Conditions: Malaria,Falciparum Parasitemia Protozoan Infections Parasitic Disease
Keywords: Malaria PfSPZ Challenge
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 16
Healthy volunteers: yes

Brief summary:
This is a single-centre, open-label, Phase Ib study designed to assess if intravenous injection of approximately 3200 P. falciparum (NF54 strain) sporozoites can be safely administered to achieve blood-stage parasitaemia with a kinetics/PCR profile that will allow for the future characterisation of antimalarial blood-stage activity of new chemical entities in a relatively small number of participants during early drug development.

Healthy, malaria-naïve adults, aged 18-55 years, will be enrolled in a maximum of 2 cohorts. Enrolment into the cohorts will proceed sequentially, with two target levels of parasitaemia, i.e., 5000 parasites/mL blood in Cohort 1 and 10000 parasites/mL blood in Cohort 2.

(Based on observed levels of parasitaemia in Cohort 1, the target threshold for treatment in Cohort 2 was maintained at 5,000 p/mL (vs 10,000 p/mL in the protocol)).

The 3-day antimalarial therapy regimen will be further administered and monitored until parasite clearance. Safety and tolerability will be monitored during the whole study duration.

Detailed description:
Up to 16 healthy, malaria-naïve males and females, aged 18-55 years, will be enrolled in a maximum of 2 cohorts (up to 8 participants per cohort; a participant may be enrolled in one cohort only). Enrolment into the cohorts will proceed sequentially, with two target levels of parasitaemia previously achieved in healthy participants enrolled in malaria Volunteer Infection Studies (VIS) at other study sites, i.e., 5000 parasites/mL blood in Cohort 1 and 10000 parasites/mL blood in Cohort 2. (Based on observed levels of parasitaemia in Cohort 1, the target threshold for treatment in Cohort 2 was maintained at 5,000 p/mL (vs 10,000 p/mL in the protocol)).

Each participant will be admitted to the clinical unit in the morning of Day -1 and inoculated with approximately 3200 P. falciparum sporozoites (NF54 strain) by DVI on Day 1. Participants will be discharged 2 h post inoculation on Day 1 and will be monitored daily via phone call from Day 2 until Day 6 to solicit any AEs. Participants will come to the clinical unit daily from Day 7 until Day 9 and together with the malaria clinical score (see Attachment 1), the presence of parasites will be assessed once daily by a specific qPCR targeting the varATS (the acidic terminal segment in Plasmodium falciparum var genes) multigenic family; this to accurately describe parasite growth even in case PCR positivity, i.e., a qPCR outcome ≥250 parasites per mL blood, is confirmed this early (very low probability and with low densities). Participants will be confined to the clinical unit from Day 10 in the morning. qPCR will be performed and malaria clinical score assessed twice daily and participants will be administered registered antimalarial therapy, i.e., Riamet®, when the following criteria are met:

1. Cohort 1: ≥5000 parasites/mL blood or earlier if a participant has a malaria clinical score \>6 or at Investigator's discretion.
2. Cohort 2: ≥10000 parasites/mL blood or earlier if a participant has a malaria clinical score \>6 or at Investigator's discretion.

The registered 3-day antimalarial therapy regimen will be further administered and monitored. qPCR assessments of parasitaemia will be carried out at multiple time points (2, 6, 8, 12, 16, 24, 36, 48 and 72 h) following initiation of Riamet® and malaria clinical score will be assessed twice daily during confinement in the clinical unit. Safety and tolerability will be monitored during the whole study duration, specific assessments will be done at periodic pre-specified time points from Day 10 and for at least 72 h after initiating antimalarial therapy, i.e., during confinement in the clinical unit (see below).

Of note, all participants must consent to receiving antimalarial therapy, i.e., the registered 3-day Riamet® regimen approved for treatment of uncomplicated malaria. Even in the case of withdrawal from the study, all participants administered the PfSPZ-DVI Challenge are to receive antimalarial therapy as soon as possible, and to have all appropriate visits and assessments as required. If an intolerance or contraindication to Riamet® develops, Malarone® will be administered.

Upon parasite clearance (defined as a qPCR value of 0 parasites per mL blood after initiating antimalarial therapy) and at least 72 h after initiating antimalarial therapy (estimated to occur on or before Day 19 and on or before Day 22 for Cohort 1 and Cohort 2, respectively), and if clinically well, participants will be discharged from the clinical unit and will be followed up for safety assessments, clinical evaluation and malaria qPCR in the clinical unit at the EOS visit on Day 28. All participants who received antimalarial therapy will be asked non-leading questions to determine the occurrence of any AEs throughout the study and at the EOS visit. All participants inoculated with PfSPZ-DVI Challenge will commence antimalarial therapy no later than Day 24 for both cohorts, regardless if they reach pre-defined cohort-specific PCR parasitaemia/malaria clinical score thresholds (i.e., 5000 parasites/mL blood for Cohort 1 and 10000 parasites/mL blood for Cohort 2 and/or a malaria clinical score ≥6 for Cohorts 1 and 2). Participants who start antimalarial therapy on Day 24 will only be discharged from confinement at the end of the EOS visit on Day 28. Antimalarial therapy may be initiated whenever deemed necessary by the Investigators, e.g., if there is a concern regarding the safety of a study participant. Therapy may be amended according to the treating physician if the participant does not respond to treatment or the condition worsens.

Arms:
arm 1: 16 healthy, malaria-naïve males and females, aged 18-55 years, were enrolled in 2 cohorts (8 participants/cohort; a participant may be enrolled in one cohort only). There were two target levels of parasitaemia previously achieved in healthy participants in malaria VIS at other study sites, i.e., 5000 parasites/mL blood in Cohort 1 and 10000 parasites/mL blood in Cohort 2. (Based on observed levels of parasitaemia in Cohort 1, the target threshold for treatment in Cohort 2 was maintained at 5,000 p/mL).

qPCR was performed, malaria clinical score assessed twice daily and participants were administered registered antimalarial therapy, i.e., Riamet®, when the following criteria were met:

1. Cohort 1: ≥5000 parasites/mL blood or earlier if a participant has a malaria clinical score \>6 or at Investigator's discretion.
2. Cohort 2: ≥10000 parasites/mL blood or earlier if a participant has a malaria clinical score \>6 or at Investigator's discretion.

Interventions: intervention 1: Artemether-Lumefantrine 20 Mg-120 Mg Oral Tablet intervention 2: PfSPZ-DVI Challenge
Intervention descriptions: intervention 1: artemether-lumefantrine 6 x of 4 tablets at approximately 0, 8, 24, 36, 48 and 60 h intervention 2: 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 (CPMP/ICH/135/95) 
and with the applicable regulatory requirement(s).
A single centre, open label, pilot phase Ib study to investigate blood 
stage malaria infection after Direct Venous Inoculation of 
cryopreserved Plasmodium falciparum (NF54 strain) Sporozoites 
(PfSPZ-DVI) in malaria naïve healthy adult volunteers
Product
Riamet® (artemether-lumefantrine)
Protocol Number
MMV_PfSPZ-DVI Blood Stage_19_01
EudraCT Number
2019-004317-14
Clinical Phase
Ib
Clinical Indication
Acute Uncomplicated Plasmodium falciparum Malaria
in Adults
Issue Date (Version)
24-Jun-2020 (Final 3.0)
(Final Approved Protocol Amendment 1 dated 
27-Jan-2020 [Final 2.0])
Sponsor
Medicines for Malaria Venture (MMV)
Sponsor Representative
Farouk Chughlay, MD
Phone: +41 22 555 0355
Mobile: +41 79 123 4289
Fax: +41 22 555 0369


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SIGNATURES 
Signature of Sponsor Representative
Title:
A single centre, open label, pilot phase Ib study to investigate blood stage 
malaria infection after Direct Venous Inoculation of cryopreserved 
Plasmodium falciparum (NF54 strain) Sporozoites (PfSPZ-DVI) in 
malaria naïve healthy adult volunteers 
Name:
Farouk Chughlay, MD 
‘This Revised Clinical Study Protocol has been reviewed and approved by the Sponsor 
to ensure compliance with Good Clinical Practice.’ 
Signature: 
Date:
24 June 2020




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PROTOCOL HISTORY
Protocol Historya
Medicines for Malaria Venture (MMV) – MMV_PfSPZ-DVI Blood Stage_19_01
Document 
Issue Date
Amendment Type
Comments
Final Approved Protocol 
[Final 1.0]
17-Dec-2019
Not applicable
-
Amendment 1
[Final 2.0]
27-Jan-2020
Substantial
Revised Clinical Study Protocol 2.0
Amendment 2
[Final 3.0]
24-Jun-2020
Substantial
Revised Clinical Study Protocol 3.0
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 2: Summary of Changes.............................................................. 9 
Protocol Amendment 1: Summary of Changes............................................................ 11 
Protocol Synopsis............................................................................................................ 15 
Time and Events Schedule............................................................................................. 29 
List of Abbreviations and Definitions of Terms .......................................................... 39 
Study Administrative Structure and Investigators ..................................................... 42 
1. 
Introduction ............................................................................................................ 44 
1.1 
Malaria Background Information....................................................................... 44 
1.2 
Malaria CHMI/VIS Models................................................................................ 44 
1.3 
Plasmodium falciparum Sporozoites Challenge Model (PfSPZ Challenge)...... 44 
1.4 
Antimalarial Therapy.......................................................................................... 46 
1.5 
Overall Rationale for the Study.......................................................................... 46 
1.6 
Risk Benefit Analysis......................................................................................... 46 
1.6.1 
Potential Risks...................................................................................... 46 
1.6.2 
Potential Benefits ................................................................................. 48 
1.6.3 
Conclusion............................................................................................ 48 
2. 
Objectives and Endpoints ...................................................................................... 49 
3. 
Study Design............................................................................................................ 53 
3.1 
Overview of Study Design ................................................................................. 53 
3.2 
Discussion of Study Design and Dose Selection................................................ 55 
3.3 
End of Study Definition...................................................................................... 60 
3.4 
Safety Review Committee (SRT)....................................................................... 60 
3.4.1 
Toxicity Criteria and Progression From Cohort 1 to Cohort 2 ............ 61 
3.4.2 
Final SRT Review at Study End .......................................................... 61 
4. 
Selection of Study Population................................................................................ 62 
4.1 
Inclusion Criteria................................................................................................ 62 
4.2 
Exclusion Criteria............................................................................................... 63 
4.3 
Lifestyle considerations...................................................................................... 66 
4.3.1 
Meals and Dietary Restrictions ............................................................ 66 
4.3.2 
Caffeine, Alcohol, and Tobacco........................................................... 66 
4.3.3 
Activity................................................................................................. 67 
4.3.4 
Other..................................................................................................... 67 
4.4 
Screen Failures ................................................................................................... 67 
5. 
Study Interventions ................................................................................................ 68 
5.1 
Study Interventions Administered...................................................................... 68 


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5.2 
Preparation/Handling/Storage/Accountability ................................................... 69 
5.2.1 
PfSPZ-DVI Challenge.......................................................................... 70 
5.2.2 
Registered Antimalarial Therapy ......................................................... 71 
5.3 
Randomisation and Blinding.............................................................................. 72 
5.4 
Dose Modification.............................................................................................. 72 
5.5 
Treatment Compliance ....................................................................................... 72 
6. 
Prior and Concomitant Therapy........................................................................... 73 
6.1 
Permitted Concomitant Therapies ...................................................................... 73 
6.2 
Prohibited Concomitant Therapies..................................................................... 73 
7. 
Assessments ............................................................................................................. 74 
7.1 
Timing of Assessments....................................................................................... 74 
7.1.1 
Screening Period .................................................................................. 74 
7.1.2 
Treatment Period.................................................................................. 75 
7.1.3 
Follow-up Period.................................................................................. 76 
7.1.4 
Unscheduled Visits............................................................................... 77 
7.2 
Pharmacodynamic Assessments......................................................................... 77 
7.2.1 
Parasitaemia ......................................................................................... 77 
7.3 
Safety Assessments ............................................................................................ 77 
7.3.1 
Adverse Events..................................................................................... 77 
7.3.2 
Malaria Clinical Score.......................................................................... 78 
7.3.3 
Clinical Laboratory Tests..................................................................... 79 
7.3.4 
Vital Signs............................................................................................ 80 
7.3.5 
Electrocardiogram ................................................................................ 80 
7.3.6 
Physical Examination........................................................................... 80 
7.3.7 
Beck Depression Inventory .................................................................. 81 
7.4 
Parasite Transcriptomics .................................................................................... 81 
7.5 
Treatment of Overdose....................................................................................... 81 
7.6 
Total Volume of Blood Sampling ...................................................................... 81 
7.7 
Appropriateness of Measurements ..................................................................... 81 
8. 
Participant Withdrawal from the Study............................................................... 82 
8.1 
Withdrawal of Participants From Study............................................................. 82 
8.2 
Lost to Follow-up ............................................................................................... 83 
9. 
Statistical Methods.................................................................................................. 84 
9.1 
Statistical Analysis ............................................................................................. 84 
9.1.1 
Initial Characteristics Data of the Participant Sample ......................... 84 
9.1.2 
Pharmacodynamic Data........................................................................ 85 
9.1.3 
Safety Data ........................................................................................... 86 
9.2 
Determination of Sample Size............................................................................ 88 
10. Adverse Event Reporting....................................................................................... 89 
10.1 
Definitions.......................................................................................................... 89 
10.2 
Intensity of Adverse Events................................................................................ 94 
10.3 
Causality Assessment......................................................................................... 94 
10.4 
Action Taken Regarding the Investigational products....................................... 95 
10.5 
Outcome ............................................................................................................. 95 
10.6 
Recording of Adverse Events............................................................................. 96 
10.7 
Reporting of Serious Adverse Events to PrimeVigilance Ltd............................ 96 


