient of variation, median, minimum and maximum. 
For PK parameters (see Section 7.2.3), descriptive statistics will be included with in 
addition geometric mean and geometric coefficient of variance (CV%); tmax will be 
summarized by using number of subjects with data, median, minimum and maximum. 
Individual and mean concentrations versus time figures will be presented. 
9.1.5 
Efficacy Data 
9.1.5.1 
PARASITAEMIA 
Primary endpoint: The duration from PfSPZ challenge DVI to positive parasitaemia will 
be analysed using descriptive statistics, including the geometric mean and corresponding 
two-sided 90% confidence intervals. In the absence of positive parasitaemia, the duration 
will be set to a maximum of 28 days. 
The number and proportion of subjects with presence of positive parasitaemia between 
inoculation with PfSPZ and Day 28 (or the administation of rescue medication) will be 
summarized by a responder analysis per treatment group. Corresponding two-sided 90% 
Exact Clopper-Pearson confidence limits will be presented as well.  
9.1.5.2 
MALARIA CLINICAL SCORE 
For the malaria clinical score that will be administered by the PI or study physician, 
actual values and changes from baseline will be evaluated by means of descriptive 
statistics. Additionally, expected signs and symptoms will be summarized by score. 
9.1.6 
Safety Data 
Safety parameters will be tabulated and analysed descriptively. 
9.1.6.1 
ADVERSE EVENTS 
The original terms entered in the eSource system by Investigators to identify AEs will be 
fully described and coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA). 
The reported AEs will be allocated to phases based on their start date. All AEs will be 
listed. For Cohort 1 all AEs with onset after first IMP treatment will be summarized by 
treatment group. For Cohorts 2 and 3 all AEs with onset after PfSPZ challenge DVI will 
be summarised by treatment group. Summaries will be made per MedDRA primary 
system organ class, MedDRA preferred term, severity, with the number and percentage 


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of subjects and the number of events. Similar summaries will be prepared for AEs 
considered to be related to IMP and AEs considered to be related to the PfSPZ challenge 
DVI, for serious AEs and AEs of special interest. 
Special attention will be paid to those subjects who died, discontinued IMP due to an AE, 
or experienced a severe or serious AE. Summaries, listings and narratives (also see 
Section 12.11) may be provided, as appropriate. 
9.1.6.2 
CLINICAL LABORATORY TESTS 
Serum folate, continuous biochemistry and hematology laboratory tests will be evaluated 
by means of descriptive statistics on the actual values, at each assessment time point and 
by treatment group. Changes from baseline will also be summarized using descriptive 
statistics by assessment time point and by treatment group. 
Relative changes in clinical laboratory test values compared to values at baseline will be 
evaluated in accordance with the normal ranges of the clinical laboratory (below, within 
or above normal range). The percentage of subjects with clinical laboratory test 
abnormalities will be summarized by treatment group. 
The number and percentage of subjects with liver enzyme elevations after IMP 
administration as defined below will be summarised: 
- 
ALT or AST >3 x Upper Limit of Normal (ULN); 
- 
ALT or AST >5 x ULN; 
- 
ALT or AST >8 x ULN; 
- 
ALT or AST >3 x ULN and bilirubin >2 x ULN at the same time point, together 
with a conjugated bilirubin fraction> 35% (Potential Hy’s law cases). 
A listing of subjects with any clinical laboratory test result outside the reference ranges 
will be provided. 
9.1.6.3 
VITAL SIGNS 
Vital signs parameters will be assessed after 5 minutes in supine position at the time 
points indicated in the Time and Events Schedule. Pulse rate, systolic blood pressure, 
diastolic blood pressure and body temperature will be evaluated by means of descriptive 
statistics (actual values and changes from baseline).  
The percentage of subjects with vital signs abnormalities will be summarized by 
treatment group in a cross-tabulation of post-baseline versus baseline abnormalities to the 
normal ranges (as defined in Attachment 3). 
9.1.6.4 
ELECTROCARDIOGRAM 
12-lead ECG recordings will be performed after subjects remained in a supine position 
for at least 10 minutes. All recordings will be performed once, except at the screening 
and before the first and second IMP administration when they will be performed in 
triplicates.  
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 


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baseline will be summarised by means of descriptive statistics at each assessment time 
point and by treatment group.  
The percentage of subjects with ECG abnormalities will be summarized by treatment 
group in a cross-tabulation of post-baseline versus baseline abnormalities to the normal 
ranges (as defined in Attachment 3).This cross-tabulation will include categorical 
assessment on actual values and changes from baseline of QTcB and QTcF prolongation. 
9.1.6.5 
PHYSICAL EXAMINATION 
Abnormal findings in physical examination will be listed. 
9.2 
DETERMINATION OF SAMPLE SIZE 
Thirty-two subjects will be enrolled in 3 cohorts of 8, 12 and 12 subjects. In agreement 
with the Sponsor, additional subjects may be recruited in each cohort, to replace 
discontinuations for non-safety reasons and achieve cohort sizes of 8 and 12.  
This is an exploratory study thus no sample size calculation is performed. However, if 
the nine treated subjects each in Cohort 2 and 3 do not develop positive parasitaemia 
(qPCR ≥ 250 asexual parasites per mL) after IMP administration and until Day 28, it may 
be concluded that the protection rate for P218 is 0.72 (72%) with a 95% probability 
(lower limit of exact, one sided test, 95%, CI 0.72). This holds true for both Cohort 2 and 
Cohort 3. 


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10. 
ADVERSE EVENT REPORTING 
10.1 
DEFINITIONS 
Adverse Event 
An AE is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An AE does not necessarily 
have a causal relationship with the treatment. An AE can therefore be any unfavourable 
and unintended sign (including an abnormal finding), symptom or disease temporally 
associated with the use of a medicinal (investigational or non-investigational) product, 
whether or not related to that medicinal (investigational or non-investigational) product. 
This includes any occurrence that is new in onset or aggravated in severity or frequency 
from the baseline condition, or abnormal result of diagnostic procedures, including 
clinical laboratory test abnormalities. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose meets any of the following 
conditions: 
- 
Results in death; 
- 
Is life-threatening, i.e. the subject was at risk of death at the time of the event 
(e.g. ventricular fibrillation and anaphylaxis). The term does not refer to an event 
which hypothetically might have caused death if it were more severe. 
- 
Requires inpatient hospitalization or prolongation of existing inpatient 
hospitalization: 
Hospitalization refers to an overnight admission into hospital for the purpose of 
investigating and/or treating the AE. Hospitalization for an elective procedure, or 
routinely scheduled treatment for a pre-existing condition that is unrelated to the 
study and has not worsened, is not an SAE. Treatment on an emergency 
outpatient basis for an event not fulfilling any of the definitions of an SAE given 
above and not resulting in hospital admission, is not an SAE. Cosmetic surgery or 
for social reasons or respite care in the absence of any deterioration in the 
subject’s general condition, is not an SAE;  
- 
Results in persistent or significant disability/incapacity, i.e. causing substantial 
disruption of the subject’s ability to conduct normal life; 
- 
Is a congenital anomaly/birth defect; 
- 
Is medically significant, i.e. may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the subject’s health or may require 
intervention to prevent one of the above outcomes. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias, or convulsions that do not result in hospitalization or 
development of drug dependency or drug abuse. 
- 
Constitutes a possible Hy’s Law case (defined as a subject with any value of ALT 
or AST greater than or equal to 3xULN together with an increase in bilirubin to a 
value greater than 2xULN [>35% direct] and NOT associated with an ALP value 
greater than 2xULN.) 


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Adverse Events of Special Interest (AESIs) 
An adverse events of special interest (AESIs) (serious or non-serious) is of scientific and 
medical concern specific to the Sponsor’s product or programme, for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor could be 
appropriate. Such an event might require further investigation in order to characterise and 
understand it. Depending on the nature of the event, rapid communication by the study 
Sponsor to other parties (e.g., regulators) might also be warranted (CIOMS VI, ICH E2F, 
2010). For the purpose of this study, any abnormalities listed below should be reported as 
AESI: 
Hepatic 
- 
Any ALT or AST above 3x ULN; 
- 
Any elevation in bilirubin 2x ULN; 
- 
Any AST or ALT above 2x ULN and (total bilirubin level (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 
- 
QTcB or QTcF at any time >480 ms; 
- 
Bundle branch block (except right bundle branch block that was present prior to 
IMP administration); 
- 
Any arrhythmia, except: 
o sinus bradycardia that is clinically asymptomatic, and not associated with 
any other relevant ECG abnormalities; 
o sinus tachycardia that is clinically asymptomatic, and associated with a 
body temperature >38.0 °C, and not associated with any other relevant 
ECG abnormalities; 
o respiratory sinus arrhythmia; 
o wandering atrial pacemaker;  
o isolated, single premature atrial/ventricular complex (i.e., no bigeminy, 
trigeminy, couplets, triplets or salvos) that does not occur more than once 
in a particular ECG tracing.  
Haematological 
- 
Haemoglobin drop >2 g/dL and under lower limit of normal from baseline prior 
to inoculation;  
- 
Absolute neutrophil count <1000/µL; 
- 
Platelet count <100,000 /mm3. 
Dermatological:*  
- 
Any suspected cutaneous adverse event, e.g., rash 
* if one of these cutaneous reaction is observed and when feasible, pictures of the lesions 
should be obtained. 


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Unlisted (Unexpected) Adverse Event 
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information (Investigator’s Brochure for drugs in clinical 
development or approved manufacturer’s prescribing information for marketed drugs). 
For this protocol, the reference documents for the assessment of expectedness for P218 
and PfSPZ Challenge are the Investigator’s Brochures for each of these products [6,7]. 
Expected reactions to the antimalarial rescue treatment are described in the product’s 
prescribing information: 
- 
P218 (DHFR inhibitor) side-effects may include bone marrow suppression 
(rarely), GI symptoms including nausea and vomiting and skin rashes. All of 
these are reversible by the addition of folates to the subject’s diet. 
- 
Malarial challenge (sporozoites) can be associated with itching, pain and swelling 
at the site of inoculation. This usually resolves within 24-48 hours. 
- 
Riamet (antimalarial/EOS treatment: artemether and lumefantrine) may be 
associated with the following adverse events; these may occur with a varying 
periodicity: 


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Frequency of Undesirable Effects 
 
Adults and adolescents above 12 years of age  
Immune system disorders 
Hypersensitivity 
Not known 
Metabolism and nutrition disorders  
Decreased appetite 
Very common 
Psychiatric disorders  
Sleep disorders 
Very common 
Insomnia 
Common 
Nervous system disorders  
Headache 
Very common 
Dizziness 
Very common 
Paraesthesia 
Common 
Ataxia, hypoaesthesia 
Uncommon 
Somnolence 
Uncommon 
Clonus 
Common 
Cardiac disorders  
Palpitations 
Very common 
Electrocardiogram QT prolonged 
Common 
Respiratory, thoracic and mediastinal disorders  
Cough 
Common 
Gastrointestinal disorders  
Vomiting 
Very common 
Abdominal pain 
Very common 
Nausea 
Very common 
Diarrhoea 
Common 
Hepatobiliary disorders  
Liver function tests increased 
Uncommon 
Skin and subcutaneous tissue disorders  
Rash 
Common 
Pruritus 
Common 
Urticaria 
Uncommon 
Angioedema* 
Not known 
Musculoskeletal and connective tissue disorders  
Arthralgia 
Very common 
Myalgia 
Very common 
General disorders and administration site conditions  
Asthenia 
Very common 
Fatigue 
Very common 
Gait disturbance 
Common 


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- 
Malarone (rescue medication: atovaquone and proguanil hydrochloride) may be 
associated with the following adverse events; these may occur with a varying 
periodicity: 
System Organ 
Class  
Very 
Common  
Common  
Uncommon  
Rare  
Not known2  
Blood and 
lymphatic 
disorders  
 
Anaemia  
Neutropenia 1  
 
 
Pancytopenia  
Immune system 
disorders  
 
Allergic reactions   
 
Angioedema3  
Anaphylaxis (see 
section 4.4) 
Vasculitis3  
Metabolism and 
nutrition disorders  
 
Hyponatraemia1 
Anorexia  
Elevated 
amylase levels1  
 
 
Psychiatric 
disorders  
 
Abnormal dreams  
Depression  
Anxiety  
Hallucinations  
Panic attack  
Crying  
Nightmares  
Psychotic disorder  
Nervous system 
disorders  
Headache  
Insomnia 
Dizziness  
 
 
Seizure  
Cardiac disorders   
 
Palpitations  
 
Tachycardia  
Gastrointestinal 
disorders  
Nausea1  
Vomiting  
Diarrhoea  
Abdominal 
pain  
 
Stomatitis  
 
Gastric 
intolerance3  
Oral ulceration3  
Hepatobiliary 
disorders  
 
Elevated liver 
enzymes1  
 
 
Hepatitis  
Cholestasis3  
Skin and 
subcutaneous 
tissue disorders  
 
Pruritus  
Rash  
Hair loss  
Urticaria  
 
Stevens-Johnson 
Syndrome  
Erythema 
multiforme  
Blister  
Skin exfoliation  
Photosensitivity 
reactions  
General disorders 
and administration 
site conditions  
 
Fever  
 
 
 
Respiratory, 
thoracic and 
mediastinal 
disorders  
 
Cough  
 
 
 
An inoculum-related event is a sign or symptom associated with malaria infection 
(confirmed by a positive P. falciparum PCR at the onset of the event) that is of expected 
intensity, frequency and duration for the individual subject in the context of this study. 
Prevention of expected signs and symptoms associated with malaria infection form part 


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of the efficacy evaluation of the study and thus, inoculum-related events are not reported 
as AE (see Section 7.3.2 and Section 9.1.5.2). 
A rescue treatment-related AE is a sign or symptom associated with the antimalarial 
rescue drug that is of expected intensity, frequency and duration for the individual 
subject in the context of this study. Expected reactions to the antimalarial rescue 
treatment are described in the product’s prescribing information. 
10.2 
INTENSITY OF ADVERSE EVENTS 
Each AE must be rated on a 5-point scale of increasing intensity according to the 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0: 
Note: the semi-colon within the description of the grade indicates ‘or’. 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate 
instrumental activities of daily life (preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc.). 
Grade 3: 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated, disabling; limiting self-care activities of daily 
life (bathing, dressing and undressing, feeding self, using the toilet, taking medications 
and not bedridden). 
Grade 4: 
Life-threatening consequences; urgent intervention indicated. 
Grade 5: 
Death related to AE. 
10.3 
CAUSALITY ASSESSMENT 
The Investigator must assess the relationship of each event to the IMP, the PfSPZ 
inoculum and the rescue treatments (separately) and decide whether, in his or her medical 
judgement, there is a reasonable possibility that the event may have been caused by any 
of the study agents. Where possible, a distinction should be made between events 
considered related to the IMP, the PfSPZ inoculum and the rescue treatments. If there is 
no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Alternatively, if there is any valid reason for suspecting a possible cause-and-
effect relationship between the investigational product(s) and the occurrence of the AE 
(even if undetermined or untested), then the AE should be considered as “related” to 
whichever product as relevant. This should be documented in the subject’s source 
document and eSource system. 
The following may guide this assessment: 


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- 
Related/suspected – the temporal relationship between the event and the 
administration of the IMP and/or PfSPZ inoculum is compelling and/or follows a 
known or suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies or accident; 
- 
Not related/not suspected – the event can be readily explained by other factors 
such as the subject’s underlying medical condition, concomitant therapy or 
accident and no plausible temporal or biologic relationship exists between the 
IMP and/or PfSPZ inoculum and the event. 
In addition to the assessments of relationship to the investigational products, the 
Investigator should comment on the adverse event record in the eSource system whether 
an adverse event is related to the study participation of the subject (study procedures 
etc.). 
Of note, a sign or symptom associated with malaria infection (confirmed by a positive 
P. falciparum PCR at the onset of the event) that is of expected intensity, frequency and 
duration for the individual subject in the context of this study is considered to be an 
inoculum-related event. Prevention of expected signs and symptoms associated with 
malaria infection form part of the efficacy evaluation of the study and thus, 
inoculum-related events are not reported as AE (see Section 7.3.2). 
10.4 
ACTION TAKEN REGARDING THE IMP 
The action taken towards the IMP must be described as follows: 
- 
Permanently discontinued; 
- 
No action taken; 
- 
Unknown/Not applicable. 
10.5 
OUTCOME 
The outcome of each AE must be rated as follows: 
- 
Recovered/resolved; 
- 
Recovering/resolving; 
- 
Not recovered/not resolved; 
- 
Recovered with sequelae/resolved with sequelae; 
- 
Fatal; 
- 
Unknown. 
10.6 
RECORDING OF ADVERSE EVENTS 
All (S)AEs occurring during the clinical investigation must be documented in the 
eSource System. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (e.g. cough, runny nose, sneezing, sore throat and head congestion 
should be reported as “upper respiratory infection”). Investigators must record their 
opinion concerning the relationship of the (S)AE to the study drugs in the eSource 
System. All measures required for (S)AE management must be recorded in the source 
documents and reported according to Sponsor’s instructions. 