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10.8 
Pregnancy ........................................................................................................... 96 
10.9 
Reporting of Serious Adverse Events to Competent Authorities/Ethics 
Committees......................................................................................................... 97 
11. Ethical Aspects........................................................................................................ 98 
11.1 
Study-Specific Design Considerations............................................................... 98 
11.2 
Regulatory Ethics Compliance........................................................................... 98 
11.2.1 
Investigator Responsibilities ................................................................ 98 
11.2.2 
Independent Ethics Committee or Institutional Review Board 
(IEC/IRB)............................................................................................. 98 
11.2.3 
Informed Consent............................................................................... 100 
11.2.4 
Privacy of Personal Data.................................................................... 101 
12. Administrative Requirements ............................................................................. 102 
12.1 
Protocol Amendments ...................................................................................... 102 
12.2 
Participant Identification, Enrolment and Screening Logs............................... 102 
12.3 
Source Documentation ..................................................................................... 102 
12.4 
Case Report Form Completion......................................................................... 103 
12.5 
Monitoring........................................................................................................ 103 
12.6 
Data Management............................................................................................. 103 
12.7 
Data Quality Assurance.................................................................................... 104 
12.8 
On-Site Audits.................................................................................................. 104 
12.9 
Study Termination............................................................................................ 105 
12.10 
Record Retention.............................................................................................. 105 
12.11 
Use of Information and Publication ................................................................. 105 
12.12 
Registration of Clinical Studies and Disclosure of Results.............................. 107 
12.13 
Confidentiality.................................................................................................. 107 
13. References.............................................................................................................. 108 
Attachment 1: Clinical Score For Malaria................................................................. 111 
Attachment 2: Beck Depression Inventory................................................................. 112 
Attachment 3: Normal Ranges for Vital Signs and ECG ......................................... 115 
Attachment 4: Clinically Acceptable Ranges for Clinically Important Study 
Inclusion Laboratory Tests............................................................................ 116 


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List of Tables
Table 1: 
Objectives and Endpoints .............................................................................. 49 
Table 2: 
Description of Study Interventions................................................................ 69 
List of Figures
Figure 1: 
Schematic Overview of the Study for Cohort 1............................................. 55 
Figure 2: 
Schematic Overview of the Study for Cohort 2............................................. 55 


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PROTOCOL AMENDMENT 2: SUMMARY OF CHANGES
This amendment is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
Overall Reason for Amending the Protocol: This amendment was created to 
implement the Sponsor’s safety measures in the protocol with regard to the coronavirus 
disease 2019 pandemic. 
Changes are summarized below together with a rationale for each change.
1. Change in Exclusion Criteria
Rationale:
Per Sponsor’s decision, the study exclusion criteria have been updated to exclude any subject 
who tests positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): since 
participants could experience flu-like symptoms following Direct Venous Inoculation of 
cryopreserved Plasmodium falciparum, for the safety of the participants, it is important to 
screen for SARS-CoV-2 infection prior to inoculation. Also before second confinement to the 
study site, participants should be tested for SARS-CoV-2 infection, and must be withdrawn 
from the study if the test result is positive.
Testing before first confinement to the study site (from the participants who already completed 
the other screening tests and are still eligible to be enrolled in the study) and before second 
confinement to the study site will be performed by taking a nasopharyngeal swab to detect 
presence of SARS-CoV-2 ribonucleic acid, using a real-time reverse transcription polymerase 
chain reaction (rRT-PCR) test.
Applicable 
Section(s)
Description of Changes
Synopsis
An additional exclusion criterion 24 was added to exclude any subject 
with SARS-CoV-2 infection. 
Time and Events 
Schedule
The schedule was updated to reflect the additional visits which can take 
place up to Day -2 (before the first confinement to the study site) and on 
Day 7-9 (before the second confinement), on which the nasopharyngeal 
swabs will be taken.
Section 4.2
An additional exclusion criterion 24 was added to exclude any subject 
with SARS-CoV-2 infection.
Section 7.1.1
The text on the screening of participants was updated to reflect the need 
for SARS-CoV-2 testing during screening.
Section 7.1.2
The text was updated to reflect the need for SARS-CoV-2 testing before 
the second confinement to the study site.
Section 8.1
The text was updated to reflect the need for participant withdrawal from 
the study if he or she tests positive for SARS-CoV-2 before confinement 
to the study site.


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2. Minor Corrections
Rationale:
Minor correction
Applicable 
Section(s)
Description of Changes
Synopsis
The text on the relationship of adverse events to malaria was updated.
The text on coagulation testing was updated to align with the text on the 
criterion for modified Hy’s law.
List of 
Abbreviations and 
Definitions of 
Terms
The list of abbreviations was updated.
Time and Events 
Schedule
The top rows of the flowchart were updated to clarify that Day -1 is not 
an actual part of the ‘Challenge, treatment and follow-up’ period.
The footnotes on coagulation testing were updated to align with the text 
on the criterion for modified Hy’s law.
The schedule was updated to include extra International normalized ratio
(INR) tests which will be performed post-baseline at the same time 
points as the post-baseline haematology and liver biochemistry tests.
Section 1.6.1
The text on total blood volume sampling was updated.
Section 5.1
The text on the relationship of adverse events to malaria was updated.
Section 7.1.1 and 
Section 7.1.2
The text on Day -1 was moved from Section 7.1.2 to Section 7.1.1 to 
clarify that Day -1 is not part of the treatment period.
Section 7.3.3
The text on coagulation testing was updated to align with the text on the 
criterion for modified Hy’s law.
Section 7.6
The text on total blood volume sampling was updated.
Section 8.1
The text on the relationship of adverse events to the PfSPZ-DVI 
Challenge agent and/or the antimalarial treatment was updated.
Section 10.1
Minor formatting corrections.
Section 10.3
The text on the relationship of adverse events to the PfSPZ-DVI 
Challenge agent and/or the antimalarial treatment was changed: this 
relationship is now classified as Related or Not related. The term 
‘suspected’ was removed from the category.
Section 10.7
The text was updated to clarify that Adverse Events of Special Interest 
must also be reported on the Serious Adverse Event Form.
Section 10.8
Induced abortion was removed from the list of abnormal pregnancy 
outcomes that are considered serious adverse events.


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PROTOCOL AMENDMENT 1: SUMMARY OF CHANGES
This amendment is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union
Overall Reason for Amending the Protocol: This amendment was created to make 
adaptations following review of the protocol by the Belgian Federal Agency for 
Medicines and Health Products (FAMHP).
Changes are summarized below together with a rationale for each change. 
1. Change in Exclusion Criteria
Rationale:
The study exclusion criteria have been updated based on the Agency’s recommendations to 
exclude any subject with hepatic disorders and in line with the Food and Drug Administration 
(FDA) Guidance pertaining to Drug-Induced Liver Injury (FDA, 20091).
1. The hepatitis blood test panel at study screening has been significantly expanded to ensure a 
comprehensive assessment of the most common causes of infectious hepatitis disorders in 
Phase 1 populations prior to study inclusion. Given that infection with hepatitis D virus only 
occurs in people who are already infected with the hepatitis B virus (HBV), testing for
hepatitis D virus will be performed exclusively in those participants who screen positive for 
HBV.
2. An exclusion criterion has been added to ensure that study participants with documented 
hepatic disorders other than common causes of hepatitis are not included (including but not 
limited to viral hepatitis, auto-immune hepatitis, non-alcoholic steatohepatitis [NASH], 
alpha-1-antitrypsin deficiency, alcoholic liver disease, primary biliary cholangitis [PBC], 
primary sclerosing cholangitis [PSC], hemochromatosis, Wilson disease or suspected 
hepatocellular carcinoma [HCC]).
Applicable 
Section(s)
Description of Changes
Synopsis
Exclusion criterion 6 was updated to expand the hepatitis blood test 
panel.
An additional exclusion criterion 7 was added to exclude any subject 
with hepatic disease. 
Serological testing in the safety assessments was updated to reflect the 
expanded hepatitis blood test panel.
Time and Events 
Schedule
Footnote related to serological testing was updated to reflect the 
expanded hepatitis blood test panel.
1 FDA Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, U.S. 
Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and 
Research (CDER) Center for Biologics Evaluation and Research (CBER), July 2009


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Applicable 
Section(s)
Description of Changes
Section 4.2
Exclusion criterion 6 was updated to expand the hepatitis blood test 
panel.
An additional exclusion criterion 7 was added to exclude any subject 
with hepatic disease.
Section 7.3.3
Serological testing was updated to reflect the expanded hepatitis blood 
test panel.
2. Change in Inclusion Criteria
Rationale:
The study inclusion criteria have been updated based on the Agency’s recommendation that 
liver transaminases at screening should not exceed the upper limit of normal (ULN) 
(>1x ULN, instead of >1.25x ULN). 
Applicable 
Section(s)
Description of Changes
Synopsis
Section 4.1
Inclusion criterion 4 has been updated to reflect that transaminases 
should not exceed >1x ULN.
3. Addition of Clinically Acceptable Ranges for Clinically Important Study 
Inclusion Laboratory Tests 
Rationale:
Based on the Agency’s recommendation, the Clinically Acceptable Ranges for Clinically 
Important Study Inclusion Laboratory Tests (including total and conjugated bilirubin) have
been added in Attachment 4 of the protocol to guide inclusion/exclusion of study participants.
Applicable 
Section(s)
Description of Changes
Section 4.1
Section 4.2
A reference to Attachment 4 was added.
Attachment 4
Clinically Acceptable Ranges for Clinically Important Study Inclusion 
Laboratory Tests have been added.


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4. Change in Composition of Safety Review Team (SRT)
Rationale:
Based on the Agency’s recommendation, and in line with the CHMP Guideline on data 
monitoring committees, an independent Early Phase and Clinical Pharmacology MD expert 
experienced in malaria volunteer infections studies was included as the chair of the SRT, in 
addition to the Medical Monitor, the Medical/Project Director, the Principal Investigator (PI)
and an independent infectious disease/malaria expert.
Applicable 
Section(s)
Description of Changes
Synopsis 
Section 3.4
Addition of an independent Early Phase and Clinical Pharmacology MD 
expert experienced in malaria volunteer infection studies as SRT chair to 
the corrected SRT composition.
5. Change in Toxicity Criteria
Rationale:
Based on the Agency’s recommendation, and in line with the European Medicines Agency 
(EMA) Guideline on strategies to identify and mitigate risks for first-in-human and early 
clinical trials with investigational medicinal products, the toxicity criteria taken into account to
progress from Cohort 1 to Cohort 2 were updated. The criterion on Riamet®-related AEs was 
changed from “two or more Riamet®-related severe (grade 3 or higher), same organ class AEs”
to “two or more Riamet®-related severe (grade 3 or higher) AEs, independent of within or not 
within the same system organ class”.
Applicable 
Section(s)
Description of Changes
Section 3.4.1
The toxicity criterion on Riamet®-related AEs was updated.


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6. Minor Corrections
Rationale:
Minor corrections
Applicable 
Section(s)
Description of Changes
Study 
Administrative 
Structure and 
Investigators
Section 12.5
Clinical Monitoring details were added.
Section 3.4
Section 3.4.1
The composition of the SRT was moved from Section 3.4.1 to the 
beginning of Section 3.4.
Synopsis
Section 3.4
Section 5.1
‘Malaria expert’ or ‘infectious diseases physician with expertise in 
malaria’ was replaced by ‘independent infectious disease/malaria 
expert’.
Synopsis
Time and Events 
Schedule
Section 7.3.2
Section 7.3.4
Temperature measurements were included into the vital signs part of the 
protocol because:
-
temperature measurement is required to assess the malaria clinical 
score - fever; but
-
the temperature also needs to be viewable as a data point for the 
medics.
Attachment 1
Timing of grading malaria clinical score was adapted.


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PROTOCOL SYNOPSIS
15
PROTOCOL SYNOPSIS
Study Title
A single centre, open label, pilot phase Ib study to investigate blood stage 
malaria infection after Direct Venous Inoculation of cryopreserved 
Plasmodium falciparum (NF54 strain) Sporozoites (PfSPZ-DVI) in malaria 
naïve healthy adult volunteers
Product
Riamet®
(artemether-lumefantrine)
Clinical Phase
Ib
Protocol Number
MMV_PfSPZ-DVI Blood 
Stage_19_01
Indication
Acute Uncomplicated 
Plasmodium falciparum
Malaria in Adults
EudraCT Number
2019-004317-14
Sponsor
Medicines for Malaria Venture (MMV)
Sponsor Representative
Farouk Chughlay, MD
Clinical Centre
SGS Life Sciences, Clinical Pharmacology Unit, Lange 
Beeldekensstraat 267, 2060 Antwerpen, Belgium
Objectives and Endpoints:
OBJECTIVES
ENDPOINTS
Primary
x
To evaluate the safety and 
tolerability associated with 
blood-stage malaria 
infection in naïve healthy 
participants after 
inoculation of Plasmodium 
falciparum sporozoites 
through direct venous 
inoculation (PfSPZ-DVI 
Challenge).
x
The incidence and severity of observed (i.e., malaria signs and 
symptoms graded by the malaria clinical score) or self-reported 
adverse events (AEs) considered PfSPZ-DVI Challenge 
inoculum-related until end of study (EOS) visit.
x
The change in malaria clinical score from PfSPZ-DVI Challenge 
until parasite clearance (defined as a quantitative polymerase 
chain reaction [qPCR] value of 0 parasites per mL blood after 
initiating antimalarial therapy).
x
Changes from baseline in haematology, clinical chemistry and 
urinalysis parameters, vital signs and electrocardiogram (ECG) 
parameters.
x
To characterise key stages 
in the blood-stage parasite 
growth profile in malaria 
infection in naïve healthy 
participants after 
PfSPZ-DVI Challenge.
x
The parasite growth profiles of Plasmodium falciparum
(P. falciparum) NF54 after infection via injection of sporozoites 
by direct venous inoculation (DVI) will be characterised by:
o
time to first PCR positivity (i.e., time elapsed between 
PfSPZ-DVI Challenge and first qPCR outcome equal to or 
greater than 250 parasites per mL blood, with a maximum of 
28 days in the absence of parasitaemia);
o
parasitaemia at first PCR positivity;
o
WLPHWRSDUDVLWDHPLDRI parasites per mL blood 
(Cohorts 1 and 2);
o
parasitaePLDDWWKHWLPHSDUDVLWDHPLD parasites per mL 
blood (Cohorts 1 and 2);
o
WLPHWRSDUDVLWDHPLDRI parasites per mL blood 
(Cohort 2); 
o
SDUDVLWDHPLDDWWKHWLPHSDUDVLWDHPLD parasites per 
mL blood (Cohort 2);