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All AEs occurring at any time during the study (including the follow-up period) will be 
followed by the Investigator until satisfactory resolution (e.g. value back to baseline 
value) or stabilization or until final database lock. If necessary, in order to obtain 
additional information to ensure safety to the subject, additional blood and urine samples 
may be taken at the discretion of the Investigator. Certain long-term AEs related to 
therapy cannot be followed until resolution within the setting of this study. In these cases 
follow-up will be the responsibility of the treating physician. 
10.7 
REPORTING OF SERIOUS ADVERSE EVENTS TO PRIMEVIGILANCE 
LTD. 
All SAEs independent of the circumstances or suspected cause must be reported on a 
Serious Adverse Event Form by the Investigator to PrimeVigilance Ltd. within 24 hours 
of their knowledge of the event, preferably by fax (+44 800 471 5694) or by e-mail  
(MMV@primevigilance.com). 
The SAE form should include a clearly written narrative describing signs, symptoms and 
treatment of the event, diagnostic procedures, as well as any relevant laboratory data and 
any sequelae, in order to allow a complete medical assessment of the case and 
independent determination of the possible causality.  
Follow-up and outcomes should be reported for all subjects who experience an SAE. 
It is critical that the information provided on the Serious Adverse Event Form matches 
the information recorded in the source documents and in the eSource system for the same 
event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital 
case reports, autopsy reports and other documents should be sent when requested and 
applicable. Follow-up reports relative to the subject’s subsequent course must be 
submitted to PrimeVigilance Ltd. until the event has subsided or, in case of permanent 
impairment, until the condition stabilizes. 
10.8 
PREGNANCY 
All initial reports of pregnancy in subjects or in partners of male subjects must be 
reported by the Investigator to PrimeVigilance Ltd. within 24 hours of his/her knowledge 
of the event using a Pregnancy Form. Any subject who becomes pregnant during the 
study must be promptly withdrawn from the study (cfr. Section 8). 
The Investigator will contact the subject at the expected time of delivery for follow-up. 
Abnormal pregnancy outcomes (e.g. spontaneous or induced abortion, stillbirth, neonatal 
death, congenital abnormality, birth defect) are considered SAEs and must be reported 
using the Serious Adverse Event Form. 
10.9 
REPORTING OF SERIOUS ADVERSE EVENTS TO COMPETENT 
AUTHORITIES/ETHICS COMMITTEES 
PrimeVigilance Ltd. assumes responsibility for appropriate reporting of AEs to the 
regulatory authorities. PrimeVigilance Ltd. will also report to the Investigator all SAEs 
that are unlisted (unexpected) and associated with the use of the drug. The Investigator 
(or PrimeVigilance Ltd. where required) must report these events to the appropriate 


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Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the 
protocol, unless otherwise required and documented by the IEC/IRB. 
Adverse events reporting, including suspected unexpected serious adverse reactions 
(SUSARs), will be carried out in accordance with applicable local regulations. 
After termination of the clinical study (determined as LPLV), any unexpected safety 
issue that changes the risks benefit analysis and is likely to have an impact on the 
subjects who have participated in the study, together with proposed actions, will be 
reported by the Sponsor/PrimeVigilance Ltd. to the competent authority(ies) concerned 
as soon as possible. 


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11. 
ETHICAL ASPECTS 
11.1 
STUDY-SPECIFIC DESIGN CONSIDERATIONS 
Potential subjects will be fully informed of the nature of the study and of the risks and 
requirements of the study before any study-related assessment will be carried out. During 
the study, subjects will be given any new information that may affect their decision to 
continue participation. They will be informed that their participation in the study is 
voluntary and that they may withdraw from the study at any time with no reason given 
and without penalty or loss of benefits to which they would otherwise be entitled. Only 
subjects who are fully able to understand the risks, benefits and potential AEs of the 
study, and who provide their consent voluntarily will be enrolled in the study. 
11.2 
REGULATORY ETHICS COMPLIANCE 
11.2.1 
Investigator Responsibilities 
The Investigator(s) should be qualified by education, training and experience to assume 
responsibility for the proper conduct of the study, should meet all the qualifications 
specified by the applicable regulatory requirement(s), and should provide evidence of 
such qualifications through up-to-date curriculum vitae or other relevant documentation 
requested by the Sponsor, the IRB/IEC or the regulatory authority(ies). 
The Investigator is responsible for ensuring that the clinical study is performed in 
accordance with the protocol, current International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines on Good 
Clinical Practice (GCP) and applicable regulatory and country-specific requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for 
designing, conducting, recording and reporting studies that involve the participation of 
human subjects. Compliance with this standard provides public assurance that the rights, 
safety and well-being of study subjects are protected, consistent with the principles 
originating from the Declaration of Helsinki (1964 and revisions), and that the clinical 
study data are credible. 
11.2.2 
Independent Ethics Committee or Institutional Review Board 
(IEC/IRB) 
An IRB/IEC should safeguard the rights, safety and well-being of all study subjects. 
Special attention should be paid to studies that may include vulnerable subjects. 
Before the start of the study, the Investigator (or Sponsor where required) will provide 
the IEC/IRB with current and complete copies of the following documents: 
- 
Final protocol and, if applicable, amendments; 
- 
Sponsor-approved Informed Consent Form (ICF) (and any updates or any other 
written materials to be provided to the subjects); 
- 
Sponsor-approved subject recruiting materials; 
- 
Investigator Brochure (or equivalent information) and addenda; 
- 
Available safety information; 


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- 
Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable; 
- 
Investigator’s current curriculum vitae or other documentation evidencing 
qualifications (unless not required, as documented by the IEC/IRB); 
- 
Information regarding funding, name of the Sponsor, institutional affiliations, 
other potential conflicts of interest and incentives for subjects; 
- 
Any other documents that the IEC/IRB may require to fulfil its obligation. 
This study will be undertaken only after the IEC/IRB has given full written approval of 
the final protocol and amendments (if any), the ICF(s) and updates (if any), applicable 
recruiting materials and any other written information to be provided to the subjects, and 
the Sponsor has received a copy of this approval. This approval letter must be dated and 
must clearly identify the IEC/IRB and the documents being approved. 
During the study, the Investigator (or Sponsor where required) will send the following 
documents and updates to the IEC/IRB for its review and approval, where appropriate:  
- 
Protocol amendments; 
- 
Revision(s) to the ICF and any other written materials to be provided to the 
subjects; 
- 
New or revised subject recruiting materials approved by the Sponsor; 
- 
Revisions to compensation for study-related injuries or payment to subjects for 
participation in the study; 
- 
Investigator’s Brochure addenda or new edition(s); 
- 
Summaries of the status of the study at intervals stipulated in guidelines of the 
IEC/IRB (at least annually); 
- 
Reports of AEs that are serious, unlisted and associated with the IMP; 
- 
New information that may adversely affect the safety of the subjects or the 
conduct of the study; 
- 
Deviations from or changes to the protocol to eliminate immediate hazards to the 
subjects; 
- 
Report of death of any subjects under the Investigator’s care; 
- 
Notification if a new Investigator is responsible for the study at the clinical unit; 
- 
Development Safety Update Report, Short-Term Study Specific Safety Summary 
and Line Listings, where applicable; 
- 
Any other requirements of the IEC/IRB. 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF 
revisions must be submitted promptly to the IEC/IRB for review and approval before 
implementation of the change(s), except when necessary to eliminate immediate hazard 
to the study subjects. If a deviation from or a change to the protocol was implemented to 
eliminate an immediate hazard to study subjects, then the implemented deviation or 
change, the reasons for it, and, if appropriate, the protocol amendment should be 
submitted to the IEC/IRB as soon as possible. 
The Investigator (or Sponsor where required) will notify the IEC/IRB about the study 
completion within 90 days after the end of the study (defined as LPLV). 


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11.2.3 
Informed Consent 
Each subject must give written consent according to local requirements after the nature 
of the study has been fully explained. The consent form must be signed before 
performance of any study-related activity. The consent form that is used must be 
approved by both the Sponsor and the reviewing IEC/IRB. The informed consent should 
be in accordance with the principles that originated in the Declaration of Helsinki, 
current ICH and GCP guidelines, applicable regulatory requirements and Sponsor policy. 
Before enrolment in the study, the Investigator or an authorized member of the clinical 
staff must explain to potential subjects the aims, methods, reasonably anticipated benefits 
and potential hazards of the study, and any discomfort participation in the study may 
entail. Subjects will be informed that their participation is voluntary and that they may 
refuse to participate or withdraw consent to participate at any time, without penalty or 
loss of benefits to which the subject was entitled. Finally, they will be told that the 
Investigator will maintain a subject identification register for the purposes of long-term 
follow-up if needed and that their records may be accessed by health authorities and 
authorized Sponsor staff without violating the confidentiality of the subject, to the extent 
permitted by the applicable law(s) or regulations. By signing the ICF the subject is 
authorizing such access, and agrees to allow his or her study physician to recontact the 
subject for the purpose of obtaining consent for additional safety evaluations, if needed. 
The language about the study used in the oral and written information, including the ICF, 
should be non-technical and practical and should be understandable to the subject (or the 
subject’s legally acceptable representative). The subject will be given sufficient time to 
read the ICF and the opportunity to ask questions. After this explanation and before entry 
into the study, consent should be appropriately recorded by means of the subject's 
personally dated signature. After having obtained consent, a copy of the ICF must be 
given to the subject. 
If a subject (or legally acceptable representative) is unable to read or write, an impartial 
witness should be present during the entire informed consent discussion. After the 
written ICF and any other written information to be provided to the subjects, is read and 
explained to the subject (or legally acceptable representative), and after the subject (or 
legally acceptable representative) has orally consented to the subject’s participation in 
the study and, if capable of doing so, has personally dated and signed the ICF, the 
witness should personally date and sign the consent form. By signing the ICF, the 
witness attests that the information in the ICF and any other written information was 
accurately explained to, and apparently understood by, the subject (or legally acceptable 
representative), and that informed consent was freely given by the subject (or legally 
acceptable representative). 
11.2.4 
Privacy of Personal Data 
The collection and processing of personal data from subjects enrolled in the study will be 
limited to those data that are necessary to investigate the safety, quality and utility of the 
IMP used in the study. 
These data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and 
regulations. Appropriate technical and organizational measures to protect the personal 


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data against unauthorized disclosures or access, accidental or unlawful destruction, or 
accidental loss or alteration must be put in place. Sponsor personnel whose 
responsibilities require access to personal data need to agree to keep the identity of the 
study subjects confidential. 
The informed consent obtained from the subjects includes explicit consent for the 
processing of personal data and for the Investigator to allow direct access to subjects’ 
original medical records for study-related monitoring, audit, IEC/IRB review and 
regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries. 


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12. 
ADMINISTRATIVE REQUIREMENTS 
12.1 
PROTOCOL AMENDMENTS 
Neither the Investigator nor the Sponsor will modify this protocol without a formal 
amendment. All protocol amendments must be issued by the Sponsor and signed and 
dated by the Investigator. Protocol amendments must not be implemented without prior 
IEC/IRB approval nor when the relevant competent authority has raised any grounds for 
non-acceptance, except when necessary to eliminate immediate hazard to the subjects, in 
which case an amendment must be promptly submitted to the IEC/IRB and relevant 
competent authority. Documentation of amendment approval by the Investigator and 
IEC/IRB must be provided to the Sponsor or his designee. When the change(s) involves 
only logistic or administrative aspects of the study, the IRB (and IEC where required) 
only needs to be notified. 
12.2 
SUBJECT IDENTIFICATION, ENROLMENT AND SCREENING LOGS 
The Investigator agrees to complete a subject identification and enrolment log to permit 
easy identification of each subject during and after the study. This document will be 
reviewed by the Sponsor site contact for completeness. 
The subject identification and enrolment log will be treated as confidential and will be 
filed by the Investigator in the study file. To ensure subject confidentiality, no copies will 
be made. All reports and communications related to the study will identify subjects by 
initials and/or assigned number only. 
The Investigator must also complete a subject screening log which reports on all subjects 
who were seen to determine eligibility for inclusion in the study. 
12.3 
SOURCE DOCUMENTATION 
The LabPas system is an electronic data capturing and information management system 
that will also serve as an eSource system for this study. The system combines all aspects 
of source data capturing with process control and clinical study management. All clinical 
and laboratory data, except those that are paper-based, will be collected directly in 
LabPas. The Source Document Identification Overview will specify which information 
will be eSource and which will be paper-based. The monitor will check data at the 
monitoring visits to the clinical unit. The Investigator will ensure that the data collected 
are accurate, complete and legible. Data will be monitored within LabPas by the study 
monitor who has only reading rights. Any changes required following monitoring will be 
made by site personnel or the Investigator and will be documented with a full audit trail 
within LabPas. 
At a minimum, source documentation must be available for the following: subject 
identification, eligibility and study identification; date of informed consent, dates of 
visits, results of safety and efficacy parameters as required by the protocol, record of all 
AEs, follow-up of AEs, concomitant medication, drug receipt/dispensing/return records, 
IMP administration information, laboratory and ECG printouts (if not available digitally), 
date of study completion and reason for early discontinuation of IMP or withdrawal from 
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It is recommended that the author of an entry in the (e)Source documents be identifiable. 
Source data may be directly captured from devices, transferred from third parties (e.g. 
laboratory data), or entered manually into the eSource system in use at the clinical unit. 
In such case, the majority of the source data will only be available electronically. The 
remainder of the data, captured initially on paper, may be entered retrospectively into the 
eSource system. 
Following the ICH-GCP guidelines, direct access to (e)Source documentation (medical 
records) must be allowed. 
12.4 
CASE REPORT FORM COMPLETION 
All source data, except those that are paper-based, will be collected directly into the 
eSource system. Paper-based source data will be manually transcribed to the eSource 
system. Only the data required for the clinical database will be transferred electronically 
from the eSource system to the clinical database. 
12.5 
MONITORING 
Medical and clinical monitoring of the study will be done under the responsibility of the 
Sponsor by ICON Clinical Research and Biologic LLP, respectively. 
The monitor will perform on-site monitoring visits as frequently as necessary. The 
monitor will record the dates of the visits in a study unit visit log that will be kept at the 
clinical unit. The first post-initiation visit will be made as soon as possible after 
enrolment has begun. At these visits, the monitor will compare the data captured in the 
eSource system for completeness and accuracy and perform data source verification to 
any data that has been captured as paper source or entered in the system later on. The 
nature and location of all source documents will be identified to ensure that all sources of 
original data required to complete the eSource system are known to the Sponsor and 
clinical staff and are accessible for verification by the Sponsor site contact. If electronic 
records are maintained at the investigational site, the method of verification must be 
discussed with the clinical staff. 
Direct access to eSource documentation (medical records) must be allowed at all times 
for the purpose of verifying that the data recorded in the eSource system are consistent 
with the source documentation data. Findings from this review of captured data will be 
discussed with the clinical staff. During on-site monitoring visits (notified and agreed in 
advance with the clinical staff), the relevant clinical staff will be available, the eSource 
documentation will be accessible, and a suitable environment for review of study-related 
documents will be provided. The monitor will meet with the Investigator on a regular 
basis during the study to provide feedback on the study conduct. 
12.6 
DATA MANAGEMENT 
Data management of the study will be performed under Sponsor delegation by SGS Life 
Sciences. 
After the data entered in the eSource system are released by the Investigator, the data will 
be uploaded into the clinical database to perform cleaning activities. Computerized data 
cleaning checks will be used in addition to manual review, including listings review, to 