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
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16
o
time to first dose of treatment with artemether-lumefantrine 
(Riamet®) (Cohorts 1 and 2); and
o
parasitaemia at first dose of treatment with Riamet®
(Cohorts 1 and 2).
x
The number and proportion of participants with presence of 
SRVLWLYH3&5DQGSDUDVLWDHPLDRIRU parasites per 
mL blood between inoculation with PfSPZ-DVI Challenge and 
Day 28 (per cohort).
Secondary
x
To determine the safety and 
tolerability of Riamet® in 
blood-stage malaria 
infection in naïve healthy 
participants after 
PfSPZ-DVI Challenge.
x
The incidence, severity and relationship to Riamet® of observed 
or self-reported, treatment-emergent adverse events (TEAEs) until 
EOS visit.
x
To characterise the blood-
stage parasite profile in 
malaria infection in naïve 
healthy participants after 
PfSPZ-DVI Challenge.
x
The blood-stage parasite profile of P. falciparum NF54 after 
infection via injection of sporozoites by DVI will be characterised 
by: 
o
parasite growth rate expressed as the parasite multiplication 
rate (PMR) standardised to 48 h (PMR48) (Cohort 1, 
Cohort 2 and overall);
o
parasite growth rate expressed as the PMR per life cycle (if 
not 48 h) (PMRLC) (Cohort 1, Cohort 2 and overall); and
o
predicted time to reach parasitaemia threshold of first 
SRVLWLYH3&5SDUDVLWHVSHUP/EORRG
 parasites per mL blood for Cohorts 1 and 2.
x
To characterise the 
blood-stage parasite 
clearance profile of 
Riamet® in malaria 
infection in naïve healthy 
participants after 
PfSPZ-DVI Challenge.
x
The effect of Riamet® on clearance of P. falciparum blood-stage 
parasites will be evaluated using:
o
time to parasite clearance, i.e., time between drug 
administration and first PCR below the limit of 
quantification (Cohort 1, Cohort 2 and overall); 
o
log10 parasite reduction ratio per 48 h (log10PRR48), i.e., ratio 
of the parasite density at a specific time point to the parasite 
density 48 h later and expressed in log10 (Cohort 1, Cohort 2 
and overall); 
o
maximum log10PRR48 (log10PRR48,max) (Cohort 1, Cohort 2 
and overall); and
o
parasite clearance half-life (PC½), i.e., time taken for the 
parasite density to be reduced by 50% after the first dose 
administration of Riamet® (Cohort 1, Cohort 2 and overall).
Exploratory
x
To characterise the 
individual variability of 
blood-stage parasite profile.
x
The individual variability of blood-stage parasite profile will be 
characterised by:
o
the inter-individual variability of the parasite growth rate; 
and
o
predicted time to reach parasitaemia threshold of first 
SRVLWLYH3&5SDUDVLWHVSHUP/EORRG
parasites per mL blood including their 95% confidence 
interval (CI).


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
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17
Overview of Study Design:
This is a single-centre, open-label, Phase Ib study designed to assess if intravenous bolus injection of 
approximately 3200 P. falciparum (NF54 strain) sporozoites can be safely administered to achieve 
blood-stage parasitaemia with a kinetics/PCR profile that will allow for the future characterisation of 
antimalarial blood-stage activity of new chemical entities in a relatively small number of participants 
during early drug development.
Up to 16 healthy, malaria-naïve males and females, aged 18-55 years, will be enrolled in a maximum of 
2 cohorts (up to 8 participants per cohort; a participant may be enrolled in one cohort only). Enrolment 
into the cohorts will proceed sequentially, with two target levels of parasitaemia previously achieved in 
healthy participants enrolled in malaria Volunteer Infection Studies (VIS) at other study sites, i.e., 
5000 parasites/mL blood in Cohort 1 and 10000 parasites/mL blood in Cohort 2.
Each participant will be admitted to the clinical unit in the morning of Day -1 and inoculated with 
approximately 3200 P. falciparum sporozoites (NF54 strain) by DVI on Day 1. Participants will be 
discharged 2 h post inoculation on Day 1 and will be monitored daily via phone call from Day 2 until 
Day 6 to solicit any AEs. Participants will come to the clinical unit daily from Day 7 until Day 9 and 
together with the malaria clinical score, the presence of parasites will be assessed once daily by a specific 
qPCR targeting the varATS (the acidic terminal segment in Plasmodium falciparum var genes) multigenic 
IDPLO\WKLVWRDFFXUDWHO\GHVFULEHSDUDVLWHJURZWKHYHQLQFDVH3&5SRVLWLYLW\LHDT3&5RXWFRPH
parasites per mL blood, is confirmed this early (very low probability and with low densities). Participants 
will be confined to the clinical unit from Day 10 in the morning. qPCR will be performed and malaria 
clinical score assessed twice daily and participants will be administered registered antimalarial therapy, 
i.e., Riamet®, when the following criteria are met:
1.
&RKRUWSDUDVLtes/mL blood or earlier if a participant has a malaria clinical score >6 or at 
Investigator’s discretion.
2.
&RKRUWSDUDVLWHVP/EORRGRUHDUOLHULIDSDUWLFLSDQWKDVDPDODULDFOLQLFDOVFRUH!RU
at Investigator’s discretion.
The registered 3-day antimalarial therapy regimen will be further administered and monitored. qPCR 
assessments of parasitaemia will be carried out at multiple time points (2, 6, 8, 12, 16, 24, 36, 48 and 72 h) 
following initiation of Riamet® and malaria clinical score will be assessed twice daily during confinement 
in the clinical unit. Safety and tolerability will be monitored during the whole study duration, specific 
assessments will be done at periodic pre-specified time points from Day 10 and for at least 72 h after 
initiating antimalarial therapy, i.e., during confinement in the clinical unit (see below).
Of note, all participants must consent to receiving antimalarial therapy, i.e., the registered 3-day Riamet®
regimen approved for treatment of uncomplicated malaria. Even in the case of withdrawal from the study, 
all participants administered the PfSPZ-DVI Challenge are to receive antimalarial therapy as soon as 
possible, and to have all appropriate visits and assessments as required. If an intolerance or 
contraindication to Riamet® develops, Malarone® will be administered.
Upon parasite clearance (defined as a qPCR value of 0 parasites per mL blood after initiating antimalarial 
therapy) and at least 72 h after initiating antimalarial therapy (estimated to occur on or before Day 19 and 
on or before Day 22 for Cohort 1 and Cohort 2, respectively), and if clinically well, participants will be 
discharged from the clinical unit and will be followed up for safety assessments, clinical evaluation and 
malaria qPCR in the clinical unit at the EOS visit on Day 28. 
All participants who received antimalarial therapy will be asked non-leading questions to determine the 
occurrence of any AEs throughout the study and at the EOS visit.
All participants inoculated with PfSPZ-DVI Challenge will commence antimalarial therapy no later than 
Day 24 for both cohorts, regardless if they reach pre-defined cohort-specific PCR parasitaemia/malaria 
clinical score thresholds (i.e., 5000 parasites/mL blood for Cohort 1 and 10000 parasites/mL blood for 
&RKRUWDQGRUDPDODULDFOLQLFDOVFRUHIRU&RKRUWV 1 and 2). Participants who start antimalarial 
therapy on Day 24 will only be discharged from confinement at the end of the EOS visit on Day 28.
Antimalarial therapy may be initiated whenever deemed necessary by the Investigators, e.g., if there is a 
concern regarding the safety of a study participant. Therapy may be amended according to the treating 
physician if the participant does not respond to treatment or the condition worsens.


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
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18
A sentinel strategy will be employed in Cohorts 1 and 2. Each cohort will consist of 2 subgroups of 
participants, to be enrolled sequentially: Subgroup 1 will be composed of 2 participants; Subgroup 2 will 
be composed of 6 participants. Participants in Subgroup 2 will not be treated until the last participant in 
Subgroup 1 has completed antimalarial therapy and only upon decision of the Principal Investigator (PI), 
medical director and medical monitor after review of available safety and tolerability data (safety 
assessments, AEs and malaria clinical scores) and parasitaemia data, including clearance of parasitaemia, 
of Subgroup 1.
Review of available Cohort 1 safety/tolerability and parasitaemia data up to the last dose of Riamet® for 
all inoculated participants in Cohort 1 will be performed by a Safety Review Team (SRT) before 
enrolment of Cohort 2. For progression from Cohort 1 to Cohort 2, the SRT members will include at least 
an independent Early Phase and Clinical Pharmacology MD expert experienced in malaria volunteer 
infection studies (SRT chair), the Medical Monitor, the Medical/Project Director, the PI and an 
independent infectious disease/malaria expert (or their delegates).
Study Population:
Approximately 16 participants are planned to be enrolled sequentially in 2 cohorts of up to 8 participants 
per cohort. A participant may be enrolled in one cohort only.
Eligibility Criteria:
Inclusion Criteria:
1.
Informed Consent Form signed voluntarily before any study-related procedure is performed, 
indicating that the participant understands the purpose of and procedures required for the study 
and is willing to participate in the study, including administration of registered antimalarial 
therapy;
2.
Male or female, between 18 and 55 years old (extremes included) at screening;
3.
Body weight of at least 50 kg and a body mass index (BMI) of 19.0 to 30.0 kg/m2 (extremes 
included);
4.
Good general health without clinically relevant medical illness, physical exam findings including 
vital signs, and laboratory abnormalities (e.g., without liver transaminases >1x the upper limit of 
normal [ULN] and as defined in the protocol) 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 the required duration and willingness to 
avoid travelling outside of Benelux during the study period;
6.
Female participants should fulfil one of the following criteria:
a.
At least 1 year postmenopausal (amenorrhea >12 months and follicle stimulating hormone 
[FSH] >30 mIU/mL) prior to screening;
b.
Surgically sterile (bilateral oophorectomy, hysterectomy or bilateral salpingectomy);
c.
Will use contraceptives as outlined in inclusion criterion 7;
7.
Female participants of childbearing potential (excluding females with female partners) must 
agree to the use of a highly effective method of birth control from the screening visit until 
40 days after the EOS visit at Day 28 (covering a full menstrual cycle of 30 days starting after 
5 half-lives of last dose of Riamet®);
Note: Highly effective birth control methods include: combined (oestrogen- and 
progestogen-containing) oral/intravaginal/transdermal hormonal contraception associated with 
inhibition of ovulation, progestogen-only oral/injectable/implantable hormonal contraception 
associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing 
system, bilateral tubal occlusion, vasectomised partner or sexual abstinence from heterosexual 
intercourse.
8.
Female participant has a negative pregnancy test at screening and upon admission in the clinical 
unit;
Note: Pregnancy testing will consist of VHUXPȕ-KXPDQFKRULRQLFJRQDGRWURSLQȕ-HCG) tests at 
VFUHHQLQJDQGDWWKH(26YLVLWDQGDXULQHȕ-HCG tests on Day -1, in all women.
9.
Different ways of being reachable 24/7 (e.g., by mobile phone, regular phone or electronic mail) 
during the whole study period.


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
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19
Exclusion Criteria:
1.
Nursing (lactating) women;
2.
Participation in any other clinical drug or vaccine study within 30 days (or 5 half-lives for drugs) 
preceding the day of PfSPZ-DVI Challenge (whichever is longer), or plans to participate in other 
investigational drug or vaccine research during the study period;
3.
Participants who took standard vaccinations within 3 months before the start of the study or are 
planning to take standard vaccinations during the study period up to 8 weeks after PfSPZ-DVI 
Challenge;
4.
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 on Day -1;
5.
Mean ECG outside normal range and deemed clinically relevant by the Investigator. Examples of 
clinically significant ECG abnormalities for this study include:
-
PR-interval >220 ms;
-
QRS-complex >120 ms;
-
Absolute QT greater than >500 ms;
-
QT interval corrected according to Bazett’s formula (QTcB) or QT interval corrected 
according to Fridericia’s formula (QTcF >450 ms for male participants, >470 ms for female 
participants;
-
Pathologic Q wave;
-
Significant ST-T wave changes;
-
Left or right ventricular hypertrophy;
-
Non-sinus rhythm except isolated premature atrial contractions and ventricular extrasystole 
<2 per 10 s ECG lead;
-
Incomplete left bundle branch block, or complete or intermittent right or left bundle branch 
block;
-
Second or third degree A-V heart block.
6.
Seropositive human immunodeficiency virus (HIV), hepatitis A immunoglobulin M (IgM)
antibody, hepatitis B virus (HBV) (hepatitis B surface antigen [HBsAg]), hepatitis C virus 
(HCV) (antibody), hepatitis D antibody, hepatitis E IgM antibody, cytomegalovirus (CMV) IgM 
antibody or Epstein Barr Virus (EBV) IgM antibody;
7.
Previous or current diagnosis of hepatitis including but not limited to viral hepatitis, 
auto-immune hepatitis, non-alcoholic steatohepatitis (NASH), alpha-1-antitrypsin deficiency, 
alcoholic liver disease, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC),
hemochromatosis, Wilson disease or suspected hepatocellular carcinoma (HCC).
8.
History or presence of diagnosed food or known drug allergies (including but not limited to 
allergy to any of the antimalarial medications to be used in the study), or history of anaphylaxis 
or other severe allergic reactions;
Note: Participants 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.
9.
History of convulsion or severe head trauma, excluding fever convulsion under 5 years of age;
Note: A medical history of a single febrile convulsion during childhood is not an exclusion 
criterion.
10. 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 will be used as an objective tool for the assessment of 
depression at screening. In addition to the conditions listed above, participants 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. Participants 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 


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
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PROTOCOL SYNOPSIS
20
considered to pose additional risk to the health of the volunteer or to the execution of the study 
and interpretation of the data gathered.
11. 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 defined as 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%).
12. Participants 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. Participants must agree 
to abstain from smoking while in the unit;
13. Use of any prescription drugs, herbal supplements (e.g., St John’s Wort) or over-the-counter 
medication within 7 days or 5 half-lives (whichever is longer) prior to the PfSPZ-DVI Challenge, 
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) and 
paracetamol (2 g/day, 10 g/week) may be acceptable at the Investigator’s discretion 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 participant safety nor the overall results of the study, 
may be permitted on a case-by-case basis by the Investigator.
14. Any surgical or medical condition possibly affecting drug absorption (e.g., cholecystectomy, 
gastrectomy, bowel disease), distribution, metabolism or excretion;
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 jeopardise the safety or rights of a 
person participating in the study or would render the person unable to comply with the protocol;
17. Personal history of malaria;
18. Volunteer has travelled to or lived in a malaria-endemic area within 6 months prior to planned 
study enrolment;
19. Plans to travel to malaria-endemic region during the study period up to last follow-up visit;
20. Previous participation in any malaria vaccine or Controlled Human Malaria Infection (CHMI) 
study/VIS;
21. Falling in moderate or higher risk category for a fatal or non-fatal cardiovascular event within 
5 years (> 5%) determined by a validated risk estimation system, e.g., SCORE;
22. Use of systemic antibiotics with known antimalarial activity within 5 half-lives of PfSPZ-DVI 
Challenge (e.g., trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, 
erythromycin, fluoroquinolones or azithromycin) or an anticipated requirement for the use of 
these during the study period;
23. Receipt of blood or blood-derived products (including immunoglobulin) within 3 months prior to 
screening. Receipt of packed red blood cells (RBCs) given for an emergent indication in an 
otherwise healthy person, and not required as ongoing treatment is not exclusionary (for example 
packed RBCs emergently given during an elective surgery).
24. Participants who test positive for severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2).
Note: In case of an out-of-range clinical laboratory test (as defined in the protocol), vital sign or 
ECG value that will determine a participant’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 participant eligibility at the 
Investigator’s discretion. Participants can be rescreened at the discretion of the Investigator.


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
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21
PfSPZ Challenge, Riamet® and Malarone®; Dose, Mode of Administration:
Manufacturing, packaging, and labelling of PfSPZ-DVI Challenge inoculum will be done under the 
responsibility of the biotechnology company Sanaria (USA).
The clinical unit will be responsible for acquiring the registered antimalarial drugs artemether 
lumefantrine (Riamet®) and atovaquone-proguanil (Malarone®):
-
Participants will be prescribed with Riamet® according to the pre-defined cohort-specific PCR 
parasitaemia/malaria clinical score thresholds (i.e., 5000 parasites/mL blood for Cohort 1 and 
SDUDVLWHVP/EORRGIRU&RKRUWDQGRUDPDODULDFOLQLFDOVFRUHIRU&RKRUWVDQGWR
ensure parasite clearance prior to the end-of-study evaluation. In addition, participants will also 
be administered with Riamet®:
o
LIWKH\H[SHULHQFHLQRFXOXP-related serious adverse event (SAE), irrespective of severity; 
or
o
LIWKH\H[SHULHQFH&RPPRQ7HUPLQRORJ\&ULWHULDIRU$GYHUVH(YHQWV&7&$(
grade  (severe) AE deemed related to malaria and not self-resolved or relieved with 
concomitant medications; or 
o
if the PI or delegate considers it necessary for participant safety. In this situation, the PI or 
delegate will consult with the independent infectious disease/malaria expert (Prof. 
Jean-Pierre Van geertruyden). However, antimalarial medication may be administered prior 
to consultation if immediate treatment is deemed necessary for participant safety.
-
If an intolerance or contraindication to Riamet® develops, Malarone® will be administered.
All participants inoculated with PfSPZ-DVI Challenge will commence antimalarial therapy no later than 
Day 24 for both cohorts, regardless if they reach pre-defined cohort-specific PCR parasitaemia/malaria 
clinical score thresholds (i.e., 5000 parasites/mL blood for Cohort 1 and 10000 parasites/mL blood for 
&RKRUWDQGRUDPDODULDFOLQLFDOVFRUHIRU&RKRUWVDQG
All participants must consent to receiving antimalarial therapy. Even in the case of withdrawal from the 
study, all participants administered the PfSPZ-DVI Challenge are to receive antimalarial therapy as soon 
as possible, and to have all appropriate visits and assessments as required.
The PfSPZ-DVI Challenge agent consists of a strain of P. falciparum NF54 sporozoites used for 
CHMI/VIS studies that is known to be sensitive to the registered antimalarial therapy treatments described 
above.


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
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PROTOCOL SYNOPSIS
22
Intervention Name
PfSPZ-DVI Challenge
artemether-lumefantrine 
(Riamet®)
atovaquone-proguanil 
(Malarone®); only to be 
used if an intolerance or 
contraindication to 
Riamet® develops
Intervention Type
inoculum
drug
Dose Formulation
cryovial
tablet
Unit Dose Strength(s)
15000 or 50000 aseptic, 
cryopreserved 
P. falciparum 
sporozoites
20 mg artemether and 
120 mg lumefantrine
250 mg atovaquone and 
100 mg proguanil 
hydrochloride
Dosage Level
3200 P. falciparum
sporozoites once
6 doses of 4 tablets over 
a period of 3 days at 
approximately 0, 8, 24, 
36, 48 and 60 h
4 tablets as a single 
daily dose for 
3 consecutive days
Route of 
Administration
intravenously by DVI
oral
Meals in Relation to 
Dosing
Not applicable
The first dose of antimalarial drug should be taken 
as soon as possible according to the pre-defined 
cohort-specific PCR parasitaemia/malaria clinical 
score thresholds (i.e., 5000 parasites/mL blood for 
Cohort 1 and 10000 parasites/mL blood for Cohort 
DQGRUDPDODULDFOLQLFDOVFRUHIRU&RKRUWV
and 2) or on reaching Day 24. Antimalarial drug 
administration should be immediately followed by 
a meal or drinks rich in fat (e.g., milk).
Use
challenge agent
antimalarial medication
Study/Treatment Duration:
It is estimated that each participant will be in the study for a maximum of 56 days, including a screening 
period of up to 28 days and a study period of 28 days, including PfSPZ-DVI Challenge on Day 1 and a 
follow-up period of 27 days afterwards.
Assessments:
Pharmacodynamics
Parasitaemia
A blood sample will be collected via direct venepuncture from each participant at the scheduled time points 
where parasitological assessments are scheduled. The assessment of malaria parasitology by qPCR will be 
as follows: varATS multigenic family targeted qPCR assay of parasite load will be performed in accordance 
with the centre of excellence for tropical medicine (ITM) standard operating procedure and the Laboratory 
Manual. Given the high sensitivity of qPCR, this method will be used to confirm parasite clearance after 
definitive antimalarial therapy for all participants. The results of the PCR at the ITM will be available in 
approximately 6 h from arrival of samples at the ITM. A participant will be considered cured following 
completion of the course of antimalarial therapy and after qPCR indicates 0 parasites per mL blood.
Safety
Adverse Events
Adverse events will be monitored continuously from informed consent until the last study-related activity. 
At regular intervals during the study, participants 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.
Close monitoring of expected signs and symptoms associated with malaria infection form part of the safety 
evaluation of the study and will be used as part of the decision criteria to administer registered antimalarial 


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
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PROTOCOL SYNOPSIS
23
therapy. These events will be classified as AEs, and may also be further sub-classified as inoculum-related 
AEs:
An inoculum-related AE is a sign or symptom associated with malaria infection, i.e., confirmed by a 
protocol-GHILQHG3&5SRVLWLYLW\GHILQHGIRUWKHSXUSRVHRIWKLVVWXG\DVDT3&5RXWFRPHSDUDVLWHV
per mL blood) at
-
the onset of the event; or
-
if the event started within 1 day of parasite clearance (defined as a qPCR value of 0 parasites per 
mL blood after initiating antimalarial therapy) or laboratory-defined PCR positivity (a qPCR 
outcome of 50-249 parasites per mL blood).
If the presence of P. falciparum malaria is confirmed (see above), then these AEs will be further 
sub-classified as inoculum-related AEs, following the guidelines on AE reporting, i.e., followed-up until 
resolution with the same causality assessment, and reported as such in the final clinical study report.
If the PCR results for P. falciparum are between 0 and <250 parasites per mL blood at the time of the onset 
of the event and the day before, usual AE/SAE reporting procedures and criteria will apply, but the event 
will not be classified as an inoculum-related AE.
Final classification of signs and symptoms as AE and inoculum-related AE, or as AE only, will occur after 
PCR results are available.
Malaria Clinical Score
The malaria clinical score, which assesses malaria signs and symptoms at the scheduled time points, will be 
part of the close monitoring for known/identified risks related to PfSPZ-DVI Challenge/malaria. The 
malaria clinical score has been widely used in the conduct of induced blood-stage malaria (IBSM)
CHMI/VIS studies in Australia and also implemented in the recently conducted PfSPZ-DVI 
Chemoprotection Challenge study with P218 (MMV_P218_17_01 study [EudraCT number: 
2018-003004-39]) at the SGS Clinical Pharmacology Unit in Antwerp, Belgium. This quantitative tool will
be used as part of the decision criteria to administer registered antimalarial therapy along with the level of 
parasitaemia.
The following 14 signs/symptoms frequently associated with malaria will be graded using a 4-point scale 
(absent: 0; mild: 1; moderate: 2; severe: 3) and summed to generate a total malaria clinical score (maximum 
score possible is 42): headache, 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 and hypotension. To determine severity of the 14 signs/symptoms 
we use the CTCAE grading scale grade 1 - 5. Mild (1) equates to CTCAE grade 1, Moderate (2) equates to 
CTCAE grade 2 and Severe (3) equates to CTCAE grade 3 or above. Individual scores for each symptom 
as well as the total score will be recorded.
For the grading of fever, the vital sign parameter body temperature (sublingual) will be assessed (see below).
Clinical Laboratory Tests
Blood samples will be collected by venepuncture or via indwelling cannula at the scheduled time points. 
Biochemistry and haematology testing will be performed on these samples, as well as viral serology testing 
(hepatitis A IgM antibody, HbsAg, anti-HCV antibody, hepatitis D antibody [only in subjects positive for 
HbsAg], hepatitis E IgM antibody, CMV IgM antibody, EBV IgM antibody and HIV) on the sample from 
VFUHHQLQJ,QDOOIHPDOHSDUWLFLSDQWVDOVRVHUXPȕ-HCG assessments at screening and at the EOS visit and 
DXULQHȕ-HCG assessment on Day-1 will be performed. FSH will be measured at screening in all women.
All blood samples for safety assessments should be taken in a fasted state (after overnight fast for at least 
8 h for unbiased glucose determination), except for the ones taken during antimalarial therapy for troponin T
PHDVXUHPHQWV DQG H[FHSW IRU WKH RQH RQ 'D\ RI ILUVW 3&5  SDUDVLWHVP/ LQ &RKRUW  RU
 parasites/mL in Cohort 2 and prior to initiating antimalarial therapy, where a non-fasted state is 
allowed.
Standard laboratory tests will be performed by ZNA Middelheim.


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
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The following biochemistry and haematology tests will be performed on the safety blood samples: 
-
Liver biochemistry: albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT),
alkaline phosphatase (ALP), gamma glutamylaminotransferase (GGT), total and direct bilirubin 
and total serum proteins;
-
Biochemistry other than liver: sodium, potassium, chloride, bicarbonate, urate, inorganic 
phosphate, creatinine, estimated glomerular filtration rate (eGFR), glucose, lactate 
dehydrogenase (LDH), blood urea nitrogen (BUN) and creatine phosphokinase (CPK); 
-
High sensitive troponin T and;
-
C-reactive protein (CRP);
-
Haematology: haemoglobin, haematocrit, 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) and activated partial thromboplastin time (aPTT) (at 
screening and on Day -1 only), and international normalized ratio (INR).
A midstream urine sample will be collected for urinalysis by dipstick for glucose, protein, nitrite, pH and 
occult blood at the scheduled time points for biochemistry other than liver. 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 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.
Vital Signs
Vital sign parameters will be assessed after at least 10 min in supine position at the scheduled time points. 
The vital sign parameters that will be assessed are supine systolic and diastolic blood pressure (SBP and 
DBP, respectively) and pulse rate. Body temperature (sublingual) will also be assessed, and this whenever 
the malaria clinical score will be evaluated (see above).Orthostatic changes to BP and pulse rate will also 
be assessed at screening: participants will be requested to stand after completion of the supine measurements 
and blood pressure and pulse rate will be recorded after at least 2 min 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.
Electrocardiogram
Twelve-lead ECG recordings will be recorded in triplicate after at least 10 min in supine position at the 
scheduled time points. 
Paper speed will be 25 mm/s, so that the different ECG intervals can be measured manually.
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.
Physical Examination
Physical examination will be performed at the scheduled time points.
Height is to be measured barefoot and at screening only. Body weight is to be measured at the scheduled 
time points. To obtain the actual body weight, participants must be weighed lightly clothed. 
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.
Full physical examination will be conducted at screening, on Day -1, within ±24 h after first PCR 
 parasites/mL blood and at the EOS visit on Day 28. Targeted, symptom-driven physical examination 