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check for discrepancies and to ensure consistency and completeness of the data. Queries 
emerging during data cleaning will be generated by the clinical data manager in the 
eSource system. The Investigator or his designee will answer the queries and update the 
source data, if needed. 
The clinical database will be locked as soon as it is considered clean. Before the clinical 
database will be locked, the study eSource system will be locked by the clinical staff. 
Only authorized and well-documented updates to the study data are possible after 
database lock. The locked database is used in the final statistical analysis for study 
reporting. Measures will be undertaken to protect subject data handed over by the 
Investigator to the data management department and during inspections against 
disclosure to unauthorized third parties. Subject confidentiality will be maintained at all 
times. 
12.7 
DATA QUALITY ASSURANCE 
The accuracy and reliability of the study data will be assured by the selection of qualified 
Investigators and appropriate study sites, review of protocol procedures with the 
Investigator and associated personnel prior to the study, and by periodic monitoring visits 
by the Sponsor or designate. 
The Sponsor or his designee will review the eSource system for accuracy and 
completeness during (on-site) monitoring visits and after transmission to the Sponsor; 
any discrepancies will be resolved with the Investigator or designee, as appropriate. After 
upload of the data into the clinical study database, their accuracy verified using 
appropriate validation programs. 
In accordance with Good Clinical Research Practice Guidelines and Recommendations, 
the Sponsor will be entitled to audit the facilities used in the clinical and laboratory parts 
of the study, as well as to access all the data files pertaining to the study. Similar 
procedures may also be conducted by agents of any regulatory body, either as part of a 
national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The Investigator should immediately notify the Sponsor if they 
have been contacted by a regulatory agency concerning an upcoming inspection. 
12.8 
ON-SITE AUDITS 
Representatives of the Sponsor’s quality assurance department may visit the clinical unit 
at any time during or after completion of the study to conduct an audit of the study in 
compliance with regulatory guidelines and company policy. These audits will require 
access to all study records, including source documents, for inspection and comparison 
with the eSource system. Subject privacy must, however, be respected. The Investigator 
and clinical staff are to be present and available for consultation during routinely 
scheduled site audit visits conducted by the Sponsor or his designee. 
Similar procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in 
support of a regulatory submission. The Investigator should immediately notify the 
Sponsor if they have been contacted by a regulatory agency concerning an upcoming 
inspection. 


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12.9 
STUDY TERMINATION 
The Sponsor has the right to terminate the study at any time. In case of an early 
termination of the study for safety reasons, or temporary halt by the Sponsor, the 
IEC/IRB and competent authorities should be notified within 15 calendar days and 
should be provided with a detailed written explanation for the termination/halt. 
An end-of-study declaration will be submitted to the regulatory authorities and IEC/IRB 
after the complete study has ended. This notification will be submitted within 90 days 
after the end of the study. 
12.10 RECORD RETENTION 
In compliance with the ICH/GCP guidelines, the Investigator/Institution will maintain all 
eSource and all paper source documents that support the data collected from each 
subject, as well as all study documents as specified in ICH/GCP Section 8, Essential 
Documents for the Conduct of a Clinical Trial and all study documents as specified by 
the applicable regulatory requirement(s). The Investigator/Institution will take measures 
to prevent accidental or premature destruction of these documents. 
Essential documents must be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IMP. These documents will be 
retained for a longer period if required according to the applicable regulatory 
requirements or per agreement with the Sponsor. It is the responsibility of the Sponsor to 
inform the Investigator/Institution as to when these documents no longer need to be 
retained. 
If the responsible Investigator retires, relocates, or for any other reasons withdraws from 
his responsibility of keeping the study records, custody must be transferred to a person 
who will accept the responsibility. The Sponsor must be notified in writing of the name 
and address of the new custodian. Under no circumstance shall the Investigator relocate 
or dispose of any study documents without having obtained written approval from the 
Sponsor. 
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review 
any documentation related to the study, the Investigator must permit access to such 
reports. 
12.11 USE OF INFORMATION AND PUBLICATION 
All information, including but not limited to, information regarding investigational 
product or the Sponsor’s operations (e.g. patent application, formulas, manufacturing 
processes, basic scientific data, prior clinical data, formulation information) supplied by 
the Sponsor to the Investigator and not previously published, and any data generated as a 
result of this study are considered confidential and remain the sole property of the 
Sponsor. The Investigator agrees to maintain this information in confidence, to use this 
information only to accomplish this study and not to use it for other purposes without the 
Sponsor’s prior written consent. 


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The Investigator understands that the information generated in this clinical study will be 
used by the Sponsor in connection with the continued development of the IMP, and thus 
may be disclosed as required to other clinical Investigators or regulatory agencies. To 
permit information derived from the clinical studies to be used, the Investigator is 
obliged to provide the Sponsor with all data obtained in the study. 
The results of the study will be reported in a Clinical Study Report generated under the 
responsibility of the Sponsor and will contain eSource system data from all clinical units 
that participated in the study. 
Clinical narratives may be written for the following events (for example): 
- 
All deaths (irrespective of drug relationship); 
- 
All other SAEs and AESIs during treatment with the IMP; 
- 
All discontinuations of the IMP due to AEs (irrespective of drug relationship); 
- 
At the discretion of the team and after statistical analysis of the data, certain 
discontinuations not related to AEs or treatment failure, i.e. related to lost to 
follow-up or withdrawal of consent (irrespective of treatment group); 
- 
Any events of special interest explicitly requested by the regulatory agencies. 
The PI will sign off the final version of the Clinical Study Report. A summary of this 
final version will be provided to the Investigators, the applicable regulatory authorities 
and the IECs/IRBs, if required by the applicable regulatory requirements, within 1 year 
after the end of the study (LPLV). 
The Sponsor shall have the right to publish study data and information without approval 
from the Investigator. If an Investigator wishes to publish information from the study, a 
copy of the manuscript must be provided to the Sponsor for review at least 60 days 
before submission for publication or presentation. Expedited reviews will be arranged for 
abstracts, poster presentations or other materials. If requested by the Sponsor in writing, 
the Investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific 
integrity or regulatory compliance, the Sponsor will review these issues with the 
Investigator. The Sponsor will not mandate modifications to scientific content and does 
not have the right to suppress information. For multicentre study designs and substudy 
approaches, results may need to be published in a given sequence (e.g. substudies should 
generally not be published before the primary endpoints of a study have been published). 
Similarly, Investigators will recognize the integrity of a multicentre study by not 
publishing data derived from an individual clinical unit until the combined results from 
the completed study have been published in full, within 12 months after conclusion, 
abandonment or termination of the study at all clinical units, or the Sponsor confirms 
there will be no multicentre study publication. Authorship of publications resulting from 
this study will be based on the guidelines on authorship, such as those described in the 
Uniform Requirements for Manuscripts Submitted to Biomedical Journals, which state 
that the named authors must have made a significant contribution to the design of the 
study or analysis and interpretation of the data, provided critical review of the paper, and 
given final approval of the final version. 


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12.12 REGISTRATION OF CLINICAL STUDIES AND DISCLOSURE OF 
RESULTS 
Public disclosure of the study is under the responsibility of the Sponsor. The study will 
be registered on the ClinicalTrials gov site. 
12.13 CONFIDENTIALITY 
All study documents are provided by the Sponsor to the Investigator and appointed 
clinical staff in confidence. None of this material may be disclosed to any party not 
directly involved in the study without the Sponsor’s written permission. 
The Investigator must assure that subjects’ anonymity will be maintained. The 
Investigator will keep a separate list with at least the initials, the subjects’ study numbers, 
names, addresses and telephone numbers. The Investigator will maintain this for the 
longest period of time allowed by his/her own institution and, in any case, until further 
communication from the Sponsor. 


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13. 
REFERENCES 
1. Bastiaens GJH, van Meer MPA, Scholzen A, et al. Safety, Immunogenicity, and 
Protective Efficacy of Intradermal Immunization with Aseptic, Purified, 
Cryopreserved Plasmodium falciparum Sporozoites in Volunteers Under 
Chloroquine Prophylaxis: A Randomized Controlled Trial. Am J Trop Med Hyg. 
2016 Mar;94(3):663-73. 
2. Burrows JN, Duparc S, Gutteridge WE, Hooft van Huijsduijnen R, Kaszubska W, 
Macintyre F, et al. New developments in anti-malarial target candidate and 
product profiles. Malar J. 2017; 16:26.  
3. Fridericia LS. The duration of systole in the electrocardiogram of normal subjects 
and of patients with heart disease. Acta Medica Scandinavica. 1920; 53:469–486. 
4. Gómez-Pérez GP, Legarda A, Muñoz J, et al. Controlled human malaria infection 
by intramuscular and direct venous inoculation of cryopreserved Plasmodium 
falciparum sporozoites in malaria-naive volunteers: effect of injection volume 
and dose on infectivity rates. Malar J. 2015 Aug 7;14:306. 
5. Hodgson SH, Juma E, Salim A, et al. Evaluating controlled human malaria 
infection in Kenyan adults with varying degrees of prior exposure to Plasmodium 
falciparum using sporozoites administered by intramuscular injection. Front 
Microbiol. 2014 Dec 12;5:686. 
6. Investigator’s Brochure P218, Version 4.0, 2018. 
7. Investigational Brochure PfSPZ Challenge (NF54). Sanaria Incorporated, 
Edition 12, 2018.  
8. Investigational Medicinal Product Dossier P218.HCl, Version 2.0, 2017. 
9. Lell B, Mordmüller B, Dejon Agobe JC, et al. Impact of Sickle Cell Trait and 
Naturally Acquired Immunity on Uncomplicated Malaria after Controlled Human 
Malaria Infection in Adults in Gabon. Am J Trop Med Hyg. 2018 Feb;98(2):508-
515. 
10. Lyke K, Laurens M, Strauss K, et al. Optimizing Intradermal Administration of 
Cryopreserved Plasmodium falciparum Sporozoites in Controlled Human Malaria 
Infection. Am J Trop Med Hyg. 2015 Dec;93(6):1274-84. 
11. Mordmüller B, Supan C, Sim KL, Gómez-Pérez GP, Ospina Salazar CL, Held J, 
et al. Direct venous inoculation of Plasmodium falciparum sporozoites for 
controlled human malaria infection: a dose-finding trial in two centres. Malar J. 
2015; 14:117. 
12. Mordmüller B, Surat G, Lagler H, et al. Sterile protection against human malaria 
by chemoattenuated PfSPZ vaccine. Nature. 2017 Feb 23;542(7642):445-449. 
13. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 
European Guidelines on cardiovascular disease prevention in clinical practice: 
The Sixth Joint Task Force of the European Society of Cardiology and Other 
Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted 
by representatives of 10 societies and by invited experts). Developed with the 
special contribution of the European Association for Cardiovascular Prevention & 


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Rehabilitation (EACPR). European Heart Journal. 2016; Volume 37 (29): 2315–
2381. 
14. Population PK Model of P218 and its Metabolites, Version 1.0, 2018. 
15. Roestenberg M, Bijker EM, Sim BK, et al. Controlled human malaria infections 
by intradermal injection of cryopreserved Plasmodium falciparum sporozoites. 
Am J Trop Med Hyg. 2013 Jan;88(1): 5-13. 
16. Sheehy SH, Spencer AJ, Douglas AD, et al. Optimising Controlled Human 
Malaria Infection Studies Using Cryopreserved P. falciparum Parasites 
Administered by Needle and Syringe. PLoS One. 2013 Jun 18;8(6):e65960. 
17. Shekalaghe S, Rutaihwa M, Billingsley PF, et al. Controlled human malaria 
infection of Tanzanians by intradermal injection of aseptic, purified, 
cryopreserved Plasmodium falciparum sporozoites. Am J Trop Med Hyg. 2014 
Sep;91(3):471-80. 
18. Sissoko MS, Healy SA, Katile A, et al. Safety and efficacy of PfSPZ Vaccine 
against Plasmodium falciparum via direct venous inoculation in healthy malaria-
exposed adults in Mali: a randomised, double-blind phase 1 trial. Lancet Infect 
Dis. 2017 May;17(5):498-509. 
19. Smith DA, Hammond T, Baillie TA. Safety assessment of acyl glucuronides – a 
simplified paradigm. Drug Metab Dispos.2018; 46:908-921. 
20. World Malaria Report 2016. World Health Organization. Geneva, Switzerland 
(http://www.who.int/publications/en/). Accessed August 2018 
21. World Malaria Report 2017. World Health Organization. Geneva, Switzerland 
(http://www.who.int/publications/en/). Accessed August 2018. 
22. 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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ATTACHMENT 1: EXAMPLE OF CLINICAL SCORE FOR 
MALARIA 
Grading of the signs and symptoms specified in the table beneath will be performed at all 
relevant protocol-specified time points over the past 24 hours in accordance with the 
following: 
- 
Absent = 0 
- 
Mild = 1 
- 
Moderate = 2 
- 
Severe = 3 
Subject ID:  
Date:  
Time of  Onset: 
 
 
 
Stop: 
Symptom/Sign 
Score (0 to 3) 
qPCR 
Headache 
 
☐ positive 
☐ negative 
Myalgia (muscle ache) 
 
Arthralgia (joint ache) 
 
 
Fatigue/lethargy 
 
Malaise (general 
discomfort/uneasiness) 
 
Chills/Shivering/Rigors 
 
Sweating/hot spells 
 
Anorexia 
 
Nausea 
 
Vomiting 
 
Abdominal discomfort 
 
Fever 
 
Tachycardia 
 
Hypotension 
 
 


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ATTACHMENT 2: BECK DEPRESSION INVENTORY 


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ATTACHMENT 3: NORMAL RANGES FOR VITAL SIGNS 
AND ECG 
NORMAL RANGES FOR VITAL SIGNS 
Systolic blood 
pressure (mmHg) 
Diastolic blood 
pressure (mmHg) 
Pulse rate 
(bpm) 
Oral temperature 
(°C) 
90 ≤ SBP ≤ 150 
45 ≤ DBP ≤ 90 
40 ≤ pulse ≤ 100 
35.0≤ t° ≤ 37.5 
 
These normal ranges are applicable in supine and sitting position (after 5 minutes) and, 
only for Cohort 1, in the standing position (after 2 minutes).  
 
NORMAL RANGES FOR ECG PARAMETERS 
PR 
(ms) 
QRS 
(ms) 
QTc F 
(ms) 
Heart rate 
(bpm) 
120 ≤ PR ≤ 220 
QRS ≤ 120 
QTc ≤ 450 
40 ≤ HR ≤ 100 
 
These normal ranges are applicable in supine and sitting position (after 10 minutes). 
 

SAP_001.pdf: 
 
 
 
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STATISTICAL ANALYSIS PLAN 
 
 A single centre, randomised, double-blind, placebo-controlled, 
Phase Ib study to evaluate the safety, tolerability and 
chemoprotective antimalarial activity of P218 against controlled 
human malaria infection with Plasmodium falciparum 
sporozoite challenge in non-immune healthy adult volunteers 
 
Protocol: MMV_P218_17_01 
SGS LS number: BE-80-1803670 
Development phase: Ib 
Sponsor: Medicines for Malaria Venture (MMV) 
SAP version 
number: Final 1.0 
SAP version date: 10MAY2019  
 
 


Statistical Analysis Plan 
 
MMV_P218_17_01 
 
Final 1.0 of 10MAY2019 
 
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SIGNATURE PAGE 
Name and function 
Date 
(ddMMMyyyy) 
Signature 
SGS LS author(s) and reviewer(s): 
Catherine Bertrand, 
biostatistical 
coordinator 
 
 
 
 
Françoise Frérart, 
pharmacokineticist 
 
 
 
 
Ben Van Baelen, sr 
biostatistician 
 
 
 
 
Hélène Bonnafous, 
pharmacokineticist 
 
 
 
 
Sponsor’s approval: 
The approver agrees the statistical analysis will be performed according to this 
statistical analysis plan. 
Nicole Andenmatten, 
project director 
 
 
 
 
Farouk Chuglay, 
medical director 
 
 
 
 
 
 


Statistical Analysis Plan 
 
MMV_P218_17_01 
 
Final 1.0 of 10MAY2019 
 
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PROTOCOL HISTORY 
Protocol: 
Version or ID 
Date 
(ddMMMyyyy) 
Impact of the changes on the statistical 
analysis 
Final 
25SEP2018 
NAP 
Final 2.0 
20MAR2019 
Including substantial amendment 1: 
Dose of cohort 3 de-escalated from 1000 mg 
(i.e. cohort 2 dose) to 100 mg 
Days of administration in cohort 3 were 
changed from D3 and D5 to D1 and D3, 
which is as in cohort 2. Therefore, placebo 
subjects of cohort 3 can now be pooled with 
placebo subjects of cohort 2 in by time-point 
summaries as well. 
PK/PD relationship was added as a 
secondary objective and endpoint. 
A PK/PD population was added 
This statistical analysis plan (SAP) only considers the latest version of the protocol, 
and of the protocol amendments, as listed above. 
 
 


Statistical Analysis Plan 
 
MMV_P218_17_01 
 
Final 1.0 of 10MAY2019 
 
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LIST OF ABBREVIATIONS 
ADaM 
analysis data model 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
BLQ 
below the limit of quantification 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CHMI 
controlled human malaria infection 
CI 
confidence interval 
CK 
creatinine kinase 
CPK 
creatine phosphokinase 
CRF 
case report form 
CRP 
C-reactive protein 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 
DVI 
direct venous inoculation 
DY 
relative day 
ECG 
electrocardiogram 
EOS 
end-of-study 
GGT 
gamma-glutamyl transferase 
GMR 
geometric mean ratio 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
LDH 
lactate dehydrogenase 
MCH 
mean corpuscular haemoglobin 
MCHC 
mean corpuscular haemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAP 
not applicable 


Statistical Analysis Plan 
 
MMV_P218_17_01 
 
Final 1.0 of 10MAY2019 
 
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PD 
pharmacodynamic(s) 
P falciparum 
Plasmodium falciparum 
PfSPZ 
P. falciparum sporozoites 
PK 
pharmacokinetic(s) 
PP 
per protocol 
qPCR 
quantitative polymerase chain reaction 
QTc 
corrected QT interval 
QTcB 
Bazett’s corrected QT interval 
QTcFri 
Fridericia’s corrected QT interval 
RBC 
red blood cell 
RND 
all randomised subjects analysis set 
SAP 
statistical analysis plan 
SAF 
safety analysis set 
SBP 
systolic blood pressure 
SCR 
all screened subjects analysis set 
SD 
standard deviation 
SE 
standard error 
SGS LS 
SGS Life Sciences 
SOP 
standard operating procedure 
SRT 
safety review team 
STAT 
statistics 
TBS 
thick blood smear 
TEAE 
treatment-emergent adverse event 
TLF 
tables, listings and figures 
VS 
vital signs 
WBC 
white blood cell 
WHO 
World Health Organisation 
WI 
work instruction 


Statistical Analysis Plan 
 
MMV_P218_17_01 
 
Final 1.0 of 10MAY2019 
 
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DEFINITION OF TERMS 
baseline 
An initial measurement of a condition that is taken at an early time 
point and used for comparison over time to look for changes. The 
study specific definition is in section 5.2.2. 
 
 
case report 
form (CRF) 
A printed, optical, or electronic document designed to record 
protocol required information to be reported to the sponsor for each 
trial subject. 
 
 
display 
Analysis table, figure or listing 
 
 
phase 
Interval of time in the planned conduct of a study associated with a 
specific purpose: for example, screening, treatment, follow-up. 
 
 
round half 
up tie-
breaking 
rule 
Convention to round values ending with 5 to positive infinity. The 
round half up rule is implemented in the SAS® ROUND function. 
Examples: 
Database value 
Rounded value 
-1.35 
-1.3 
-1.25 
-1.2 
 1.25 
 1.3 
 1.35 
 1.4 
significant 
digit 
All digits of a number used to express it to the required degree of 
accuracy, starting from the first non-zero digit. 
 
 
study drug 
Pharmaceutical form of an active ingredient or placebo, being tested 
or used as a reference in a clinical study. 
 
 
treatment-
emergent 
abnormality 
Any post-baseline abnormality that was not present at baseline (e.g. 
haemoglobin normal at baseline and grade 1 post-baseline; glucose 
low at baseline and high post-baseline; QTcFri ]450; 480] ms at 
baseline and >500 ms post-baseline) 
 
 
 


Statistical Analysis Plan 
 
MMV_P218_17_01 
 
Final 1.0 of 10MAY2019 
 
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TABLE OF CONTENTS 
Signature page .............................................................................................................. 2 
Protocol history ............................................................................................................ 3 
List of abbreviations .................................................................................................... 4 
Definition of terms ....................................................................................................... 6 
Table of contents .......................................................................................................... 7 
1. 
Introduction ....................................................................................................... 10 
1.1 
Study objectives ............................................................................................. 10 
1.2 
Study design .................................................................................................. 10 
1.3 
Expected sample size ..................................................................................... 12 
1.4 
Randomisation and blinding .......................................................................... 12 
1.5 
Interim analysis ............................................................................................. 12 
1.6 
Software ......................................................................................................... 12 
1.7 
Validation model ........................................................................................... 12 
2. 
Pharmacodynamic and pharmacokinetic analyses ........................................ 14 
2.1 
Pharmacodynamics ........................................................................................ 14 
2.1.1 
Available data .................................................................................. 14 
2.1.2 
Derivation rules ............................................................................... 14 
2.1.3 
Presentation of results ..................................................................... 14 
2.2 
Pharmacokinetics ........................................................................................... 15 
2.2.1 
Available data .................................................................................. 15 
2.2.2 
Derivation rules ............................................................................... 15 
2.2.3 
Presentation of results ..................................................................... 17 
3. 
Safety analyses ................................................................................................... 19 
3.1 
Adverse events ............................................................................................... 19 
3.1.1 
Available data .................................................................................. 19 
3.1.2 
Derivation rules ............................................................................... 19 
3.1.3 
Presentation of results ..................................................................... 20 
3.2 
Clinical laboratory evaluation ....................................................................... 21 
3.2.1 
Available data .................................................................................. 21 
3.2.2 
Derivation rules ............................................................................... 21 
3.2.3 
Presentation of results ..................................................................... 22 
3.3 
Vital signs ...................................................................................................... 22 
3.3.1 
Available data .................................................................................. 22 


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3.3.2 
Derivation rules ............................................................................... 22 
3.3.3 
Presentation of results ..................................................................... 23 
3.4 
Electrocardiograms ........................................................................................ 23 
3.4.1 
Available data .................................................................................. 23 
3.4.2 
Derivation rules ............................................................................... 23 
3.4.3 
Presentation of results ..................................................................... 24 
3.5 
Physical examinations ................................................................................... 24 
4. 
General characteristics analyses ...................................................................... 25 
4.1 
Subject disposition ......................................................................................... 25 
4.2 
Protocol deviations and eligibility ................................................................. 25 
4.3 
Demographic and other baseline characteristics ........................................... 25 
4.3.1 
Available data .................................................................................. 25 
4.3.2 
Derivation rules ............................................................................... 25 
4.3.3 
Presentation of results ..................................................................... 26 
4.4 
Medical history and concomitant diseases .................................................... 26 
4.4.1 
Available data .................................................................................. 26 
4.4.2 
Derivation rules ............................................................................... 26 
4.4.3 
Presentation of results ..................................................................... 26 
4.5 
Prior and concomitant therapies and rescue medication ............................... 27 
4.5.1 
Available data .................................................................................. 27 
4.5.2 
Derivation rules ............................................................................... 27 
4.5.3 
Presentation of results ..................................................................... 27 
4.6 
Exposure to study drug and challenge agent ................................................. 27 
4.6.1 
Available data .................................................................................. 27 
4.6.2 
Derivation rules ............................................................................... 27 
4.6.3 
Presentation of results ..................................................................... 27 
5. 
General methodology ........................................................................................ 28 
5.1 
Analysis sets .................................................................................................. 28 
5.1.1 
Analysis sets .................................................................................... 28 
5.1.2 
As planned versus as actual analysis ............................................... 28 
5.2 
Phases and time points ................................................................................... 29 
5.2.1 
Phases .............................................................................................. 29 
5.2.2 
Baseline and change from baseline ................................................. 29 
5.2.3 
Relative day ..................................................................................... 29 


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5.2.4 
Analysis visits ................................................................................. 29 
5.2.5 
Worst-case visit ............................................................................... 30 
5.3 
Imputation and rounding rules ....................................................................... 30 
5.3.1 
Missing values ................................................................................. 30 
5.3.2 
Handling partially or completely missing dates in calculations ...... 30 
5.3.3 
Values below or above a threshold ................................................. 30 
5.3.4 
Rounding of derived variables ........................................................ 30 
5.3.5 
Outliers ............................................................................................ 31 
5.4 
Presentation of results .................................................................................... 31 
5.4.1 
Calculation of descriptive statistics and percentages ...................... 31 
5.4.2 
Presentation of treatments ............................................................... 32 
5.4.3 
Ordering in tables, figures and listings ............................................ 32 
6. 
Changes to the planned analysis ....................................................................... 33 
6.1 
Changes not covered by protocol amendments before database lock ........... 33 
6.2 
Changes not covered by protocol amendments after database lock .............. 33 
6.3 
Changes to the final statistical analysis plan ................................................. 33 
7. 
References ........................................................................................................... 34 
8. 
List of tables, listings and figures ..................................................................... 35 
8.1 
Tables ............................................................................................................ 35 
8.2 
Listings .......................................................................................................... 36 
8.3 
Figures ........................................................................................................... 38 
9. 
Appendices ......................................................................................................... 39 
9.1 
SAS code ....................................................................................................... 39 
9.2 
Adverse Events of Special Interest ................................................................ 39 
9.3 
Schedule of assessments ................................................................................ 40 
9.3.1 
Cohort 1 ........................................................................................... 40 
9.3.2 
Cohort 2 and 3 ................................................................................. 43 
 


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1. 
INTRODUCTION 
This SAP describes the final statistical analysis to be performed for the 
MMV_P218_17_01 (BE-80-1803670) study. 
This SAP covers the pharmacodynamic (PD), pharmacokinetic (PK), safety, and 
general characteristics parts of the statistical analysis. It specifies the analysis displays 
to be presented and describes the methods and procedures in a more elaborated way 
than in the statistical methods section of the protocol. The PK/PD analysis is not in 
scope of this SAP. 
The statistical analysis will process and present the results following the International 
Council for Harmonisation (ICH) standards, in particular the ICH-E3, ICH-E6, and 
ICH-E9 guidelines. 
1.1 
STUDY OBJECTIVES 
According to the protocol, the primary objective of cohort 1 is to assess the safety and 
tolerability of two single doses of 1000 mg P218 administered 48 hours apart in 
healthy adult volunteers. The primary objective of cohorts 2 and 3 is to assess the 
chemoprotective activity of P218 in Plasmodium falciparum (P. falciparum) 
controlled human malaria infection (CHMI) in non-immune healthy volunteers 
after P. falciparum sporozoites (PfSPZ) challenge through direct venous inoculation 
(DVI). 
According to the protocol, secondary objectives are:  
• To assess the pharmacokinetic (PK) profile of P218, and in Cohort 1 only 
also of its main metabolites, up to 8 days after the first P218 administration 
to healthy adult volunteers; 
• To establish the pharmacokinetic/pharmacodynamic (PK/PD) relationship 
between P218 plasma concentration and its chemoprotective activity using 
blood stage parasitaemia as a surrogate in non immune healthy volunteers in 
a CHMI PfSPZ Challenge model; 
• To assess the safety and tolerability of P218 in non-immune healthy 
volunteers in a CHMI PfSPZ Challenge model (Cohorts 2 and 3); 
• To assess the safety and tolerability of PfSPZ Challenge in non immune 
healthy volunteers before and after P218 administration during CHMI 
(Cohorts 2 and 3). 
1.2 
STUDY DESIGN 
This is a single centre, randomised, double-blind, placebo-controlled phase Ib study. 
Thirty-two healthy men and women aged 18 to 45 years will be enrolled in 3 cohorts 
of 8, 12 and 12 subjects. A subject may be enrolled in one cohort only and is 
randomised in a 3:1 ratio, to receive two consecutive administrations of either P218 
or placebo. Enrolment in cohorts proceeds sequentially, to facilitate review of Cohort 
1 and Cohort 2 data by a safety review team (SRT) before populating Cohort 2 and 
Cohort 3, respectively.  
Subjects of cohort 1 are admitted to the clinical unit in the morning of Day -1 and are 
confined to the unit for 3 days thereafter (until Day 4, i.e. 36 hours after second 


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investigational medicinal product (IMP) administration), for close safety monitoring 
and PK assessments. First administration of 1000 mg of P218 or placebo takes place 
on Day 1. Second administration of 1000 mg of P218 or placebo takes place 48 hours 
later, on Day 3. After discharge from the clinical unit on Day 4, subjects are followed 
up with daily ambulatory visits to the clinical unit up to Day 9.  
Progression to Cohort 2 is assessed by an SRT, who reviews safety and tolerability 
after data up to Day 9 for Cohort 1 are available. 
Subjects of Cohort 2 are admitted to the clinical unit in the morning of Day -1 and are 
confined to the unit until 12 days post the PfSPZ Challenge on Day 1 (i.e. until Day 
13), for close safety monitoring and PK assessments. Each subject is administered 
3200 P. falciparum sporozoites by DVI. First administration of 1000 mg of P218 or 
placebo takes place 2 hours after PfSPZ Challenge inoculation. Second administration 
of 1000 mg of P218 or placebo takes place 48 hours after first administration of P218 
or placebo, on Day 3. 
Progression to Cohort 3 is assessed by the SRT, who reviews safety, parasitaemia and 
malaria signs and symptoms after data up to Day 35 for Cohort 2 are available, or 
after successful completion of the last rescue treatment, whichever is later. 
Subjects in Cohort 3 are admitted to the clinical unit in the morning of Day -1. On 
Day 1, subjects are administered 3200 P. falciparum sporozoites by DVI and are 
confined to the unit until 12 days post PfSPZ Challenge (i.e. until Day 13), for close 
safety monitoring and PK assessments. 100 mg of P218 or placebo are administered 
on Day 1 (2 hours after PfSPZ Challenge inoculation) and 48 hours after first 
administration of P218 or placebo, on Day 3. 
Safety, parasitaemia and malaria signs and symptoms are assessed as of Day 7, i.e. 
during confinement in the unit until Day 13 and on daily ambulatory visits to the 
clinical unit as of Day 14, until development of positive parasitaemia or until Day 28 
otherwise. If positive parasitaemia is confirmed, the subject receives rescue therapy 
and continues to be monitored daily at the clinical unit until treatment success. Upon 
treatment success, daily visits to the clinical unit are stopped, except for subjects that 
first need to complete the 3-day rescue treatment regimen and associated assessments. 
All subjects are assessed again for parasitaemia at the end-of-study (EOS) visit on 
Day 35. Subjects not developing positive parasitaemia until Day 28 receive rescue 
therapy on that day. Instead of daily monitoring at the clinical unit until treatment 
success, these subjects are only to be assessed again for parasitaemia at the EOS visit 
on Day 35. All subjects that receive rescue therapy are asked non-leading questions to 
determine the occurrence of any adverse events approximately two weeks after 
initiation of the rescue treatment, either during a planned study visit or by phone in 
case there is no planned study visit at that time. 
Antimalarial rescue therapy may be initiated whenever deemed necessary by the 
investigators, e.g. if there is a concern regarding the safety of a study subject or if a 
study subject decides to withdraw from the study. Therapy may be amended 
according to the treating physician if the patient does not respond to treatment or the 
condition worsens.  
The assessments performed are summarized per visit in the schedule of assessments 
in appendix 9.3. 