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
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25
will be performed in case malaria clinical score >6 on Day 10 (upon confinement to the clinical unit), within 
KDIWHUILUVW3&5&RKRUWRU&RKRUWSDUDVLWHVP/EORRGDQGDWSUH-discharge from 
clinical unit; and will be focused on changes since the previous examination, but will always include at 
least: chest/respiratory, general appearance, heart/cardiovascular, abdomen, neurological and skin/mucous 
membranes examination.
Beck Depression Inventory
The Beck Depression Inventory is performed at screening only.
The questionnaire is scored by the participant. The inventory completed by the participant will be 
reviewed/checked for completeness and the total score calculated by the study personnel.
Parasite Transcriptomics
Different environmental conditions that occur during a human infection (such as the presence of drugs) 
can select for parasites with different expression patterns. We aim to evaluate the effect of in-host factors 
on parasite transcriptional/epigenetic responses during experimental infections. 
To this aim, blood samples will be collected via direct venepuncture at the scheduled time points. Sample 
aliquots will be stored in Trizol for RNA preservation and cryopreserved for parasite culture in case 
higher parasite densities are needed to increase starting material for transcriptomic analysis of parasite 
isolates.
Protocols for transcriptomic analysis of parasite isolates have been validated and are currently in use at the 
Malariology Unit at the ITM.
Statistical Methods:
All statistical analysis will be performed by SGS Life Sciences, under the supervision and responsibility 
of the Sponsor, using SAS® (SAS Institute Inc., Cary, NC, USA; version 9.4 or higher) software for 
statistical computations. 
All statistical methods shall be detailed in a Statistical Analysis Plan (SAP) that will be finalised before 
database lock.
The final analysis will be performed once all participants have completed the follow-up visit or have 
discontinued earlier. 
Data from all participants enrolled and inoculated with PfSPZ-DVI Challenge will be included in the data 
analysis. The following analysis populations will be defined:
-
Inoculation Set: all participants who were inoculated with PfSPZ-DVI Challenge;
-
Pharmacodynamic (PD) Analysis Set: all inoculated participants with at least one available PD 
data who received all Riamet® doses and who experienced no protocol deviations with relevant 
impact on PD data;
-
Safety Analysis Set: all inoculated participants who received any treatment.
Unless specified otherwise, the Inoculation Set will be used for analysis of demographics, the PD analysis 
set will be used for pharmacodynamic statistical analysis and the Safety Analysis Set will be used for 
safety/tolerability analysis.
Sample Size
Up to 16 participants will be enrolled in 2 cohorts of 8 participants per cohort. In agreement with the 
Sponsor, additional participants may be recruited in each cohort, to replace discontinuations for non-safety 
reasons and achieve the required cohort size.
This is an exploratory study focusing on the methodology of malaria inoculation in healthy participants, 
thus no formal sample size calculation is performed.
Initial Characteristics Data of the Participant Sample
For all participants who receive PfSPZ-DVI Challenge, descriptive statistics will be provided for 
demographic (e.g., age, height, weight, BMI, race, gender) and other initial participant characteristics 
(alcohol and drug screening tests, pregnancy test, orthostatic changes to blood pressure and pulse rate, 
serology, medical and social history, concomitant diseases, Beck Depression Inventory). Standard 
descriptive statistics for continuous variables are the number of participants (N), mean, standard deviation 
(SD), median, minimum and maximum values. The standard descriptive statistics for categorical variables 
are the number of participants in the category and the proportion expressed as a percentage.
Prior and concomitant medications will be coded using the WHO_DRUG Dictionary.


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
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26
Pharmacodynamic Data
Parasitaemia
Primary endpoints:
To characterise key stages in the parasite growth:
-
first PCR positivity;
-
threshold of 5000 parasites/mL for Cohort 1 and threshold of 10000 parasites/mL for Cohort 2;
and
-
parasitaemia levels at drug administration.
This will be done by calculating:
-
Descriptive statistics (geometric mean, SD, 95% CI, range) of time to first PCR positivity. In the 
absence of positive PCR, the duration will be set to a maximum of 28 days;
-
Descriptive statistics (N, geometric mean, SD, 95% CI, range) of parasitaemia at first PCR 
positivity;
-
Descriptive statistics (geometric mean, SD, 95% CI, range) of time to parasitaemia of 
 parasites per mL blood (Cohorts 1 and 2);
-
Descriptive statistics (geometric mean, SD, 95% CI, range) of parasitaemia at the time 
SDUDVLWDHPLDSDUDVLWHVSHUP/EORRG&RKRUWVDQG
-
Descriptive statistics (geometric mean, SD, 95% CI, range) of time to parasitaemia of 
 parasites per mL blood (Cohort 2); 
-
Descriptive statistics (geometric mean, SD, 95% CI, range) of parasitaemia at the time 
SDUDVLWDHPLDSDUDVLWHVSHUP/EORRG&RKRUW
-
Descriptive statistics per cohort (geometric mean, SD, 95% CI, range) of time to first dose of 
treatment with Riamet® (Cohorts 1 and 2); and
-
Descriptive statistics per cohort (geometric mean, SD, 95% CI, range) of parasitaemia at first 
dose of treatment with Riamet® (Cohorts 1 and 2).
7KHQXPEHUDQGSURSRUWLRQRISDUWLFLSDQWVZLWKSUHVHQFHRISRVLWLYH3&5DQGSDUDVLWDHPLDRI or 
SDUDVLWHVSHUP/EORRGEHWZHHQLQRFXODWLRQZLWKPfSPZ-DVI Challenge and Day 28 will be 
summarised per cohort. Corresponding two-sided 90% Exact Clopper-Pearson confidence limits will be 
presented as well.
Secondary endpoints:
To characterise the blood-stage parasite profile, a model will be fitted to the measured parasitaemia data 
prior to Riamet® administration to be able to predict the growth of parasites as a function of time. This 
model may be a log-linear model or, if the parasitaemia profile shows a cyclic behaviour due to 
synchronicity of the parasites and their sequestration during the late stages of their lifecycle, it may 
include a sinus function. The latter will allow the estimation of the period of the observed waves in
addition to the parasite growth. The following parameters will be calculated from the individual fits of the 
data:
-
Descriptive statistics per cohort and overall (geometric mean, SD, 95% CI, range) of parasite 
growth rate expressed as the PMR48;
-
If cycles are observed and if their estimated period is not 48 h, descriptive statistics per cohort 
and overall (geometric mean, SD, 95% CI, range) of parasite growth rate expressed as the 
PMRLC; and
-
Descriptive statistics (geometric mean, SD, 95% CI, range) of predicted time to reach 
SDUDVLWDHPLDWKUHVKROGRIILUVWSRVLWLYH3&5SDUDVLWHVSHUP/EORRGSDUDVLWHVSHU
mL blood for Cohorts 1 and 2.
To characterise the blood-stage parasite clearance profile of Riamet® in malaria infection in naïve healthy 
participants after PfSPZ-DVI Challenge; by calculating:
-
Descriptive statistics per cohort and overall (geometric mean, SD, 95% CI, range) of time to 
parasite clearance, i.e., time between drug administration and first PCR below the limit of 
quantification;
-
Descriptive statistics per cohort and overall (geometric mean, SD, 95% CI, range) of log10PRR48;
-
Descriptive statistics per cohort and overall (geometric mean, SD, 95% CI, range) of 
log10PRR48,max; and
-
Descriptive statistics per cohort and overall (geometric mean, SD, 95% CI range) of PC½.


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
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PROTOCOL SYNOPSIS
27
The parasite reduction ratios (PRRs) and the clearance half-life will be estimated from a log-linear model 
that will be fitted to the parasitaemia data observed from the administration of the treatment onwards. The 
PRR48, PRR48,max and PC½ will be calculated from the individual parameters and summarised by cohort.
Exploratory endpoints:
To characterise the individual variability of blood-stage parasite profile: 
-
Obtain the inter-individual variability of the parasite growth rate; and
-
5th, 50th and 95th percentiles of predicted time to reach parasitaemia threshold of first positive 
3&5SDUDVLWHVSHUP/EORRGSDUDVLWHVSHUP/EORRGLQFOXGLQJWKHLU&,
Both these estimates will be based on the mixed model on parasite growth data described above.
Safety
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. All AEs with 
onset after PfSPZ-DVI Challenge will be summarised by cohort. Summaries will be made per MedDRA 
primary system organ class, MedDRA preferred term, severity, with the number and percentage of 
participants and the number of events. Similar summaries will be prepared for AEs considered to be 
related to Riamet® and AEs considered to be related to the PfSPZ-DVI Challenge, for serious AEs and 
AEs of special interest.
Special attention will be paid to those participants who died, discontinued the investigational products due 
to an AE or experienced a severe or serious AE. Summaries, listings and narratives may be provided, as 
appropriate.
Malaria Clinical Score 
For the malaria clinical score that will be administered by the PI or his/her trained delegate, actual values 
and changes from baseline will be evaluated by means of descriptive statistics. Additionally, expected 
signs and symptoms will be summarised by score.
Clinical Laboratory Tests
Each continuous biochemistry and haematology laboratory test will be evaluated by means of descriptive 
statistics on the actual values, at each assessment time point and by cohort. Changes from baseline will 
also be summarised using descriptive statistics by assessment time point and by cohort.
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 participants with clinical laboratory test abnormalities will be summarised by cohort.
The number and percentage of participants with liver enzyme elevations after inoculation with the 
PfSPZ-DVI Challenge as defined below will be summarised:
-
ALT or AST >3 x 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).


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
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28
A listing of participants with any clinical laboratory test result outside the reference ranges will be 
provided.
Vital Signs
Vital signs parameters will be assessed after at least 10 min in supine position at the scheduled time 
points. Pulse rate, SBP and DBP will be evaluated by means of descriptive statistics (actual values and 
changes from baseline). 
The percentage of participants with vital signs abnormalities will be summarised by cohort in a 
cross-tabulation of post-baseline versus baseline abnormalities to the normal ranges.
Electrocardiogram
Twelve-lead ECG recordings will be performed in triplicate after participants remained in a supine 
position for at least 10 min. 
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 cohort. 
The percentage of participants with ECG abnormalities will be summarised by cohort 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.


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01
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TIME AND EVENTS SCHEDULE
Cohort 1
Assessments
Screening Visit
Day -28 to Day -2
Challenge, treatment and follow-up
EOS Visit
Day 28v
Study Day/Event
Day -1a
Day 1
Day 2-6
Day 7-9
Day 10: Start 
of 
Confinement 
in Clinical 
Unit
Day of First PCR 
 Parasites/mL Until 
Day of First PCR 
 Parasites/mL
Day of First PCR 
 Parasites/mL Until 
 h After Initiating 
Antimalarial Therapy
Day of Discharge From 
Confinement: Day of 
Parasite Clearance 
(0 Parasites/mL) AND 
K$IWHU,QLWLDWLQJ
Antimalarial Therapy
Time point (h) in 
relation to 
PfSPZ-DVI 
Challenge
0b
2
Estimated On or Before 
Day 19
Ambulatory visit
X
X
X
Ambulatory visit 
(SARS-CoV-2 test)
X
X
Confinement in 
clinical unitc
X
X
X
X
X
(X)
Discharge from 
clinical unit
X
X
(X)
Telephonic 
Monitoring for AEs
X
Eligibility criteria
X
X
Informed consentd
X
Demographics
X
Medical and social 
history
X
Beck Depression 
Inventory
X
Alcohol & drug 
screene
X
X
Height & weightf
X
X
X
Physical 
examinationg
X
X
X
X
X
X
X
Vital signsh
X
X
X
X
X
X
X
X
X
12-lead ECGi
X
X
Viral serologyj
X
Pregnancy testk
X
X
X


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01
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30
Assessments
Screening Visit
Day -28 to Day -2
Challenge, treatment and follow-up
EOS Visit
Day 28v
Study Day/Event
Day -1a
Day 1
Day 2-6
Day 7-9
Day 10: Start 
of 
Confinement 
in Clinical 
Unit
Day of First PCR 
 Parasites/mL Until 
Day of First PCR 
 Parasites/mL
Day of First PCR 
 Parasites/mL Until 
 h After Initiating 
Antimalarial Therapy
Day of Discharge From 
Confinement: Day of 
Parasite Clearance 
(0 Parasites/mL) AND 
K$IWHU,QLWLDWLQJ
Antimalarial Therapy
Time point (h) in 
relation to 
PfSPZ-DVI 
Challenge
0b
2
Estimated On or Before 
Day 19
DVI of PfSPZ 
Challenge
X
Riamet®l
Xl
Malaria Clinical 
Scorem
X
X
X
X
X
X
X
Haematology &
liver biochemistryn
X
X
X
X
X
X
X
X
Biochemistry other 
than livero
X
X
X
X
X
CRP analysisp
X
X
X
X
X
X
X
Coagulation 
parametersq
X
X
X
X
X
X
X
X
rRT-PCR for 
SARS-CoV-2
Xr
Xs
qPCR for parasitest
X
X
X
X
X
X
X
Parasite 
Transcriptomicsu
X
X
X
X
X
X
Previous 
medications
X
Concomitant 
medications
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X
AEs
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X
SAE reporting
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X
ȕ-HCG: ȕ-human chorionic gonadotropin, AE: adverse event, aPTT: activated partial thromboplastin time, CMV: cytomegalovirus, CRP: C-reactive protein, DVI: direct venous 
inoculation, EBV: Epstein Barr Virus, ECG: electrocardiogram, EOS: end of study, FSH: follicle stimulating hormone, HbsAg: hepatitis B surface antigen , HCV: hepatitis C virus,
HIV: human immunodeficiency virus, IgM: immunoglobulin M, INR: international normalized ratio, PfSPZ: Plasmodium falciparum sporozoites, PT: prothrombin time,
qPCR: quantitative polymerase chain reaction, rRT-PCR: real-time reverse transcription polymerase chain reaction, SAE: serious adverse event, SARS-CoV-2: severe acute respiratory 
syndrome coronavirus 2