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1.3 
EXPECTED SAMPLE SIZE 
Thirty-two subjects are enrolled in 3 cohorts of 8, 12 and 12 subjects. In agreement 
with the sponsor, additional subjects may be recruited in each cohort, to replace 
discontinuations for non-safety reasons and achieve cohort sizes of 8 and 12. 
This is an exploratory study thus no sample size calculation is performed. However, if 
the nine treated subjects do not develop positive parasitaemia (quantitative 
polymerase chain reaction (qPCR) ≥ 250 asexual parasites per mL) after IMP 
administration and until Day 28, it may be concluded that the protection rate for P218 
is 0.72 (72%) with a 95% probability (lower limit of exact, one-sided test, 95%, 
confidence interval (CI) 0.72). This holds true for both Cohort 2 and Cohort 3. 
1.4 
RANDOMISATION AND BLINDING 
At screening, subjects receive a unique screening number using the letter S and a 
number ranging from 001 to 999. Subjects who are rescreened are assigned a new 
screening number. 
Subjects are assigned to 1 of 3 cohorts. Within each cohort, they are randomised in a 
3:1 ratio to receive two consecutive administrations of either P218 or placebo. 
Allocation of each subject to a given treatment are described in a randomization list 
prepared prior to study start by SGS Life Sciences Secure Data Office using SAS® 
software. 
The randomization is using randomly permuted blocks across the treatment groups. 
In agreement with the Sponsor, additional subjects may be recruited in each cohort, to 
replace discontinuations for non-safety reasons and achieve cohort sizes of 8 (cohort 
1) or 12 (cohorts 2 and 3). Replacement subjects receive the number of the subject to 
be replaced, increased by 100, and are administered the same treatment. 
Blinding is achieved with placebo identical in appearance. 
1.5 
INTERIM ANALYSIS 
No interim analyses are foreseen. 
1.6 
SOFTWARE 
SAS version 9.4 or later will be used for programming. 
WinNonlin Phoenix 8.0 or later (Pharsight Corporation, Palo Alto, Ca, USA) will be 
used for calculations of PK parameters. 
1.7 
VALIDATION MODEL 
SGS Life Sciences (SGS LS) – Clinical Research statistics (STAT) standard 
operating procedures (SOPs) and work instructions (WIs) as effective at the project 
start will be followed throughout the project, in full compliance with the applicable 
regulatory requirements. 


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Primary endpoint tables will be validated according to model C, All other 
tables/figures/listings follow validation model B (see SOP.STAT.020): 
• Model B: review by an independent person (biostatistician) 
• Model C: review by an independent person and independent programming 
of tables 14.2.1.1 and 14.3.1.1 
PK tables/figures/listings will be validated following model B (see SOP.PK.020 for 
more details): 
• Model B: review by an independent person (pharmacokineticist) 
PK analysis will be validated according SOP.PK.001. 


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2. 
PHARMACODYNAMIC AND 
PHARMACOKINETIC ANALYSES 
2.1 
PHARMACODYNAMICS 
2.1.1 
Available data 
For the challenge cohorts 2 and 3, parasitaemia and malaria signs and symptoms will 
be assessed pre-challenge and daily from day 7 on. 
Parasitaemia is assessed by qPCR and thick blood smear (TBS) microscopy. 
The following malaria signs and symptoms will be scored: headache, myalgia, 
arthralgia, fatigue/lethargy, malaise, chills/shivering/rigors, sweating/hot spells, 
anorexia, nausea, vomiting, abdominal discomfort, fever, tachycardia and 
hypotension. Each of the previously mentioned symptoms is attributed a severity 
score that can be one of the following: 0 (absent), 1 (mild), 2 (moderate) and 3 
(severe). 
2.1.2 
Derivation rules 
The primary endpoint is time to positive parasitaemia, in days, which is calculated as: 
(date of first positive parasitaemia - date of inoculation + 1)/(24*60*60).  
Positive parasitaemia is defined as qPCR outcome (MBTESTCD = 
PARADENS) ≥ 250 asexual parasites per mL. 
In the absence of positive parasitaemia, the duration will be set to a 
maximum of 28 days. Consistently, for the Kaplan-Meier plot, subjects 
without positive parasitaemia will be censored at 28 days. 
Malaria clinical score is calculated as the sum of all (14) malaria sign and symptoms 
scores (maximum score is 42). Missing individual scores will be imputed as detailed 
in section 5.3.1. The score will be rounded as detailed in section 5.3.4. 
For individual signs and symptoms, a worst-case analysis visit, as defined in section 
5.2.5 will be derived. 
2.1.3 
Presentation of results 
The primary analysis is the summary of the time to positive parasitaemia by means of 
descriptive statistics, including the geometric mean and corresponding two-sided 90% 
confidence interval (CI). 


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The following secondary analyses will be performed: 
• The incidence of positive parasitaemia between inoculation with PfSPZ and 
Day 28 will be presented, including two-sided 90% exact Clopper-Pearson 
CI. 
• For the malaria clinical score, actual values and changes from baseline will 
be evaluated by means of descriptive statistics at each time point and at the 
worst-case analysis visit. This will be done by analysis phase (treatment + 
rescue / treatment). 
• Individual malaria signs and symptoms scores will be presented as 
frequency tabulations at the worst-case analysis visit. Numbers and 
percentage of subjects with any post-baseline non-zero score will also be 
shown. 
Graphs of the median actual values over time and spaghetti plots will be prepared for 
parasitaemia and malaria clinical score. For the spaghetti plots, the median will also 
be plotted and different plotting symbols will be used on days on which rescue 
medication was given. A Kaplan-Meier plot of the time to positive parasitaemia will 
also be shown. 
Parasitaemia and malaria signs and symptoms will be listed, including all derived 
parameters. The onset date of rescue medication will be added to the listing. 
2.2 
PHARMACOKINETICS 
2.2.1 
Available data 
Blood samples will be collected for the determination of P218 in all cohorts, and its 
major metabolites (P218 β-acyl-glucuronide, P218-OH β-acyl-glucuronide and P218-
OH) in Cohort 1 only, at the time points indicated in the flow charts (see section 9.3). 
Allowed time deviations from the nominal time are: 
• ± 5 min from 0.5 to 4 hours post dose; 
• ± 15 min from >4 to 12 hours post dose; 
• ± 30 min >12 to <24 hours post dose; 
• ± 60 min for 24 hours post dose; 
• ± 10% deviation from theoretical post dose times for >24 hours to <120 
hours post dose; 
• A deviation of ± 1 day for further days. 
Predose sample should be taken with 1 hour before IMP administration. 
The time zero is defined as the moment of the last IMP administration before the 
sampling. All concentration data-points with deviations outside these permitted 
ranges will be excluded from the descriptive statistics on concentrations, explained by 
a footnote in the appropriate tables, but kept in PK parameters estimation. 
2.2.2 
Derivation rules 
Pharmacokinetic parameter calculations will be performed using Phoenix WinNonLin 
8.0 or later (Pharsight Corporation, Palo Alto, CA, USA). The PK analysis will be 
based on actual times. 


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Standard noncompartmental methods will be used for the calculation of the following 
parameters from the individual plasma drug concentrations versus time profile, for 
P218, and in Cohort 1 only also for its major metabolites (P218 β-acyl-glucuronide, 
P218-OH β-acyl-glucuronide and P218-OH): 
• AUCτ = AUC0-48h (area under the plasma concentration-time curve from 
time zero until 48 h post-dose) after each administration (i.e. AUC0-48h and 
AUC48-96h);  
• AUC48h-inf (calculated from AUC48h-t + (Ct/λz), where Ct is the last 
observed quantifiable concentration and λz the first order terminal rate 
constant), after the second administration;  
• AUC48h-last (area under the plasma concentration-time curve from time zero 
until the last observed quantifiable concentration), after the second 
administration; 
• CL/F (apparent oral clearance, calculated as Dose/AUC48h-inf) and Vz/F 
(apparent volume of distribution during the terminal phase, calculated as 
Dose/(λz * AUC48h-inf)) after the second administration (not for 
metabolites); 
• Cmax (maximum observed plasma concentration) and tmax (the time of 
occurrence of Cmax) after each administration; 
• t1/2 (apparent terminal half-life, calculated from (ln 2)/λz) after the second 
administration; 
• Rac, calculated as AUC48-96h/AUC0-48h; 
• Metabolic ratio of AUCτ and AUC48h-inf for P218 β-acyl glucuronide, 
P218-OH and P218-OH β-acyl glucuronide over parent P218 (Cohort 1 
only), calculated as [(AUC for metabolite)*100/(sum of AUC for P218 and 
AUC of each of the 3 metabolites)]. 
Additional pharmacokinetic parameters may be calculated as appropriate. 


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For PK analysis, the following rules will be applied: 
• Concentration below limit of quantification (BLQ) will be imputed 
according to the rules mentioned in section 5.3.3. 
• Exposures (areas under the curve) will be calculated according to linear 
up/log down trapezoidal method using actual sampling time points 
• Terminal elimination half-life estimation: At least three time points 
(excluding tmax) should be used for determination of the elimination rate 
constant (λz); the adjusted correlation coefficient of the linear regression 
should be ≥0.85. If these two criteria are not met the terminal elimination 
will not be reported as well as all derived parameters (AUC48h-inf, CL/F and 
Vz/F). 
• When for a subject the AUC48h-last / AUC48h-inf > 20%, this AUC48h-inf, as 
well as all derived parameters (CL/F and Vz/F), will be excluded from the 
statistical analyses 
• First administration (Day 1) predose values exceeding 5% of the Cmax will 
be flagged in the tables.  
Rules on how to deal with missing values when deriving PK AUC: 
• If the first administration (Day 1) predose value is missing, then it will be 
set to 0. 
• If intermediate values (not the predose, not more than 3 and not 2 
consecutive) are missing, they will be considered as missing for the PK 
analysis. 
• If multiple (>1) adjacent values are missing or more than 3 values are 
missing, then the AUCs will also be set to missing. 
PK parameters that cannot be estimated will be reported as missing. More specific 
details will be provided in the PK Data Review document. 
2.2.3 
Presentation of results 
All data issues with how the issue will be handled will be listed per subject, cohort, 
day of administration and time point (if applicable). 
Actual blood sampling times from the last IMP administration for PK assessments 
will be listed. 
Individual P218, P218 β-acyl-glucuronide, P218-OH β-acyl-glucuronide and P218-
OH concentration data together with descriptive statistics will be presented in tables, 
per cohort and treatment, day of administration and time point. Individual data 
excluded from statistics will be flagged. 
Individual P218, P218 β-acyl-glucuronide, P218-OH β-acyl-glucuronide and P218-
OH PK parameters together with descriptive statistics will be presented in tables, per 
cohort and treatment, and day of administration. Individual data excluded from 
statistics will be flagged. 
All plasma concentration/time curves for P218, P218 β-acyl-glucuronide, P218-OH 
β-acyl-glucuronide and P218-OH will be presented in linear/linear and log/linear 
scale. Mean (±SD) graphs will be presented as followed: 


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•  with all treatments on the same graph, one graph for the first administration 
and another one for the second administration; 
• with all treatments and all administrations on the same graph (from predose 
of the first administration to 192 h (9 days) post first administration).  
@Sponsor: Please confirm whether this is what you expect  
Spaghetti plots will be presented as followed: 
• by treatment separately, for the two days of administration separately 
• by treament separately, with both days of administration on the same graph 
(from predose of the first administration to 192 h (9 days) post first 
administration) 
@Sponsor: Please confirm whether this is what you expect  
Individual graphs will be presented per cohort and treatment, and subject, with both 
days of administration on the same graph. 


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3. 
SAFETY ANALYSES 
3.1 
ADVERSE EVENTS 
3.1.1 
Available data 
Adverse events (AEs) are coded into system organ classes and preferred terms using 
the medical dictionary for regulatory activities (MedDRA). For each AE, start and 
stop date(time)s are collected as well as severity, a seriousness flag, P218 relatedness, 
action taken towards the study drug, outcome and a flag for AEs of special interest 
(listed in appendix 9.2). For cohorts 2 and 3, relatedness to PfSPZ inoculum, 
procedure and rescue drug will also be collected. 
3.1.2 
Derivation rules 
Treatment-emergent adverse events (TEAE) are defined as AEs starting on or after 
first administration of any study drug. In case the AE start date(time) is incomplete or 
missing, AE will be considered as TEAE unless the available parts of the AE start or 
stop date(time) provide evidence for the event to be a pre-existing condition. 
A fatal AE is defined as an AE with outcome ‘fatal’. 
An AE for which the study was discontinued is defined as an AE mentioned as reason 
for study discontinuation. An AE for which the study drug was discontinued is 
defined as an AE with action taken ‘drug withdrawn’. 
Relatedness will be dichotomised as follows in tables: 
• Related: Related/suspected or missing 
• Not related: Not related/not suspected or NAP 
Treatment relatedness will be assessed for P218, and for challenge cohorts 2 and 3 
also for PfSPZ inoculum, procedure and rescue drug. 
AE onset and duration will be calculated as follows when start and stop dates are 
fully known: 
• AE onset (days / hours) (vs. first dose) =  
o AE start date > reference date: AE start date – reference date + 1 day 
o AE start date < reference date: AE start date reference date 
o AE start date = reference date: (AE start datetime – reference 
datetime)/(60*60) 
The reference date is the date of first administration of any study drug. 
• AE onset day (vs. start of phase) =  
o AE start date > analysis phase start date: AE start date – analysis 
phase start date + 1 day 
o AE start date = analysis phase start date: (AE start datetime – analysis 
phase start datetime)/(60*60) 


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• AE duration (days) =  
o Resolved AEs: AE end date – AE start date + 1 day 
o Unresolved AEs: study discontinuation date – AE start date + 1 day 
In this case the duration will be presented as “>x days”. 
3.1.3 
Presentation of results 
Tables will present TEAEs only. Pre-treatment AEs will only be listed. Unless stated 
otherwise, tables will not be shown by phase (treatment/rescue). 
An overview table will show the number and percentage of subjects with at least one 
event and the number of events for the following: 
• TEAEs 
• Serious TEAEs 
• Non-serious TEAEs 
• Grade ≥ 3 TEAEs 
• Fatal TEAEs 
• P218 related TEAEs 
• TEAEs related to PfSPZ inoculum (Cohorts 2 and 3 only),  
• TEAEs related to procedure (Cohorts 2 and 3 only) 
• TEAEs related to rescue drug (Cohorts 2 and 3 only) 
• Serious P218 related TEAEs 
• TEAEs for which the study was discontinued 
• TEAEs for which the study drug was discontinued 
• TEAEs of special interest 
Summary tables by MedDRA system organ class and preferred term will show the 
number and percentage of subjects with at least one event. The table of TEAEs will 
additionally show the number of events. Separate tables will be prepared for the 
following: 
• TEAEs (by phase (treatment/rescue - challenge cohorts only) and overall) 
• Serious TEAEs 
• Non-serious TEAEs This table is needed for the legally required results 
posting to the EU clinical trials register (former EudraCT, newly renamed 
to EUCTR), so we would advise to keep it. 
• Grade ≥ 3 TEAEs 
• P218 related TEAEs 
• TEAEs related to PfSPZ inoculum (Cohorts 2 and 3 only),  
• TEAEs related to procedure (Cohorts 2 and 3 only) 
• TEAEs related to rescue drug (Cohorts 2 and 3 only) 
• Serious P218 related TEAEs 
• TEAEs of special interest 


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Additionally, a summary table by MedDRA preferred term will show the number and 
percentage of subjects with at least one event, by descending order of frequency 
(number of subjects with events in the active (total) group). This table will be shown 
by phase (treatment/rescue - challenge cohorts only) and overall. 
All AEs, including pre-treatment events will be listed. Separate listings will be 
prepared for serious AEs (including the reason of seriousness), AEs after rescue 
medication, AEs for which the study and the study drug was discontinued and fatal 
AEs. A listing showing all MedDRA coding information will be prepared as well. 
3.2 
CLINICAL LABORATORY EVALUATION 
3.2.1 
Available data 
Per protocol, the following laboratory parameters are expected: 
• Serum folate 
• Biochemistry: sodium, potassium, chloride, bicarbonate, urate, inorganic 
phosphate, creatinine, albumin, glucose, AST, ALT, alkaline phosphatase 
(ALP), gamma glutamylaminotransferase (GGT), lactate dehydrogenase 
(LDH), total and direct bilirubin, total serum proteins, blood urea nitrogen 
(BUN), C-reactive protein (CRP), creatine phosphokinase (CPK) and 
troponin I (Cohorts 2 and 3 only); 
• Haematology: haemoglobin, haematocrit, red blood cell (RBC) count, mean 
corpuscular haemoglobin (MCH), mean corpuscular haemoglobin 
concentration (MCHC), mean corpuscular volume (MCV), white blood cell 
(WBC) count, platelet count, reticulocytes, neutrophils, eosinophils, 
basophils, lymphocytes and monocytes; 
• Urinalysis: dipstick for glucose, protein, nitrite, pH and occult blood; 
microscopic examination for WBC, RBC and casts 
Normal ranges are available as provided by the laboratory. 
3.2.2 
Derivation rules 
The following abnormality categories will be defined: 
• Low: value < lower limit of normal range 
• Normal: lower limit of normal range ≤ value ≤ upper limit of normal range 
• High: value > upper limit of normal range 
Note: 
• Classification will be done in standardised units, using non imputed values 
and limits. 
• For the worst-case analysis visit, as defined in section 5.2.5, an additional 
category low + high is defined in case there are both low and high values. 