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01
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a. Assessments begin as of participant confinement in the clinical unit and must be completed and safety assessment outcomes must be available before PfSPZ-DVI Challenge on 
Day 1.
b. On Day 1, assessments begin as of 3 h before challenge (except for urinalysis assessments, morning void allowed). The assessments indicated must be completed and safety 
assessment outcomes must be available before PfSPZ-DVI Challenge inoculation.
c. Confinement to the clinical unit will occur as follows:
x
Participants will be admitted to the clinical unit in the morning of Day -1 and discharged from confinement 2 h post PfSPZ-DVI Challenge on Day 1.
x
Participants will be admitted to the clinical unit in the morning of Day 10 and discharged on Day of discharge from confinement (Day of parasite clearance $1'KDIWHU
initiating antimalarial therapy), estimated to occur on or before Day 19. Of note, participants who commence antimalarial therapy on Day 24 (see l) will only be discharged from 
confinement at the end of the EOS visit on Day 28.
d. No study-related procedure is to be performed before voluntarily signing of the informed consent form.
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, at admission on Day -1 and at the EOS visit.
g. Physical examination will be conducted:
x
once at screening and once on Day -1;
x
once on Day 10 (upon admission to clinical unit for confinement); 
x
once within 24 h after ILUVW3&5SDUDVLWHVP/
x
once within 24 h after first 3&5SDUDVLWHVP/
x
once at pre-discharge from clinical unit on Day of discharge from confinement (Day of parasite FOHDUDQFH$1'KDIWHULQLWLDWLQJDQWLPDODULDOWKHUDS\); and
x
once at the EOS.
Full physical examination will be conducted at screening, on Day -1, within ±24 h after ILUVW3&5SDUDVLWHVP/ and at the EOS visit on Day 28. Targeted (symptom-driven) 
physical examination will be performed on the other time points in case malaria clinical score >6.
h. Vital signs (blood pressure and pulse) will be measured after remaining in a supine position for at least 10 min. All measurements will be performed as follows:
x
once at screening and once on Day -1;
x
on Day 1 (pre and post PfSPZ-DVI Challenge);
x
twice daily from Day 10 (admission to clinical unit for confinement) onwards until Day of discharge from confinement (Day of SDUDVLWHFOHDUDQFH$1' h after initiating 
antimalarial therapy); and
x
once at the EOS.
Body temperature (sublingual) will also be assessed, and this whenever the malaria clinical score will be evaluated (see m).
At screening, orthostatic changes to blood pressure and pulse rate will also be assessed: participants will be requested to stand after completion of the supine measurements and 
blood pressure and pulse rate will be recorded after at least 2 min in the standing position.
i. 12-lead ECGs recordings will be performed in triplicate after participants have remained in a supine position for at least 10 min. All recordings will be performed as follows:
x
once at screening; and
x
once on Days 2 and 3 of antimalarial therapy.
j. Serological testing for HIV, hepatitis A IgM antibody, HbsAg, anti-HCV antibody, hepatitis D antibody (only in subjects positive for HbsAg), hepatitis E IgM antibody, CMV IgM 
antibody and EBV IgM antibody, to determine eligibility for the study.
k. 3UHJQDQF\WHVWLQJFRQVLVWVRIVHUXPȕ-HCG assessments at screening and at the EOS visit and a XULQHȕ-HCG assessment on Day-1.
l. Every participant will be prescribed a 3-day oral course of Riamet® (20 mg artemether and 120 mg lumefantrine tablets) (see Section 5.1). The first dose should be taken as soon as 
possible when a PCR threshold of 5000 parasites/mL is achieved or earlier if a participant has a malaria clinical score >6 or at Investigator’s discretion. Of note, all participants 
inoculated with PfSPZ-DVI Challenge will commence antimalarial therapy no later than Day 24, regardless if they reach the pre-defined cohort-specific PCR parasitaemia/malaria 
clinical score thresholds (i.e., 5000 parasites/mL blood and/or DPDODULDFOLQLFDOVFRUH (see Section 4.3).
If an intolerance or contraindication to Riamet® develops since inclusion, Malarone® will be administered (see Section 5.1).


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01
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m.Malaria clinical score for malaria signs and symptoms and the vital sign parameter body temperature (sublingual) (see h) are assessed:
x
on Day 1 (pre-PfSPZ-DVI Challenge);
x
once daily during ambulatory visits on Day 7, 8 and 9;
x
twice daily from Day 10 (admission to clinical unit for confinement) onwards until Day of discharge from confinement (Day of parasite clearance AND KDIWHULQLWLDWLQJ
antimalarial therapy); and
x
once at the EOS.
n. Haematology and liver biochemistry laboratory tests will be performed after overnight fast for at least 8 h (see Section 4.3):
x
once at screening and once on Day -1;
x
once during ambulatory visit on Day 7;
x
once on Day 10 (upon admission to clinical unit for confinement);
x
once within 24 h after ILUVW3&5SDUDVLWHVP/;
x
once on Day of first 3&5SDUDVLWHVP/$1'SULRUWRLQLWLDWLQJDQWLPDODULDOWKHUDS\ (non-fasted state allowed);
x
once at pre-discharge from clinical unit on Day of discharge from confinement (Day of parasite clearance $1'KDIWHULQLWLDWLQJDQWLPDODULDOWKHUDS\); and
x
once at the EOS.
Troponin T will be measured at screening (fasted state), at baseline prior to inoculation on Day -1 (fasted state), and on Days 1, 2 and 3 of antimalarial therapy (non-fasted state).
FSH will be measured at screening in all women.
o. Biochemistry laboratory tests other than liver (including urinalysis; morning void allowed) will be performed after overnight fast for at least 8 h (see Section 4.3):
x
once at screening and once on Day -1;
x
once on Day 10 (upon admission to clinical unit for confinement);
x
RQFHRQ'D\RIILUVW3&5SDUDVLWHVP/$1'SULRUWRLQLWLDWLQJDQWLPDODULDOWKHUDS\QRQ-fasted state allowed); and
x
once at the EOS.
p. CRP laboratory tests will be performed at the following time points:
x
on Day -1;
x
once during ambulatory visit on Day 7; 
x
once on Day 10 (upon admission to clinical unit for confinement);
x
RQFHZLWKLQKDIWHUILUVW3&5SDUDVLWHVP/
x
RQFHRQ'D\RIILUVW3&5SDUDVLWHVP/$1'SULRUWRLQLWLDWLQJDQWLPDODULDOWKHUDS\
x
on Days 2 and 3 of antimalarial therapy;
x
once at pre-GLVFKDUJHIURPFOLQLFDOXQLWRQ'D\RIGLVFKDUJHIURPFRQILQHPHQW'D\RISDUDVLWHFOHDUDQFH$1'KDIWHULQLWLDWLQJDQWLPalarial therapy); and
x
once at the EOS.
q. INR, PT and aPTT laboratory tests will be performed once at screening and once on Day -1. On the other time points thereafter, only the INR test will be performed.
r. A nasopharyngeal swab will be taken at an ambulatory visit during screening up to Day -2 (preferably as close as possible to the day of admission, based on test capacity and 
according to national laws) from participants who are still eligible to be enrolled in the study after completing all other screening tests. An rRT-PCR test will be performed on these 
swabs to screen for infection with SARS-CoV-2.
s. A nasopharyngeal swab will be taken prior to confinement to the study site on Day 10, based on test capacity and according to national laws.
t. Blood samples for the assessment of parasitaemia by qPCR will be drawn at the following time points:
x
on Day 1 (pre-PfSPZ-DVI Challenge);
x
once daily during ambulatory visits on Day 7, 8 and 9;
x
twice daily from Day 10 (admission to clinical unit for confinement) onwards until Day of ILUVW3&5SDUDVLWHVP/$1'SULRUWR initiating antimalarial therapy;
x
at multiple time points (2, 6, 8, 12, 16, 24, 36, 48 and 72 h) following initiation of Riamet®;
x
RQFHRQ'D\RIGLVFKDUJHIURPFRQILQHPHQW'D\RISDUDVLWHFOHDUDQFH$1'KDIWHULQLWLDWLQJDQWLPDODULDOWKHUDS\; and
x
once at the EOS.


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01
24-Jun-2020 (Final 3.0)
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33
All qPCR blood samples will be drawn for immediate analysis, except for the ones drawn at the multiple time points during Riamet® therapy.
u. Blood samples for parasite transcriptomics will be drawn at the following time points:
x
once daily during ambulatory visits on Day 7, 8 and 9;
x
once daily from Day 10 (admission to clinical unit for confinement) onwards until Day of discharge from confinement (Day of pDUDVLWHFOHDUDQFH$1'KDIWHULQLWLDWLQJ
antimalarial therapy); and
x
once at the EOS.
v. All participants will be asked non-leading questions to determine the occurrence of any AEs at the EOS visit.
Of note, for participants who commence antimalarial therapy on Day 24 (l), the Day of discharge from confinement will coincide with the EOS. In this case, applicable assessments will 
not be performed in duplicate.


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01
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Cohort 2
Assessments
Screening Visit
Day -28 to Day -2
Challenge, treatment and follow-up
EOS Visit
Day 28v
Study Day/Event
Day -1a
Day 1
Day 2-6
Day 7-9
Day 10: Start 
of 
Confinement 
in Clinical 
Unit
Day of First PCR 
 Parasites/mL Until 
Day of First PCR 
 Parasites/mL
Day of First PCR 
 Parasites/mL Until 
 h After Initiating 
Antimalarial Therapy
Day of Discharge From 
Confinement: Day of 
Parasite Clearance 
(0 Parasites/mL) AND 
K$IWHU,QLWLDWLQJ
Antimalarial Therapy
Time point (h) in 
relation to 
PfSPZ-DVI 
Challenge
0b
2
Estimated On or Before 
Day 22
Ambulatory visit
X
X
X
Ambulatory visit 
(SARS-CoV-2 test)
X
X
Confinement in 
clinical unitc
X
X
X
X
X
(X)
Discharge from 
clinical unit
X
X
(X)
Telephonic 
Monitoring for AEs
X
Eligibility criteria
X
X
Informed consentd
X
Demographics
X
Medical and social 
history
X
Beck Depression 
Inventory
X
Alcohol & drug 
screene
X
X
Height & weightf
X
X
X
Physical 
examinationg
X
X
X
X
X
X
X
Vital signsh
X
X
X
X
X
X
X
X
X
12-lead ECGi
X
X
Viral serologyj
X
Pregnancy testk
X
X
X
DVI of PfSPZ 
Challenge
X
Riamet®l
Xl


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01
24-Jun-2020 (Final 3.0)
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35
Assessments
Screening Visit
Day -28 to Day -2
Challenge, treatment and follow-up
EOS Visit
Day 28v
Study Day/Event
Day -1a
Day 1
Day 2-6
Day 7-9
Day 10: Start 
of 
Confinement 
in Clinical 
Unit
Day of First PCR 
 Parasites/mL Until 
Day of First PCR 
 Parasites/mL
Day of First PCR 
 Parasites/mL Until 
 h After Initiating 
Antimalarial Therapy
Day of Discharge From 
Confinement: Day of 
Parasite Clearance 
(0 Parasites/mL) AND 
K$IWHU,QLWLDWLQJ
Antimalarial Therapy
Time point (h) in 
relation to 
PfSPZ-DVI 
Challenge
0b
2
Estimated On or Before 
Day 22
Malaria Clinical 
Scorem
X
X
X
X
X
X
X
Haematology &
liver biochemistryn
X
X
X
X
X
X
X
X
Biochemistry other 
than livero
X
X
X
X
X
CRP analysisp
X
X
X
X
X
X
X
Coagulation 
parametersq
X
X
X
X
X
X
X
X
rRT-PCR for 
SARS-CoV-2
Xr
Xs
qPCR for parasitest
X
X
X
X
X
X
X
Parasite 
Transcriptomicsu
X
X
X
X
X
X
Previous 
medications
X
Concomitant 
medications
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X
AEs
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X
SAE reporting
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X
ȕ-+&*ȕ-human chorionic gonadotropin, AE: adverse event, aPTT: activated partial thromboplastin time, CMV: cytomegalovirus, CRP: C-reactive protein, DVI: direct venous 
inoculation, EBV: Epstein Barr Virus, ECG: electrocardiogram, EOS: end of study, FSH: follicle stimulating hormone, HbsAg: hepatitis B surface antigen , HCV: hepatitis C virus, 
HIV: human immunodeficiency virus, IgM: immunoglobulin M, INR: international normalized ratio, PfSPZ: Plasmodium falciparum sporozoites, PT: prothrombin time, 
qPCR: quantitative polymerase chain reaction, rRT-PCR: real-time reverse transcription polymerase chain reaction,  SAE: serious adverse event, SARS-CoV-2: severe acute respiratory 
syndrome coronavirus 2
a. Assessments begin as of participant confinement in the clinical unit and must be completed and safety assessment outcomes must be available before PfSPZ-DVI Challenge on
Day 1.
b. On Day 1, assessments begin as of 3 h before challenge (except for urinalysis assessments, morning void allowed). The assessments indicated must be completed and safety 
assessment outcomes must be available before PfSPZ-DVI Challenge inoculation.