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Additionally, for liver enzymes, the following elevation categories will be defined: 
• ALT: >3 x Upper Limit of Normal (ULN); >5 x ULN; >8 x ULN 
• AST: >3 x Upper Limit of Normal (ULN); >5 x ULN; >8 x ULN 
• ALT or AST >3 x ULN; 
• Total bilirubin >2 x ULN; 
• ALT or AST >3 x ULN and total bilirubin >2 x ULN at the same time 
point, together with a conjugated bilirubin fraction (direct bilirubin / total 
bilirubin) > 35% (Potential Hy’s law cases). 
3.2.3 
Presentation of results 
The statistical analysis will present results in standardised units. 
Continuous laboratory parameters will be summarised by means of descriptive 
statistics at each analysis visit. Actual values and changes from baseline will be 
tabulated separately. Categorical and semi-quantitative parameters will be listed only. 
Laboratory abnormalities will be presented as cross-tabulations of the abnormality at 
each post-baseline analysis visit and at the worst-case analysis visit versus the 
baseline abnormality. Numbers of subjects with treatment-emergent abnormalities 
will also be shown. 
Additionally, a frequency table showing the liver enzyme elevation categories for the 
highest postdose values will be prepared. 
All laboratory data will be listed. In addition, a listing will be provided showing only 
parameters for which abnormal values were reported. 
Box plots of the actual values over time will be prepared for folates, the lab parameter 
of interest. 
3.3 
VITAL SIGNS 
3.3.1 
Available data 
The following vital signs parameters are collected: supine heart rate, supine systolic 
(SBP) and diastolic blood pressure (DBP), oral body temperature and weight.  
3.3.2 
Derivation rules 
Abnormalities are defined in below table. 
 
Pulse rate 
(bpm) 
SBP 
(mmHg) 
DBP 
(mmHg) 
Temp 
(°C) 
Low 
<40 
<90 
<45 
<35.0 
Normal 40-100 
90-150 
45-90 
35.0-37.5 
High 
>100 
>150 
>90 
>37.5 
Note: For the worst-case analysis visit, as defined in section 5.2.5, an additional 
category low + high is defined in case there are both low and high values. 


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3.3.3 
Presentation of results 
Vital signs parameters will be summarised by means of descriptive statistics at each 
analysis visit. Actual values and changes from baseline will be tabulated separately.  
Abnormalities will be presented as cross-tabulations of the abnormality at each post-
baseline analysis visit versus the baseline abnormality and as cross-tabulations of the 
worst-case abnormality versus the baseline abnormality. Numbers of subjects with 
treatment-emergent abnormalities will also be shown. 
All vital signs data will be listed. In addition, a listing will be provided showing only 
abnormal values and their baseline. 
Box plots of the actual values over time will be prepared for heart rate. 
3.4 
ELECTROCARDIOGRAMS 
3.4.1 
Available data 
The following electrocardiogram (ECG) parameters will be collected: heart rate (HR), 
QRS interval, PR interval, QT interval and corrected QT interval (Bazett and 
Fridericia). Screening and predose recordings will be performed in triplicate. 
3.4.2 
Derivation rules 
Mean values of the triplicates will be calculated per time point and rounded as 
detailed in section 5.3.4. Throughout the analysis, including the derivation of baseline 
and abnormalities, the mean values will be used. Individual triplicate values will only 
be listed. 
Abnormalities for HR, QRS and PR interval are defined in below table. 
 
HR (bpm) 
PR (ms) 
QRS (ms) 
Low 
<40 
<120 
- 
Normal 40-100 
120-220 
<=120 
High 
>100 
>220 
>120 
Note: For the worst-case analysis visit, as defined in section 5.2.5, an additional 
category low + high is defined in case there are both low and high values. 
For QTc interval (ms), the following categories are defined: 
• Actual values: 
o ≤ 450 (normal) 
o ]450; 480] 
o ]480; 500] 
o > 500 
• Changes: 
o ≤ 30 (normal) 
o ]30; 60] 
o > 60 


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Note: The worst-case, as defined in section 5.2.5, is the highest value and associated 
change. 
3.4.3 
Presentation of results 
Uncorrected QT interval will only be listed. 
Continuous ECG parameters will be summarised by means of descriptive statistics at 
each analysis visit. Actual values and changes from baseline will be tabulated 
separately. 
Abnormalities of the actual values will be presented as cross-tabulations of the 
abnormality at each post-baseline analysis visit, and at the worst-case analysis visit 
versus the baseline abnormality. Numbers and cumulative numbers (QTc only) of 
subjects with treatment-emergent abnormalities will also be shown. 
Abnormalities of the QTc changes will be presented as tabulations of the change 
abnormality at each post-baseline analysis visit and at the worst-case analysis visit. 
Cumulative numbers of subjects with change abnormalities will also be shown. 
All ECG data will be listed. In addition, a listing will be provided showing only 
abnormal values and their baseline. 
Box plots of the actual values over time will be prepared for QTcFri. 
3.5 
PHYSICAL EXAMINATIONS 
Abnormal physical examination findings will be listed. 


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4. 
GENERAL CHARACTERISTICS ANALYSES 
4.1 
SUBJECT DISPOSITION 
The following subject data will be tabulated: 
• The number of subjects in each analysis set, as defined in section 5.1.1 of 
this SAP 
• Dates of first signed informed consent, last visit and last contact (overall 
only) 
• The number and percentage of subjects who completed or discontinued the 
study as documented on the study termination page and the number and 
percentage of subjects for each study discontinuation reason 
All information collected in the CRF concerning allocation, code breaking and study 
discontinuation and information on phases will be listed. The phases listing will also 
include the date of challenge and start and stop dates of rescue medication 
4.2 
PROTOCOL DEVIATIONS AND ELIGIBILITY 
The number and percentage of subjects with major protocol deviations will be 
tabulated, overall and per class of deviation. 
All available information concerning major protocol deviations, violations on 
eligibility criteria and subjects not treated will be listed. 
4.3 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
4.3.1 
Available data 
The following parameters will be available in the clinical database: 
• Demographics: gender, women of childbearing potential, age, race, 
ethnicity, height, weight at baseline, date of birth, date of signing informed 
consent form (ICF), alcohol consumption and smoking history 
• Screening tests: serology, G6PD enzyme test, alcohol breath test and urine 
drug screen, pregnancy tests, standing heart rate and standing SBP and DBP 
(cohort 1 only), Beck depression inventory (question 9 - suicidal thoughts - 
and total score) 
4.3.2 
Derivation rules 
The following parameters will be derived: 
• Body mass index (BMI) at baseline (kg/m²) = (weight at baseline (kg)) / 
(height (m))² 
Note: The BMI will only be recalculated and rounded as detailed in section 
5.3.4, when not available in the database. 
• Smoking status: 
o Non smoker: SUOCCUR = N 
o Ex-smoker: SUOCCUR = Y and SUENRTPT = BEFORE 
o Smoker: SUOCCUR = Y and SUENRTPT = ONGOING 


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• Orthostatic change = value in supine position – value in standing position 
• Beck depression inventory interpretation: 
o 0-10: Normal 
o 11-16: Mild mood disturbance 
o 17-20: Borderline clinical depression 
o 21-30: Clinical depression 
o 31-40: Severe depression 
o >40: Extreme depression 
4.3.3 
Presentation of results 
Demographics will be presented using descriptive statistics for age, height, weight 
and BMI and frequency tabulations for gender, smoking status, race and ethnicity. 
Orthostatic change and Beck depression inventory will be presented using descriptive 
statistics for the total score and frequency tabulations for interpretation. 
All demographic data will be listed. Separate listings will also be created for Beck 
depression inventory, smoking history and alcohol consumption, serology and 
pregnancy tests (including EOS result). 
4.4 
MEDICAL HISTORY AND CONCOMITANT DISEASES 
4.4.1 
Available data 
Medical history and concomitant diseases findings are coded using the medical 
dictionary for regulatory activities (MedDRA) into system organ classes and 
preferred terms. For each finding, a start and stop date or ongoing flag is collected. 
4.4.2 
Derivation rules 
The following parameters will be derived: 
• Medical history finding: not ongoing at screening (MHENRTPT = 
SCREENING) 
• Concomitant disease finding: still ongoing at screening (MHENRTPT = 
ONGOING) 
4.4.3 
Presentation of results 
Medical history and concomitant diseases will be tabulated separately. Each table will 
show: 
• The number and percentage of subjects with and without findings 
• The number and percentage of subjects with findings by system organ class 
and preferred term 
All medical history and concomitant diseases data will be listed separately. 


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4.5 
PRIOR AND CONCOMITANT THERAPIES AND RESCUE MEDICATION 
4.5.1 
Available data 
All therapies (excluding rescue medication) are coded using WHO-DRUG. ATC 
selection is performed. ATC coding up to level 4 is available in the clinical database. 
For each therapy, a start date(time) and stop date(time) or ongoing flag are collected. 
For rescue medication (cohorts 2 and 3) the start and end date(times) and the dose 
will be recorded. 
4.5.2 
Derivation rules 
Based on their start and stop date(time), prior and concomitant therapies will be 
allocated to each phase during which they were administered. A therapy can therefore 
be reported in more than one phase. 
Phases are defined in section 5.2.1. Therapies with (partially) missing dates will be 
allocated to each phase unless the available parts of the therapy start or stop 
date(time) provide evidence the therapy was not taken during that phase. 
4.5.3 
Presentation of results 
The number and percentage of subjects with and without concomitant therapies and 
the number and percentage of subjects with therapies by generic term will be 
tabulated by phase (screening / treatment / rescue) and overall (treatment + rescue - 
challenge cohorts only). 
The number and percentage of subjects with and without concomitant therapies and 
the number and percentage of subjects with therapies by ATC class (level 1, 2 and 4) 
and generic term will be tabulated by phase (screening / treatment / rescue) and 
overall (treatment + rescue - challenge cohorts only). 
For the challenge cohorts 2 and 3, a table will be prepared showing the timing of 
rescue medication (prior to day 28 / on day 28) and the generic name and dose 
(malarone 250/100 mg / riamet 20/120 mg / primaquine 30 mg). 
All prior and concomitant therapies data will be listed. A separate listing will be 
prepared for rescue medication. 
4.6 
EXPOSURE TO STUDY DRUG AND CHALLENGE AGENT 
4.6.1 
Available data 
For all study drug administrations, the start date(times) and the dose will be recorded. 
For the challenge agent (cohorts 2 and 3) the start and end date(times) and the dose 
will be recorded. 
4.6.2 
Derivation rules 
Not applicable 
4.6.3 
Presentation of results 
All exposure and challenge data will be listed. 


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5. 
GENERAL METHODOLOGY 
5.1 
ANALYSIS SETS 
5.1.1 
Analysis sets 
The following analysis sets will be considered in the statistical analysis: 
All screened subjects set 
(SCR): 
all subjects who signed an informed consent to 
participate in this study 
All randomised subjects 
set (RND): 
all subjects who were randomised into this study 
Safety analysis set 
(SAF): 
all subjects who were exposed to the study drug 
PD analysis set: 
all randomised subjects who were exposed to the study 
drug, have at least one evaluable PD data and no major 
protocol deviation affecting PD and who received the 
PfSPZ challenge inoculation (for cohort 2 and 3 only) 
PK analysis set: 
all randomised isubjects who have received at least 1 
dose of P218, have at least one evaluable PK data and 
no major protocol deviation affecting PK 
Programmer notes: 
• Having signed an informed consent is defined as having a complete 
informed consent signature date in the database. 
• Randomised is defined as having a complete randomisation date in the 
database or any information to confirm randomisation. 
• Being exposed to the study drug is defined as having a complete exposure 
date in the database or any information to confirm an administration. 
• The PK analysis set will be defined in the PK data review document, as 
elaborated in section 5.3.5. The major deviations and impact on analysis set 
will be determined prior to unblinding. 
Unless stated otherwise, the SAF will be used for the general, safety and tolerability 
tables, listings and figures (TLFs). The PD set will be used for the pharmacodynamic 
TLFs and the PK set will be used for the analyses of PK data. 
5.1.2 
As planned versus as actual analysis 
For all analyses, the actual treatment of the subject will be considered. 
5.2 
PHASES AND TIME POINTS 
5.2.1 
Phases 
All events and assessments will be allocated to phases. 


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Phase 
Start 
End 
Screening 
Date of signing the ICF, with 
00:00 added as time part 
First administration date(time) – 
1 minute  
Treatment 
First administration date(time) 
First administration date(time) of 
rescue medication - 1 minute 
Rescue 
First administration date(time) of 
rescue medication 
Date of last contact, with 23:59 
added as time part 
Rescue phase is not applicable for cohort 1. Per definition, and for each subject, the 
first phase starts on the date of the earliest available ICF signature, and the last 
available phase ends on the date of last contact, with 23:59 added as time part. 
AEs and concomitant medications will be allocated to phases as described in sections 
3.1.2 and 4.5.2 respectively. All other assessments will be allocated to phases based 
on the assessment date(time).  
In case of (partially) missing date(time) fields, the visit label will be used to allocate 
to the correct phase. If this is not possible (unscheduled visits or visits on a turning 
point between phases), assessments will be allocated to the treatment phase unless the 
available parts of the assessments start or stop date(time) provide evidence for 
allocating to the screening/rescue phase. 
5.2.2 
Baseline and change from baseline 
The baseline value is the last available and non-missing value before the first 
administration of any study drug. If all values are missing, the baseline will be 
reported as missing. 
Wherever in this document ‘change from baseline’ is mentioned, it concerns the 
absolute change from baseline, defined as: 
Absolute change from baseline at time point t = value at time point t – baseline value. 
5.2.3 
Relative day 
Relative days (DY) will be calculated according to the following rule: 
• Concerned date < reference date: DY = concerned date – reference date 
• Concerned date ≥ reference date: DY = concerned date – reference date + 1 
The reference date is the date of first administration of any study drug (cohort 1) / the 
date of inoculation (cohorts 2 and 3). 
5.2.4 
Analysis visits 
For assessments after the reference date, the analysis will use the visits and time 
points indicated on the subject’s case report form (CRF). Unscheduled assessments 
after the reference date will only be listed. 
The screening value is the last available and non-missing value before day -1. This 
value corresponds to the screening visit, except in case of retesting. Reason for this 
approach is the use of retest results for subject eligibility assessment. 