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01
24-Jun-2020 (Final 3.0)
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36
c. Confinement to the clinical unit will occur as follows:
x
Participants will be admitted to the clinical unit in the morning of Day -1 and discharged from confinement 2 h post PfSPZ-DVI Challenge on Day 1.
x
Participants will be admitted to the clinical unit in the morning of Day 10 and discharged on Day of discharge from FRQILQHPHQW'D\RISDUDVLWHFOHDUDQFH$1'KDIWHU
initiating antimalarial therapy), estimated to occur on or before Day 22. Of note, participants who commence antimalarial therapy on Day 24 (see l) will only be discharged from 
confinement at the end of the EOS visit on Day 28.
d. No study-related procedure is to be performed before voluntarily signing of the informed consent form.
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, at admission on Day -1 and at the EOS visit.
g. Physical examination will be conducted:
x
once at screening and once on Day -1;
x
once on Day 10 (upon admission to clinical unit for confinement); 
x
RQFHZLWKLQKDIWHUILUVW3&5SDUDVLWHVP/
x
once ZLWKLQKDIWHUILUVW3&5SDUDVLWHVP/
x
once at pre-discharge from clinical unit on Day of discharge from confinement (Day of parasite clearance $1'KDIWHULQLWLDWLQJDQWLPDODULDOWKHUDS\); and
x
once at the EOS. 
Full physical examination will be conducted at screening, on Day -ZLWKLQKDIWHUILUVW3&5SDUDVLWHVP/DQGDWWKH(26YLVLWRQ'D\7DUJHWHGV\PSWRP-driven) 
physical examination will be performed on the other time points in case malaria clinical score >6.
h. Vital signs (blood pressure and pulse) will be measured after remaining in a supine position for at least 10 min. All measurements will be performed as follows:
x
once at screening and once on Day -1;
x
on Day 1 (pre and post PfSPZ-DVI Challenge);
x
twice daily from Day 10 (DGPLVVLRQWRFOLQLFDOXQLWIRUFRQILQHPHQWRQZDUGVXQWLO'D\RIGLVFKDUJHIURPFRQILQHPHQW'D\RISDUDVLWHFOHDUDQFH$1'2 h after initiating 
antimalarial therapy); and
x
once at the EOS.
Body temperature (sublingual) will also be assessed, and this whenever the malaria clinical score will be evaluated (see m).
At screening, orthostatic changes to blood pressure and pulse rate will also be assessed: participants will be requested to stand after completion of the supine measurements and 
blood pressure and pulse rate will be recorded after at least 2 min in the standing position.
i. 12-lead ECGs recordings will be performed in triplicate after participants have remained in a supine position for at least 10 min. All recordings will be performed as follows:
x
once at screening; and
x
once on Days 2 and 3 of antimalarial therapy.
j. Serological testing for HIV, hepatitis A IgM antibody, HbsAg, anti-HCV antibody, hepatitis D antibody (only in subjects positive for HbsAg), hepatitis E IgM antibody, CMV IgM 
antibody and EBV IgM antibody, to determine eligibility for the study.
k. 3UHJQDQF\WHVWLQJFRQVLVWVRIVHUXPȕ-HCG assessments at screening and at the EOS visit and a XULQHȕ-HCG assessment on Day-1.
l. Every participant will be prescribed a 3-day oral course of Riamet® (20 mg artemether and 120 mg lumefantrine tablets) (see Section 5.1). The first dose should be taken as soon as 
possible when a PCR threshold of 10000 parasites/mL is achieved or earlier if a participant has a malaria clinical score >6 or at Investigator’s discretion. Of note, all participants 
inoculated with PfSPZ-DVI Challenge will commence antimalarial therapy no later than Day 24, regardless if they reach the pre-defined cohort-specific PCR parasitaemia/malaria 
FOLQLFDOVFRUHWKUHVKROGVLHSDUDVLWHVP/EORRGDQGRUDPDODULDFOLQLFDOVFRUHVHH6HFWLRQ 4.3).
If an intolerance or contraindication to Riamet® develops since inclusion, Malarone® will be administered (see Section 5.1).
m.Malaria clinical score for malaria signs and symptoms and the vital sign parameter body temperature (sublingual) (see h) are assessed:
x
on Day 1 (pre-PfSPZ-DVI Challenge); 
x
once daily during ambulatory visits on Day 7, 8 and 9;
x
twice daily from Day 10 (admission to clinical unit for confinement) onwards until Day of discharge from confinement (Day of parasiWHFOHDUDQFH$1'2 h after initiating 
antimalarial therapy); and
x
once at the EOS.


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01
24-Jun-2020 (Final 3.0)
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37
n. Haematology and liver biochemistry laboratory tests will be performed after overnight fast for at least 8 h (see Section 4.3):
x
once at screening and once on Day -1;
x
once during ambulatory visit on Day 7; 
x
once on Day 10 (upon admission to clinical unit for confinement);
x
RQFHZLWKLQKDIWHUILUVW3&5SDUDVLWHVP/
x
once on Day of first 3&510000 parasites/mL AND prior to initiating antimalarial therapy (non-fasted state allowed);
x
once at pre-discharge from clinical unit RQ'D\RIGLVFKDUJHIURPFRQILQHPHQW'D\RISDUDVLWHFOHDUDQFH$1'KDIWHULQLWLDWLQJDQWLPDODULDOtherapy); and
x
once at the EOS.
Troponin T will be measured at screening (fasted state), at baseline prior to inoculation on Day -1 (fasted state), and on Days 1, 2 and 3 of antimalarial therapy (non-fasted state).
FSH will be measured at screening in all women.
o. Biochemistry laboratory tests other than liver (including urinalysis; morning void allowed) will be performed after overnight fast for at least 8 h (see Section 4.3):
x
once at screening and once on Day -1;
x
once on Day 10 (upon admission to clinical unit for confinement);
x
RQFHRQ'D\RIILUVW3&5SDUDVLWHVP/$1'SULRUWRLQLWLDWLQJDQWLPDODULDOWKHUDS\QRQ-fasted state allowed); and
x
once at the EOS.
p. CRP laboratory tests will be performed at the following time points:
x
on Day -1;
x
once during ambulatory visit on Day 7; 
x
once on Day 10 (upon admission to clinical unit for confinement);
x
RQFHZLWKLQKDIWHUILUVW3&5SDUDVLWHVP/
x
oncHRQ'D\RIILUVW3&5SDUDVLWHVP/$1'SULRUWRLQLWLDWLQJDQWLPDODULDOWKHUDS\
x
on Days 2 and 3 of antimalarial therapy;
x
once at pre-GLVFKDUJHIURPFOLQLFDOXQLWRQ'D\RIGLVFKDUJHIURPFRQILQHPHQW'D\RISDUDVLWHFOHDUDQFH$1'KDIWHULQLWLDting antimalarial therapy); and
x
once at the EOS.
q. INR, PT and aPTT laboratory tests will be performed once at screening and once on Day -1. On the other time points thereafter, only the INR test will be performed.
r. A nasopharyngeal swab will be taken at an ambulatory visit during screening up to Day -2 (preferably as close as possible to the day of admission, based on test capacity and 
according to national laws) from participants who are still eligible to be enrolled in the study after completing all other screening tests. An rRT-PCR test will be performed on these 
swabs to screen for infection with SARS-CoV-2.
s. A nasopharyngeal swab will be taken prior to confinement to the study site on Day 10, based on test capacity and according to national laws.
t. Blood samples for the assessment of parasitaemia by qPCR will be drawn at the following time points:
x
on Day 1 (pre-PfSPZ-DVI Challenge);
x
once daily during ambulatory visits on Day 7, 8 and 9;
x
twice daily from Day 10 (admission to clinical unit for confinement) onwards XQWLO'D\RIILUVW3&5SDUDVLWHVP/$1'SULRUWRLQLWLDWLQJDQWLPDODULDOWKHUDS\
x
at multiple time points (2, 6, 8, 12, 16, 24, 36, 48 and 72 h) following initiation of Riamet®;
x
RQFHRQ'D\RIGLVFKDUJHIURPFRQILQHPHQW'D\RISDUDVLWHFOHDUDQFH$1'KDIWHULQLWLDWLQJDQWLPDODULDOWKHUDS\DQG
x
once at the EOS.
All qPCR blood samples will be drawn for immediate analysis, except for the ones drawn at the multiple time points during Riamet® therapy.
u. Blood samples for parasite transcriptomics will be drawn at the following time points:
x
once daily during ambulatory visits on Day 7, 8 and 9;
x
once daily from Day 10 (adPLVVLRQWRFOLQLFDOXQLWIRUFRQILQHPHQWRQZDUGVXQWLO'D\RIGLVFKDUJHIURPFRQILQHPHQW'D\RISDUDVLWHFOHDUDQFH$1'h after initiating 
antimalarial therapy); and
x
once at the EOS.


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01
24-Jun-2020 (Final 3.0)
CONFIDENTIAL
38
v. All participants will be asked non-leading questions to determine the occurrence of any AEs at the EOS visit.
Of note, for participants who commence antimalarial therapy on Day 24 (l), the Day of discharge from confinement will coincide with the EOS. In this case, applicable assessments will 
not be performed in duplicate.


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
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39
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
List of Abbreviations
ABV
Alcohol by volume
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
ȕ-HCG
ȕ-human chorionic gonadotropin
BMI
Body mass index
BSC
Biosafety cabinet
CHMI
Controlled Human Malaria Infection
CI
Confidence interval
CMV
Cytomegalovirus
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
DBP
Diastolic blood pressure
DVI
Direct venous inoculation
EBV
Epstein Barr Virus
ECG
Electrocardiogram
EOS
End of study
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HSA
Human serum albumin
IBSM
Induced blood-stage malaria
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements 
for Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgM
Immunoglobulin M
IMP
Investigational medicinal product
INR
International normalized ratio
IRB
Institutional Review Board
ITM
Centre of excellence for tropical medicine
Log10PRR48
Log10 parasite reduction ratio per 48 h 
Log10PRR48,max
Maximum log10 parasite reduction ratio per 48 h
LPLV
Last Patient Last Visit
MedDRA
Medical Dictionary for Regulatory Activities
NCE
New chemical entities
NSAID
Non-steroidal anti-inflammatory drug
PBS
Phosphate buffered saline


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
CONFIDENTIAL
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PC½
Parasite clearance half-life
PCR
Polymerase chain reaction
PD
Pharmacodynamics
Pf
P. falciparum 
P. falciparum
Plasmodium falciparum
PfSPZ
P. falciparum sporozoites
PfSPZ-DVI
Challenge
Inoculation of P. falciparum sporozoites through direct venous 
inoculation
PI
Principal Investigator
PMR
Parasite multiplication rate
PMR48
Parasite multiplication rate standardised to 48 h
PMRLC
Parasite multiplication rate per life cycle (if not 48 h)
PRR
Parasite reduction ratio
PT
Prothrombin time
qPCR
Quantitative polymerase chain reaction
QTc
Corrected QT interval 
QTcB
QT interval corrected according to Bazett’s formula
QTcF
QT interval corrected according to Fridericia’s formula
RBC
Red blood cell
rRT-PCR
Real-time reverse transcription polymerase chain reaction
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SBP
Systolic blood pressure
SD
Standard deviation
SmPC
Summary of Product Characteristics
SPZ
Sporozoites
SRT
Safety Review Team
TBS
Thick Blood Smear
ULN
Upper Limit of Normal
varATS
The acidic terminal segment in Plasmodium falciparum var genes
VIS
Volunteer Infection Study
WBC
White blood cell
WHO
World Health Organization


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
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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
Laboratory-defined 
PCR positivity
qPCR outcome 50-249 parasites per mL blood
Protocol-defined PCR 
positivity
qPCR outcome 250 parasites per mL blood
PCR negative
Applies to all qPCR assessments undertaken prior to initiating 
antimalarial therapy, with a value of 1-49 parasites per mL 
blood
Parasite clearance
Defined as a qPCR value of 0 parasites per mL blood after 
initiating antimalarial therapy
Time to first PCR
positivity
Time elapsed between PfSPZ-DVI Challenge and first qPCR 
outcome equal to or greater than 250 parasites per mL blood, 
with a maximum of 28 days in the absence of parasitaemia
Time to parasitaemia 
of 5000 parasites per 
mL blood
Time elapsed between PfSPZ-DVI Challenge and first qPCR 
equal to or greater than 5000 parasites per mL blood, with a 
maximum of 28 days in the absence of parasitaemia
Time to parasitaemia 
of 10000 parasites 
per mL blood
Time elapsed between PfSPZ-DVI Challenge and first qPCR 
equal to or greater than 10000 parasites per mL blood, with a 
maximum of 28 days in the absence of parasitaemia
Parasite growth rate
Expressed as the PMR48 or as the PMRLC
Time to parasite 
clearance
Time between drug administration and first PCR below the 
limit of quantification
Log10PRR48
Ratio of the parasite density at a specific time point to the 
parasite density 48 h later and expressed in log10
Log10PRR48,max
Maximum log10PRR48
PC½
Time taken for the parasite density to be reduced by 50% 
after the first dose administration of Riamet®


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
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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 and Project Director:
Farouk Chughlay
Clinical Trial Manager:
Julia Flynn
Clinical Scientist:
Amina Haouala
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 MONITORING
IQVIA RDS & Integrated Services Belgium 
NV/SA
Corporate Village, Davos Building
Leonardo Da Vincilaan 7 
1930 Zaventem
Belgium
MEDICAL MONITORING
ICON Clinical Research
Heinrich-Hertz Str. 26 
63225 Langen
Germany
CLINICAL LABORATORY
ZNA Klinisch Laboratorium
Campus Middelheim
Lindendreef 1
2020 Antwerpen
Belgium
BIOANALYTICAL LABORATORY
Institute of Tropical Medicine Antwerp
Nationalestraat 155
2000 Antwerpen
Belgium


REVISED CLINICAL STUDY PROTOCOL - MMV_PfSPZ-DVI Blood Stage_19_01 24-Jun-2020 (Final 3.0)
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43
PHARMACOVIGILANCE
PrimeVigilance Ltd. (Head office)
1 Occam Court
Surrey Research Park
Guildford, Surrey GU2 7HJ
United Kingdom


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1. INTRODUCTION
1.1
MALARIA BACKGROUND INFORMATION
Malaria is an infectious disease that threatens half of the world’s population and is 
caused mainly by two protozoan parasites: Plasmodium falciparum (P. falciparum) and 
Plasmodium vivax. The World Health Organization (WHO) reported 219 million cases of 
the disease in 2017. In the same year, malaria caused 435000 deaths; 93% of the 
mortality was in Africa, with children <5 years of age attributing 61.1% of deaths [29].
Around the world, effective disease control programs relying on artemisinin-containing 
combination therapies (ACT) such as Coartem®/Riamet® 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 
[28].
Malaria is a serious and life-threatening disease and due to increasing resistance of the 
current antimalarial therapies, new antimalarial therapies are required for both treatment 
and prevention of the disease to address a growing unmet medical need.
1.2
MALARIA CHMI/VIS MODELS
Volunteer Infection Studies (VIS) in malaria (previously referred to as Controlled 
Human Malaria Infection (CHMI) studies) are a valuable tool in antimalarial drug 
development, providing an opportunity to rapidly assess drug efficacy and obtain 
pharmacokinetic and pharmacodynamic (PD) data in healthy, non-immune volunteers 
and earlier entry into patients. VIS entail deliberate infection with malaria parasites, 
either by inoculation of sporozoites through mosquito bite or direct injection of 
sporozoites (i.e., inoculation of P. falciparum sporozoites through direct venous 
inoculation, PfSPZ-DVI Challenge) or by direct venous injection of parasitised 
erythrocytes (i.e., Induced Blood-Stage Malaria, IBSM). VIS has been applied in malaria 
vaccine and drug development, where it is used to evaluate products in well-controlled 
early-phase proof-of-concept clinical studies, thus facilitating progression of only the 
most promising candidates for further evaluation in areas where malaria is endemic. 
1.3
PLASMODIUM FALCIPARUM SPOROZOITES CHALLENGE MODEL 
(PFSPZ CHALLENGE)
Recent advances to support vaccine and drug development have included 
cryopreservation of sporozoites (PfSPZ-DVI Challenge model). PfSPZ-DVI Challenge 
consists of aseptic, purified, live, fully infectious, cryopreserved (to maintain potency for 
an extended period) Plasmodium falciparum (Pf) sporozoites (SPZ) (PfSPZ) obtained 
from the salivary glands of Anopheles stephensi mosquitoes reared under aseptic 
conditions and infected with PfSPZ of either the NF54 strain or 7G8 clone. This advance 
will help to accelerate malaria vaccine and drug development by making the reagents for 
VIS more widely accessible and enabling a more rigorous evaluation with multiple 
parasite strains and species.
The PfSPZ-DVI Challenge agent was developed to be used to infect Phase I volunteers in 
VIS to assess the protective efficacy or efficacy of antimalarial drugs and vaccines, and 