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Baseline is defined in section 5.2.2. 
5.2.5 
Worst-case visit 
A worst-case analysis visit will be created to summarise values considered as the 
worst-case. For abnormalities it is derived per parameter and in case both the lowest 
and the highest values are considered abnormal, a subject can have two worst-case 
analysis visits for a same parameter, which will be shown in tables as a combined 
high+low category. For malaria signs and symptoms, the worst-case corresponds to 
the highest score and is also derived per sign/symptom. Note to François: would 
prefer to keep wording of two analysis visits, as this is how it will be in ADLB. 
Details added to show how it will be in table. 
All non-missing post-baseline values, including unscheduled assessments and follow-
up will be considered when deriving the worst-case analysis visit. For challenge 
cohorts 2 and 3, worst-case will be derived both by phase (treatment/rescue) as 
relevant and overall. 
5.3 
IMPUTATION AND ROUNDING RULES 
5.3.1 
Missing values 
For the calculation of the malaria clinical score, missing individual signs and 
symptom scores will be imputed with the mean of all non-missing scores. 
For the pharmacokinetic analysis, if the first administration (Day 1) predose value is 
missing, then it will be set to 0 for the calculation of PK parameters (also see section 
2.2.2). 
5.3.2 
Handling partially or completely missing dates in 
calculations 
Not applicable 
5.3.3 
Values below or above a threshold 
Safety values expressed as below (or above) the detection limit will be imputed by the 
value of the detection limit itself. Listings will always show the non-imputed values. 
PK concentrations below the quantification limit will be flagged as Below the Limit 
of Quantification (BLQ) in the concentration tables. All BLQ values will be 
considered as 0.00 for PK and descriptive statistical analyses. 
5.3.4 
Rounding of derived variables 
Derived variables will be rounded to the appropriate number of significant digits (see 
Definition of terms) at TLF level: 
• Malaria clinical score will be rounded to 1 decimal. 
• Mean of triplicates, mean scores and BMI will be rounded to 1 decimal. 
All derivations will be done before rounding. Rounding will be done using the round 
half to up rule (see Definition of terms). 


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5.3.5 
Outliers 
For safety and PD, there will be no outlier detection. All measured values will be 
included in the analyses. 
For PK values, it will be decided whether extreme values are to be excluded from the 
analysis based on a detailed data review performed by SGS PK after the data base 
lock and before performing the PK analysis. 
Clinical deviations that could affect the PK data of a subject, as well as the observed 
abnormal drug levels, sampling time deviations and their impact on PK 
population/analysis will be discussed with the sponsor during this data review 
process, to decide keeping or excluding data points/subjects from PK 
population/analysis. 
The PK Data Review document, detailing such kind of decisions, will be agreed and 
signed by both parts before running the final PK analysis. 
5.4 
PRESENTATION OF RESULTS 
5.4.1 
Calculation of descriptive statistics and percentages 
For continuous parameters, full descriptive statistics will only be presented if there 
are at least 2 non-missing observations. Alternatively, only the number of non-
missing data points and mean are shown. 
Descriptive statistics for non-PK data will include the number of non-missing data 
points, the arithmetic mean, the standard deviation (SD), the median, minimum and 
maximum. 
Descriptive statistics of the primary endpoint will additionally include the geometric 
mean and the corresponding 90% confidence interval (CI). Geometric mean and CI 
are calculated as the exponentials of the arithmetic mean and corresponding CI (based 
on t-distribution, without continuity correction) of the log-transformed data. 
Descriptive statistics of PK concentrations will include the number of subjects with 
data, the number of subjects with BLQ data, arithmetic mean, SD, coefficient of 
variation (CV) % of arithmetic mean, median, minimum and maximum. 
Descriptive statistics on PK parameters will additionally include geometric mean and 
geometric CV% (= 100 x ඥ𝑒𝑒(𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑙𝑙𝑙𝑙−𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑)² −1), except 
tmax: descriptive statistics will include the number of non-missing data points, the 
median, minimum and maximum. The descriptive statistics will be presented with 3 
significant digits, except values >1000, which will be presented without decimals and 
tmax which will be presented with 2 decimals. 
For event-type data, the denominator will be all subjects in the analysis set. All 
treatments will be shown, even if no events are present. 
For frequency tabulations and cross-tabulations, missing values will not be included 
in the denominator count when computing percentages. For cross-tabulations of post-
baseline results versus baseline results, a ‘missing’ category will be shown for 
baseline results if applicable. For the frequency tabulation of positive parasitaemia, 
two-sided 90% exact Clopper-Pearson confidence limits will be added. 


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5.4.2 
Presentation of treatments 
The following treatment labels will be used in the TLFs (excluding PK): 
• Cohort 1: 
o Placebo 
o P218 1000 mg 
• Challenge cohorts 2 and 3: 
o Placebo 
o P218 100 mg 
o P218 1000 mg 
o P218 total (only for AE tables) 
In the PK analysis, the following treatment labels will be used in the TLFs: 
• Cohort 1: 
o P218 1000 mg 
• Challenge cohort 2: 
o P218 1000 mg 
• Challenge cohort 3: 
o P218 100 mg 
5.4.3 
Ordering in tables, figures and listings 
All general and safety tables and figures will be presented per part and treatment, 
unless specified otherwise. The following parts are defined: 
• Cohort 1 
• Challenge cohorts 2 and 3 
All PD tables and figures will be presented per treatment, unless specified otherwise. 
All PK tables and figures will be presented per cohort, treatment and administration 
day, unless specified otherwise. 
All listings will be ordered by cohort, treatment, subject, analysis visit and time point, 
unless specified otherwise. 
 
 


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6. 
CHANGES TO THE PLANNED ANALYSIS 
6.1 
CHANGES NOT COVERED BY PROTOCOL AMENDMENTS BEFORE 
DATABASE LOCK 
The protocol states placebo subjects will be pooled in tables. This can however not be 
done in all tables, as cohort 1 was not challenged and different cohorts have different 
assessment time points. 
As the definitions of ITT and EFF set are identical, only the EFF set was retained. On 
request of the sponsor, PD is used rather than efficacy. 
No AE tabulation by severity is foreseen in the present SAP. As this is a healthy 
volunteers study with a limited number of subjects and as malaria related symptoms 
are not captured as AEs, not many AEs are expected and a table by severity would be 
of limited added value. As an alternative, a table of grade ≥ 3 AEs is added. 
The protocol mentions 1st and 3rd quartiles will be shown in the descriptive tables. 
However, the sponsor doubts these will be of added value and it was decided not to 
show them to improve readibility of the tables. 
6.2 
CHANGES NOT COVERED BY PROTOCOL AMENDMENTS AFTER 
DATABASE LOCK 
Not applicable 
6.3 
CHANGES TO THE FINAL STATISTICAL ANALYSIS PLAN 
Not applicable 


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7. 
REFERENCES 
ICH Topic E6(R2) Guideline for Good Clinical Practice – Step 4, 9 November 2016. 
ICH Topic E9 Statistical Principles for Clinical Trials – Step 5 – Note for Guidance 
on Statistical Principles for Clinical Trials (CPMP/ICH/363/96), September 1998. 


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8. 
LIST OF TABLES, LISTINGS AND FIGURES 
8.1 
TABLES 
GENERAL CHARACTERISTICS 
14.1.1.1 
Analysis Sets 
SCR 
14.1.1.2 
First and Last Contact in the Study 
SCR 
14.1.1.3 
Study Discontinuation 
SAF 
14.1.1.4 
Protocol Deviations 
SAF 
14.1.2.1 
Demographic Data 
SAF 
14.1.2.2 
Orthostatic Change in Vital Signs at Screening 
SAF 
14.1.2.3 
Beck Depression Inventory at Screening 
SAF 
14.1.2.4 
Medical History 
SAF 
14.1.2.5 
Concomitant Diseases 
SAF 
14.1.2.6 
Prior and Concomitant Therapies by ATC Class (Level 4) and Generic 
Term 
SAF 
14.1.2.7 
Rescue Therapies 
SAF 
PHARMACODYNAMICS 
14.2.1.1 
Primary Endpoint: Descriptive Statistics of Time to Positive Parasitaemia 
PD 
14.2.1.2 
Incidence of Positive Parasitaemia 
PD 
14.2.1.3 
Descriptive Statistics of Malaria Symptom Score 
PD 
14.2.1.4 
Frequency Table of the Worst-case Individual Malaria Signs and Symptoms 
PD 
PHARMACOKINETICS 
14.2.2.1 
P218 Plasma Concentrations (unit) 
PK 
14.2.2.2 
P218 beta-acyl-glucuronide Plasma Concentrations (unit) 
PK 
14.2.2.3 
P218-OH beta-acyl-glucuronide Plasma Concentrations (unit) 
PK 
14.2.2.4 
P218-OH Plasma Concentrations (unit) 
PK 
14.2.2.5 
P218 Plasma PK Parameters 
PK 
14.2.2.6 
P218 beta-acyl-glucuronide Plasma PK Parameters 
PK 
14.2.2.7 
P218-OH beta-acyl-glucuronide Plasma PK Parameters 
PK 
14.2.2.8 
P218-OH Plasma PK Parameters 
PK 
SAFETY 
ADVERSE EVENTS 
14.3.1.1 
Adverse Events Overview 
SAF 
14.3.1.2 
Treatment-Emergent Adverse Events by MedDRA System Organ Class and 
Preferred Term 
SAF 
14.3.1.3 
Treatment-Emergent Adverse Events by MedDRA Preferred Term by 
Descending Order of Frequency 
SAF 
14.3.1.4 
Serious Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Preferred Term 
SAF 


Statistical Analysis Plan 
 
MMV_P218_17_01 
 
Final 1.0 of 10MAY2019 
 
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14.3.1.5 
Non-serious Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term 
SAF 
14.3.1.6 
Grade 3 or More Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term 
SAF 
14.3.1.7 
P218 Related Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term 
SAF 
14.3.1.8 
PfSPZ Inoculum Related Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
SAF 
14.3.1.9 
Procedure Related Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term 
SAF 
14.3.1.10 
Rescue Drug Related Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term 
SAF 
14.3.1.11 
Serious P218 Related Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term 
SAF 
14.3.1.12 
Treatment-Emergent Adverse Events for which the Study Was 
Discontinued by MedDRA System Organ Class and Preferred Term 
SAF 
14.3.1.13 
Treatment-Emergent Adverse Events for which the Study Drug Was 
Discontinued by MedDRA System Organ Class and Preferred Term 
SAF 
LABORATORY DATA 
14.3.2.1 
Descriptive Statistics of Laboratory Test Results 
SAF 
14.3.2.2 
Cross-Tabulation of Laboratory Abnormalities Versus Baseline 
SAF 
14.3.2.3 
Liver Enzyme Elevation Categories 
SAF 
VITAL SIGNS 
14.3.3.1 
Descriptive Statistics of Vital Signs 
SAF 
14.3.3.2 
Cross-Tabulation of Vital Signs Abnormalities Versus Baseline 
SAF 
ECG 
14.3.4.1 
Descriptive Statistics of ECG 
SAF 
14.3.4.2 
Cross-Tabulation of ECG Abnormalities Versus Baseline 
SAF 
14.3.4.3 
Tabulation of QTc Change Abnormalities 
SAF 
8.2 
LISTINGS 
GENERAL CHARACTERISTICS 
16.2.1.1 
Allocation 
RND 
16.2.1.2 
Code Breaking Information 
RND 
16.2.1.3 
Analysis Phases 
RND 
16.2.1.4 
Study Discontinuation  
RND 
16.2.2.1 
Protocol Deviations 
RND 
16.2.2.2 
Violations on Eligibility Criteria 
RND 
16.2.2.3 
No-Treatment Subjects 
SCR 
minus 
SAF 
16.2.2.4 
Subjects Excluded from Any Analysis Sets 
SCR 


Statistical Analysis Plan 
 
MMV_P218_17_01 
 
Final 1.0 of 10MAY2019 
 
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16.2.4.1 
Demographic Data 
SAF 
16.2.4.2 
Smoking History and Alcohol Consumption 
SAF 
16.2.4.3 
Orthostatic Change in Vital Signs at Screening 
SAF 
16.2.4.4 
Beck Depression Inventory at Screening 
SAF 
16.2.4.5 
Screening Tests 
SAF 
16.2.4.6 
Pregnancy Tests 
SAF 
16.2.4.7 
Medical History 
SAF 
16.2.4.8 
Concomitant Diseases 
SAF 
16.2.4.9 
Prior and Concomitant Therapies  
SAF 
16.2.4.10 
Rescue Medication 
SAF 
16.2.4.11 
Comments 
SAF 
16.2.5.1 
Exposure and Challenge Data 
SAF 
PHARMACOKINETICS 
16.2.5.2 
PK Data Handling 
PK 
16.2.5.3 
Actual Blood Sampling Times for PK Assessments (h) 
PK 
PHARMACODYNAMICS 
16.2.6.1 
Parasitaemia 
PD 
16.2.6.2 
Malaria Signs and Symptoms 
PD 
SAFETY 
ADVERSE EVENTS 
16.2.7.1 
Adverse Events 
SAF 
16.2.7.2 
Serious Adverse Events 
SAF 
16.2.7.3 
Fatal Adverse Events  
SAF 
16.2.7.4 
Treatment Emergent Adverse Events for Which the Study Were 
Discontinued  
SAF 
16.2.7.5 
Treatment Emergent Adverse Events for Which the Study Drug Were 
Discontinued  
SAF 
16.2.7.6 
Treatment Emergent Adverse Events After Administration of Rescue Drug 
SAF 
16.2.7.7 
Adverse Events: Coding Information 
SAF 
16.2.7.8 
Physical Examinations Abnormalities 
SAF 
LABORATORY DATA 
16.2.8.1 
Laboratory Test Results 
SAF 
16.2.8.2 
Abnormal Laboratory Test Results 
SAF 
VITAL SIGNS 
16.2.9.1 
Vital Signs Results 
SAF 
16.2.9.2 
Abnormal Vital Signs Results 
SAF 
ECG 
16.2.10.1 
ECG Results 
SAF 
16.2.10.2 
Abnormal ECG Results 
SAF 


Statistical Analysis Plan 
 
MMV_P218_17_01 
 
Final 1.0 of 10MAY2019 
 
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16.2.10.3 
ECG Interpretation and Morphology for Subjects with any Abnormal 
Interpretation 
SAF 
8.3 
FIGURES 
PHARMACODYNAMICS 
14.2.1.1 
Median Parasitaemia Actual Values Over Time 
PD 
14.2.1.2 
Kaplan-Meier Plot of Time to Positive Parasitaemia 
PD 
14.2.1.3 
Mean (SE) Malaria Clinical Score Actual Values Over Time 
PD 
16.2.6.1 
Individual Parasitaemia Actual Values Over Time 
PD 
16.2.6.2 
Individual Malaria Clinical Score Actual Values Over Time 
PD 
PHARMACOKINETICS 
14.2.2.1 
Mean (SD) P218 Plasma Concentration vs. Time Profiles 
PK 
14.2.2.2 
Mean (SD) P218 beta-acyl-glucuronide Plasma Concentration vs. Time 
Profiles 
PK 
14.2.2.3 
Mean (SD) P218-OH beta-acyl-glucuronide Plasma Concentration vs. Time 
Profiles 
PK 
14.2.2.4 
Mean (SD) P218-OH Plasma Concentration vs. Time Profiles 
PK 
16.2.5.1 
Individual P218 Plasma Concentration vs. Time Profiles, per Cohort 
PK 
16.2.5.2 
Individual P218 beta-acyl-glucuronide Plasma Concentration vs. Time 
Profiles, per Cohort 
PK 
16.2.5.3 
Individual P218-OH beta-acyl-glucuronide Plasma Concentration vs. Time 
Profiles, per Cohort 
PK 
16.2.5.4 
Individual P218-OH Plasma Concentration vs. Time Profiles, per Cohort 
PK 
16.2.5.5 
Individual P218 Plasma Concentration vs. Time Profiles, per Subject 
PK 
16.2.5.6 
Individual P218 beta-acyl-glucuronide Plasma Concentration vs. Time 
Profiles, per Subject  
PK 
16.2.5.7 
Individual P218-OH beta-acyl-glucuronide Plasma Concentration vs. Time 
Profiles, per Subject 
PK 
16.2.5.8 
Individual P218-OH Plasma Concentration vs. Time Profiles, per Subject 
PK 
LABORATORY DATA 
14.3.2.1 
Box plots of Folate Actual Values Over Time 
SAF 
VITAL SIGNS 
14.3.3.1 
Box plots of Heart Rate Actual Values Over Time 
SAF 
ECG 
14.3.4.1 
Box plots of QTcFri Actual Values Over Time 
SAF 


Statistical Analysis Plan 
 
MMV_P218_17_01 
 
Final 1.0 of 10MAY2019 
 
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Page 14 of 52 
9. 
APPENDICES 
9.1 
SAS CODE 
Not applicable 
9.2 
ADVERSE EVENTS OF SPECIAL INTEREST 
Hepatic 
• Any ALT or AST above 3x ULN; 
• Any elevation in bilirubin 2x ULN; 
• Any AST or ALT above 2x ULN and (total bilirubin level (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 
• QTcB or QTcF at any time >480 ms; 
• Bundle branch block (except right bundle branch block that was present 
prior to IMP administration); 
• Any arrhythmia, except: 
o sinus bradycardia that is clinically asymptomatic, and not associated 
with any other relevant ECG abnormalities; 
o sinus tachycardia that is clinically asymptomatic, and associated with 
a body temperature >38.0 °C, and not associated with any other 
relevant ECG abnormalities; 
o respiratory sinus arrhythmia; 
o wandering atrial pacemaker;  
o isolated, single premature atrial/ventricular complex (i.e., no 
bigeminy, trigeminy, couplets, triplets or salvos) that does not occur 
more than once in a particular ECG tracing.  
Haematological 
• Haemoglobin drop >2 g/dL and under lower limit of normal from baseline 
prior to inoculation;  
• Absolute neutrophil count <1000/µL; 
• Platelet count <100,000 /mm3. 
Dermatological:*  
• Any suspected cutaneous adverse event, e.g., rash 
* if one of these cutaneous reaction is observed and when feasible, pictures of the 
lesions should be obtained. 
 


Statistical Analysis Plan 
 
MMV_P218_17_01 
 
Final 1.0 of 10MAY2019 
 
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9.3 
SCHEDULE OF ASSESSMENTS 
9.3.1 
Cohort 1 
Description 
SCR Treatment and follow-up 
EOS 
Study Day 
-28 
to -2 -1a 1 
2 
3 
4 
5 
6 
7 
8 
9 
Timepoint (h) in 
relation to 1st IMP 
administration 
 
0 
0b 
1 
2b 
4 
6 
10 
24 
36 
48 
48.5 49 
49.5 50 
52 
54 
58 
72 
84 
96c 
120c 144c 168c 192c 
Ambulatory visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Confinement in 
clinical unitd 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consento 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and social 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beck depression 
inventory 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisationp 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol & drug 
screene 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height & weightf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 


Statistical Analysis Plan 
 
MMV_P218_17_01 
 
Final 1.0 of 10MAY2019 
 
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Page 41 of 47 
 
Description 
SCR Treatment and follow-up 
EOS 
Study Day 
-28 
to -2 -1a 1 
2 
3 
4 
5 
6 
7 
8 
9 
Timepoint (h) in 
relation to 1st IMP 
administration 
 
0 
0b 
1 
2b 
4 
6 
10 
24 
36 
48 
48.5 49 
49.5 50 
52 
54 
58 
72 
84 
96c 
120c 144c 168c 192c 
Physical 
examinationg 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Vital signsh 
X 
X 
X 
X 
X 
 
 
X 
X 
 
X 
 
 
 
X 
 
 
X 
X 
X 
 
X 
 
 
X 
12-lead ECGi 
X 
X 
Xi 
 
 
 
 
 
X 
 
Xi 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Serologyj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testk 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
IMP administrationl  
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology, 
chemistry & 
urinalysisq 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Serum folate 
X 
Xr  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Coagulation 
parametersm 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
PK blood samplen 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
X 
X 
X 
X 
X 
Previous 
medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
X 


Statistical Analysis Plan 
 
MMV_P218_17_01 
 
Final 1.0 of 10MAY2019 
 
Document Nr.: OTH.STAT.010                  Version Nr.: 1               Effective Date:        
Page 42 of 47 
 
Description 
SCR Treatment and follow-up 
EOS 
Study Day 
-28 
to -2 -1a 1 
2 
3 
4 
5 
6 
7 
8 
9 
Timepoint (h) in 
relation to 1st IMP 
administration 
 
0 
0b 
1 
2b 
4 
6 
10 
24 
36 
48 
48.5 49 
49.5 50 
52 
54 
58 
72 
84 
96c 
120c 144c 168c 192c 
AEs 
 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
X 
SAE reporting 
X----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
AE: adverse event, ECG: electrocardiogram, EOS: end of study, IMP: investigational medicinal product, PK: pharmacokinetic, SAE: serious adverse event, SCR: screening 
a 
Assessments begin as of subject confinement in the clinical unit and must be completed and outcomes must be available before IMP administration. 
b 
The assessments indicated must be completed and outcomes must be available before IMP administration. Predose PK sample should be taken within 1 hour before IMP administration. 
c 
The assessments indicated will be performed daily during ambulatory visits to the clinical unit. 
d 
Subjects will be admitted to the clinical unit in the morning of Day -1 and will remain in confinement until Day 4, i.e. 36 hours after second IMP administration. 
e 
Alcohol breath test and urine dipstick screening for drug abuse. 
f 
Height to be measured at screening only; body weight to be measured at screening, upon admission to the clinical unit on Day-1, upon discharge from the clinical unit on Day 4 and at the EOS visit on Day 9. 
g 
Full physical examination will be conducted at screening and at the EOS visit on Day 9. Targeted (symptom-driven) physical examination will be conducted on all other occasions. Symptom-driven physical 
examination will be conducted at any time during follow-up, if indicated. 
h 
Vital signs (blood pressure, pulse and body temperature) will be measured after remaining 5 minutes in a supine position. At screening, orthostatic changes to blood pressure and pulse rate will also be assessed: subjects 
will be requested to stand after completion of the supine measurements and blood pressure and pulse rate will be recorded after 2 min in the standing position. 
i 
12-lead ECGs recordings will be performed after subjects have remained in a supine position for at least 10 minutes. All recordings will be performed once, except at the screening and before the first and second IMP 
administration when they will be performed in triplicates. 
j 
Serological testing for human immunodeficiency virus (HIV) antibody and antigen, hepatitis B surface antigen (HbsAg) and anti-hepatitis C virus (HCV) antibody, to determine eligibility for the trial. 
k 
Pregnancy testing consists of serum β-human chorionic gonadotropin (β-HCG) assessment at screening and urine β-HCG assessments on Day-1 and at the EOS visit. 
l 
In each instance, the subject will receive a single oral dose of 1000 mg P218 or placebo after fasting at least 8 hours.  
m 
International Normalised Ratio (INR), prothrombin time (PT) and activated partial thromboplastin time (aPTT). 
n 
On Day 4, the subject will be discharged from the clinical unit only after the PK sample at 84 hours is drawn. 
o 
No study-related procedure is to be performed before voluntarily signing of the informed consent form. 
p 
Randomization will be performed before first IMP administration. 
q 
Laboratory tests will be performed after fasting for at least 8 hours. 
r 
This assessment can be done at either D-3 or D-1, upon Investigator's decision. 
 
 


Statistical Analysis Plan 
 
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9.3.2 
Cohort 2 and 3 
Description 
SC
R 
Challenge, treatment and follow-up 
EOS 
visit 
EOSu 
Study Day 
-28 
to -2 -1a 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 
13 
14-
28c 35 
45 
max 
Timepoint (h) in 
relation to 
PfSPZ Challenge 
 
0 
0b 2b 
2.5 3 
3.5 4 
6 
8 
12 
24 36 50 50.5 51 51.5 52 54 56 60 
72 84 96 120 144 168 192 216 240 264 288  
 
 
Ambulatory visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Confinement in 
clinical unitd 
 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consente 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
social history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beck depression 
inventory 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisationt 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol & drug 
screenf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height & weightg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Physical 
examinationh 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Xh 
 
 
X 
 
Xh 
 
 
X 
Xh 
X 
 
Vital signsi 
X 
X 
X X 
 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
X X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Xi 
X 
 
12-lead ECGj 
X 
X Xj Xj 
 
 
 
X 
 
 
X 
X 
 
Xj 
 
 
 
X X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Xj 
X 
 


Statistical Analysis Plan 
 
MMV_P218_17_01 
 
Final 1.0 of 10MAY2019 
 
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Description 
SC
R 
Challenge, treatment and follow-up 
EOS 
visit 
EOSu 
Study Day 
-28 
to -2 -1a 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 
13 
14-
28c 35 
45 
max 
Timepoint (h) in 
relation to 
PfSPZ Challenge 
 
0 
0b 2b 
2.5 3 
3.5 4 
6 
8 
12 
24 36 50 50.5 51 51.5 52 54 56 60 
72 84 96 120 144 168 192 216 240 264 288  
 
 
G6PD deficiency 
enzyme test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serologyk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testl 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
DVI of PfSPZ 
Challenge 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP 
administrationm 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Malaria clinical 
scoren 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Haematology, 
chemistry & 
urinalysiso 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Xo 
X 
 
Serum folate 
X 
Xv 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Xo 
X 
 
Coagulation 
parametersp 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
PK blood sample 
 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Rescue therapyq 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
TBSr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


Statistical Analysis Plan 
 
MMV_P218_17_01 
 
Final 1.0 of 10MAY2019 
 
Document Nr.: OTH.STAT.010                  Version Nr.: 1               Effective Date:        
Page 45 of 47 
 
Description 
SC
R 
Challenge, treatment and follow-up 
EOS 
visit 
EOSu 
Study Day 
-28 
to -2 -1a 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 
13 
14-
28c 35 
45 
max 
Timepoint (h) in 
relation to 
PfSPZ Challenge 
 
0 
0b 2b 
2.5 3 
3.5 4 
6 
8 
12 
24 36 50 50.5 51 51.5 52 54 56 60 
72 84 96 120 144 168 192 216 240 264 288  
 
 
qPCR for 
parasitess 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Previous 
medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
AEs 
 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
SAE reporting 
X-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
AE: adverse event, DVI: direct venous inoculation, ECG: electrocardiogram, EOS: end of study, G6PD: glucose-6-phosphate dehydrogenase, IMP: investigational medicinal product, PfSPZ: 
Plasmodium falciparum sporozoites, PK: pharmacokinetic, qPCR: quantitative polymerase chain reaction, SAE: serious adverse event, SCR: screening, TBS: thick blood smear 
a 
Assessments begin as of subject confinement in the clinical unit and must be completed and safety assessment outcomes must be available before PfSPZ Challenge DVI on Day 1. 
b 
On Day 1, assessments begin as of 3 hours before challenge. The assessments indicated must be completed and safety assessment outcomes must be available before PfSPZ inoculation or before IMP administration. 
Predose PK sample should be taken within 1 hour before IMP administration. 
c 
The assessments indicated will be performed daily during ambulatory visits to the clinical unit. 
d 
Subjects will be admitted to the clinical unit in the morning of Day -1 and will remain in confinement until Day 13, i.e. 12 days post PfSPZ Challenge. 
e 
No study-related procedure is to be performed before voluntarily signing of the informed consent form. 
f 
Alcohol breath test and urine dipstick screening for drug abuse. 
g 
Height to be measured at screening only; body weight to be measured at screening, upon admission to the clinical unit on Day-1, upon discharge from the clinical unit on Day 13 and at the EOS visit on Day 35. 
h 
Full physical examination will be conducted at screening, at Days -1, 2, 4, 8 and 13, and at the EOS visit on Day 35. Targeted (symptom-driven) physical examination will be conducted on Days 5, 10, 15, 20 and 25, 
and at the start of rescue treatment. Symptom-driven physical examination will be conducted at any time during follow-up, if indicated. 
i 
Vital signs (blood pressure, pulse and body temperature) will be measured after remaining 5 minutes in a supine position. During the period between Day 14 and 28, vital signs will be measured on Days 15, 20 and 25 
and on the first day of rescue treatment only. 
j 
12-lead ECGs recordings will be performed after subjects have remained in a supine position for at least 10 minutes. All recordings will be performed once, except at the screening and before the first and second IMP 
administration when they will be performed in triplicates. During the period between Day 14 and 28, one record will be performed on the first day of rescue treatment only. 
k 
Serological testing for HIV antibody and antigen, HbsAg and anti-HCV antibody, to determine eligibility for the trial. 
l 
Pregnancy testing consists of serum β-HCG assessment at screening and urine β-HCG assessments on Day-1 and at the EOS visit. 


Statistical Analysis Plan 
 
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Final 1.0 of 10MAY2019 
 
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m 
In each instance, the subject will receive a single oral dose of 1000 mg P218 or placebo (Cohort 2) or a single oral dose of 100 mg P218 or placebo (Cohort 3) after fasting 8 hours at least. The initial dose at Day 1 must 
not be given prior to 2 hours post-inoculation. 
n 
Malaria clinical score for malaria signs and symptoms is assessed on Day 1, in the 3 hours before PfSPZ Challenge, and daily from Day 7 to the day subject is positive for parasitaemia and at the EOS visit at Day 35. 
Daily assessments will take place during rescue treatment. For subjects that not develop positive parasitaemia until Day 28, after Day 28, assessments will take place only at the EOS visit at Day 35. 
o 
During the period between Day 14 and Day 28, haematology, clinical chemistry and urinalysis laboratory tests will be performed and serum folate measured after fasting for at least 8 hours on Days 14, 21 and 28, and 
additionally one day after the subject turned positive for parasitaemia, if not coincident with one of these scheduled timepoints. Troponin I will be measured at screening, baseline prior to inoculation and on Days 2 and 
3 of rescue treatment. 
p 
INR, PT and aPTT. 
q 
Every subject will receive a three-day course of antimalarial rescue medication as soon as positive for parasitaemia or on Day 28 in subjects who do not develop positive parasitaemia throughout the follow-up period. 
On the first day of rescue treatment, the subject will also receive a single oral dose of Primaquine® to ensure complete clearance of gametocytes.  
r 
Blood samples for the assessment of parasitaemia by TBS microscopy will be drawn daily from Day 7 to Day 28. In subjects who develop parasitaemia and receive rescue treatment, TBS microscopy will be performed 
daily for confirmation of the qPCR outcomes until treatment completion and success, and at the EOS visit on Day 35. In subjects who do not develop positive parasitaemia until Day 28 of the study, rescue treatment 
will be initiated on Day 28. Instead of daily qPCR and TBS assessments until treatment success, for these subjects only a final qPCR will be performed at the EOS visit on Day 35. 
s 
Blood samples for the assessment of parasitaemia by qPCR will be drawn at the following timepoints: immediately before PfSPZ Challenge DVI and daily from Day 7 to Day 28. In subjects who develop parasitaemia 
and receive rescue treatment, qPCR will be performed daily until treatment completion and one negative outcome is obtained, and at the EOS visit on Day 35. In subjects who do not develop positive parasitaemia until 
Day 28 of the study, rescue treatment will be initiated on Day 28. Instead of daily qPCR and TBS assessments until treatment completion and success, for these subjects only a final qPCR will be performed at the EOS 
visit on Day 35. 
t 
Randomisation will be performed before first IMP administration. 
u 
All subjects that receive rescue therapy will be asked non leading questions to determine the occurrence of any AEs approximately two weeks after initiation of the rescue treatment, either during a planned study visit or 
by phone in case there is no planned study visit at that time. If this time point is after the EOS visit on Day 35, the moment of the phone call will be considered the EOS and not Day 35. 
v 
This assessment can be done at either D-3 or D-1, upon Investigator’s decision. 


Statistical Analysis Plan 
 
MMV_P218_17_01 
 
Final 1.0 of 10MAY2019 
 
Document Nr.: OTH.STAT.010                  Version Nr.: 1               Effective Date:        
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