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the effects of naturally acquired immunity and innate resistance. By facilitating the 
development of liver stage infection, PfSPZ-DVI Challenge can be utilized in the 
assessment of causal prophylactic activity of drugs, in contrast with IBSM model which 
results in blood-stage infection only, and consequently, for only assessing drug activity 
against the blood stage of malaria. As is the case with IBSM, the PfSPZ-DVI Challenge 
model, which has been extensively used for testing vaccine and drug prevention 
strategies, has the potential to also be utilised in the assessment of blood-stage activity of 
new antimalarial drugs, and thus increasing the existing MMV and MMV partners’ 
capability for conducting blood-stage malaria VIS at various study centres during early 
drug development of new chemical entities (NCEs).
Conducting VIS in antimalarial vaccine and drug studies with PfSPZ-DVI Challenge as 
compared to P. falciparum sporozoite-infected mosquitoes or parasitised red blood cells
(RBCs) (IBSM model) provides the following potential advantages: 
1. Capacity to conduct clinical studies at multiple sites that do not have access to 
PfSPZ-infected mosquitoes or a Master Cell Bank with parasitised erythrocytes;
2. Increased capacity to conduct VIS critical to the development of NCEs/drugs for 
acute treatment of blood-stage malaria;
3. Capacity to determine and control the specific numbers of PfSPZ with which 
volunteers are inoculated;
4. Capacity to eliminate the potential impact of batch to batch variation on 
infectivity of sporozoites when performing parallel clinical studies at multiple 
sites or sequential clinical studies at the same site
5. Capacity to conduct VIS in volunteers without the study schedule being 
contingent upon a time-consuming and financially expensive process for 
producing infected mosquitoes that must be used within a one to two-week 
window. Benefits include the ability to perform repeated low-dose VIS for time-
course studies with vaccines and drugs, to stagger the VIS for different groups, to 
“catch-up” volunteers that miss the scheduled VIS day, and to use adaptive study
designs where the date and nature of VIS can be made dependent on outcome 
variables measured during the study;
6. Potentially significantly reduced costs.
PfSPZ-DVI Challenge has been safely used in multiple clinical studies in the United 
States, Europe and Africa via the intradermal (ID), intravenous (IV) and intramuscular 
(IM) routes [1,2,7,8,10,11,18,19,23,24,25,26]. As of 17 April 2018, 913 volunteers have 
received 1439 doses of PfSPZ Challenge (NF54) and 34 volunteers have received 
34 doses of PfSPZ Challenge (7G8). Extensive safety and efficacy data are available [9]. 
In addition, PfSPZ-DVI Challenge has been safely administered to volunteers in 
combination with antimalarial drugs and to assess the effects of naturally acquired 
immunity and innate resistance (e.g., sickle cell trait). Currently, the validated 
inoculation method for drug and vaccine evaluation consists of direct venous inoculation 
(DVI) with an inoculum size of 3200 sporozoites which has been shown to induce 
subclinical malaria in 100% of inoculated healthy volunteers [18].
For more detailed information on the PfSPZ-DVI Challenge (NF54 strain) used in this 
study, refer to the current IB [9]. 


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1.4
ANTIMALARIAL THERAPY
The registered antimalarial therapy Riamet® (tablet containing 20 mg artemether and 
120 mg lumefantrine) has been approved for the treatment of acute uncomplicated 
P. falciparum PDODULDLQIHFWLRQLQDGXOWVFKLOGUHQDQGQHZERUQVZHLJKLQJNJ)RU
adult patients, the treatment regimen consists of 6 doses of 4 tablets administered over a 
period of 60 h (1 intake at diagnosis and the 5 following doses at 8, 24, 36, 48 and 60 h
after the initial dose). This Riamet® therapeutic regimen was tested in the IBSM model in 
Australia [15] and will also be used in this study.
In adults, the most frequently reported adverse reactions are decreased appetite, sleep 
disorders, headache, dizziness, palpitations, vomiting, abdominal pain, nausea, arthralgia 
DQGP\DOJLDUHSRUWHGLQSDWLHQWV>YHU\FRPPRQ@DQGLQVRPQLDSDUHVWKHVLD
clonus electrocardiogram (ECG) QT prolonged, diarrhoea, rash and pruritus (reported in 
WR patients [common]). 
For more information on Riamet®, refer to the Summary of Product Characteristics 
(SmPC) [22].
1.5
OVERALL RATIONALE FOR THE STUDY
The intent of this study is to evaluate the feasibility of PfSPZ-DVI Challenge in the 
assessment of NCEs and drugs for the acute treatment of blood-stage malaria. Unlike 
malaria chemoprotection studies where study participants are treated early with rescue 
medication, the intention of utilising the PfSPZ-DVI Challenge for the assessment of 
NCEs/drugs for the acute treatment of blood-stage malaria, is to safely and reliably 
generate blood-stage malaria with appropriate/acceptable parasitaemia densities in 
healthy participants to generate key data supporting further dose selection for patient 
studies in the field. To our knowledge the PfSPZ-DVI Challenge model has not been 
used for assessing antimalarial blood-stage activity in an early-drug development 
context, and a study in healthy participants is needed to determine its safety/tolerability 
and feasibility in assessing antimalarial blood-stage activity.
Existing evidence in support of this methodology in achieving blood-stage parasitaemia
in healthy participants, whilst demonstrating acceptable safety and tolerability is based 
on published literature [7,18,10,2].
1.6
RISK BENEFIT ANALYSIS
1.6.1
Potential Risks
Participants receiving the PfSPZ-DVI Challenge will be exposed to potential risks, 
including the development of malaria symptoms as well as adverse effects of the 
registered antimalarial therapy (Riamet® or Malarone®; see SmPCs [22] and [12]) to be 
prescribed as curative therapy for parasite clearance prior to the end of the study.
The VIS PfSPZ-DVI 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 studies, inoculation of 
PfSPZ-DVI Challenge was found to be safe and well tolerated with the optimal dose 
established as 3200 PfSPZ administered by DVI [18].


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Overall, the PCR (Polymerase chain reaction) monitoring used in these studies ensure 
early treatment preventing high levels or prolonged duration of parasitaemia that would 
put the participant at undue risk. Severe/complicated malaria has never been reported in a 
VIS. Mild malaria symptoms are expected in some study participants and include 
headache, myalgia, fever, chills, sweats, nausea, vomiting and diarrhoea. Rapid diagnosis 
by quantitative PCR (qPCR) and subsequent treatment by Riamet® in the study is 
expected to quickly attenuate the illness so that the infection does not place the 
participant at undue risk. 
Risks to participants in this Phase Ib study will be minimised in the following ways:
-
Sentinel strategy for both Cohort 1 and 2 (please refer to Section 3.1);
-
Progression to consecutive study Cohort 2 only after evaluation of data from 
previous Cohort 1 and approval from Safety Review Team (SRT) (please refer 
to Section 3.4);
-
Adherence to the inclusion/exclusion criteria: only participants considered 
suitable according to these criteria and who are not at any perceived risk will be 
included;
-
The dose of PfSPZ-DVI Challenge and route of administration has previously 
been shown to be safe and well-tolerated in healthy human participants
[2,7,10,18];
-
Routine monitoring to ensure the safety and well-being of the study participants
will include the following:
o
Admission to the clinical unit in the morning of Day -1, i.e. before 
PfSPZ-DVI Challenge, until 2 h post PfSPZ-DVI Challenge and again 
from Day 10 in the morning until parasite clearance (defined as a qPCR 
value of 0 parasites per mL blood after initiating antimalarial therapy) and 
at least 72 h after initiating antimalarial therapy or until Day 28 when 
antimalarial therapy initiated on Day 24;
o
Vital signs (blood pressure, heart rate);
o
12-lead ECGs;
o
Safety laboratory assessments of biochemistry and haematological blood 
parameters performed at scheduled time points and repeated, if necessary
(including repeat of any alanine aminotransferase [ALT] or aspartate
aminotransferase [AST] >2x ULN), to ensure appropriate follow-up of 
any clinically relevant abnormality;
o
Daily parasitaemia assessments by qPCR during daily visits to the clinical 
unit from Day 7 until Day 9 and twice daily from Day 10 post inoculation 
until parasite clearance and at the EOS visit at Day 28;
o
Objective/directed evaluation of Malaria signs and symptoms through a 
clinical score.
-
All participants will be prescribed curative therapy for malaria for radical 
clearance during the study;
-
The total volume of blood drawn per the Time and Events Schedule from each 
participant will not exceed the maximum allowable volume of approximately 
460 mL;
-
In addition to the Principal Investigator (PI) or his representative, the site has 
access to an expert medical malariologist to help in making clinical decisions as 


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necessary, including in the rare event that hospitalisation is required, which will 
be done at the Antwerp University Hospital (UZA). Serious adverse event 
(SAEs) will be treated according to their nature at a specialist inpatient facility. 
1.6.2
Potential Benefits
Benefits of the study are society-based and related to contributing to the future 
development of new antimalarial therapies. Taking into consideration the proposed risk-
management plan as described, the risk to participants participating in this study is 
considered to be minimal and acceptable.
1.6.3
Conclusion
No benefit is expected for individual participants participating in this study. Benefits of 
the study are society-based and related to possible future antimalarial therapies that 
would be developed using this VIS model. Taking into consideration the proposed 
risk-management plan as described, the risk to participants participating in this study is 
considered to be minimal and acceptable.


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2. OBJECTIVES AND ENDPOINTS
Table 1:
Objectives and Endpoints
OBJECTIVES
ENDPOINTS
For definitions of terms, see List of 
Abbreviations and Definitions of Terms
Primary
x
To evaluate the safety and 
tolerability associated with 
blood-stage malaria infection in 
naïve healthy participants after 
PfSPZ-DVI Challenge.
x
The incidence and severity of observed 
(i.e., malaria signs and symptoms graded 
by the malaria clinical score; see 
Attachment 1) or self-reported adverse 
events (AEs) considered PfSPZ-DVI 
Challenge inoculum-related until end of 
study (EOS) visit.
x
The change in malaria clinical score from 
PfSPZ-DVI Challenge until parasite 
clearance.
x
Changes from baseline in haematology, 
clinical chemistry and urinalysis 
parameters, vital signs and ECG 
parameters.


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OBJECTIVES
ENDPOINTS
For definitions of terms, see List of 
Abbreviations and Definitions of Terms
Primary
x
To characterise key stages in the 
blood-stage parasite growth profile 
in malaria infection in naïve 
healthy participants after 
PfSPZ-DVI Challenge.
x
The parasite growth profiles of 
P. falciparum NF54 after infection via 
injection of sporozoites by DVI will be 
characterised by: 
o time to first PCR positivity (for the 
purpose of this study, ‘PCR positivity’ 
is used for the ‘protocol-defined PCR 
positivity’, unless mentioned 
otherwise);
o parasitaemia at first PCR positivity;
o time to parasitaemia of 
5000 parasites per mL blood 
(Cohorts 1 and 2);
o parasitaemia at the time parasitaemia 
SDUDVLWHVSHUP/EORRG
(Cohorts 1 and 2);
o time to parasitaemia of 
10000 parasites per mL blood 
(Cohort 2);
o parasitaemia at the time parasitaemia 
SDUDVLWHVSHUP/EORRG
(Cohort 2);
o time to first dose of treatment with 
artemether-lumefantrine (Riamet®)
(Cohorts 1 and 2); and
o parasitaemia at first dose of treatment 
with Riamet® (Cohorts 1 and 2).
x
The number and proportion of participants 
with presence of positive PCR and 
SDUDVLWDHPLDRIRUSDUDVLWHV
per mL blood between inoculation with 
PfSPZ-DVI Challenge and Day 28 (per 
cohort).


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OBJECTIVES
ENDPOINTS
For definitions of terms, see List of 
Abbreviations and Definitions of Terms
Secondary
x
To determine the safety and 
tolerability of Riamet® in 
blood-stage malaria infection in 
naïve healthy participants after 
PfSPZ-DVI Challenge.
x
The incidence, severity and relationship to 
Riamet® of observed or self-reported, 
treatment-emergent adverse events 
(TEAEs) until EOS visit.
x
To characterise the blood-stage 
parasite profile in malaria infection 
in naïve healthy participants after 
PfSPZ-DVI Challenge.
x
The blood-stage parasite profile of 
P. falciparum NF54 after infection via 
injection of sporozoites by DVI will be 
characterised by: 
o parasite growth rate expressed as the 
parasite multiplication rate (PMR) 
standardised to 48 h (PMR48)
(Cohort 1, Cohort 2 and overall);
o parasite growth rate expressed as the 
PMR per life cycle (if not 48 h) 
(PMRLC) (Cohort 1, Cohort 2 and 
overall); and
o predicted time to reach parasitaemia 
threshold of first positive PCR, 
 parasites per mL blood, 
 parasites per mL blood for 
Cohorts 1 and 2.
x
To characterise the blood-stage 
parasite clearance profile of 
Riamet® in malaria infection in 
naïve healthy participants after 
PfSPZ-DVI Challenge.
x
The effect of Riamet® on clearance of 
P. falciparum blood-stage parasites will 
be evaluated using:
o time to parasite clearance (Cohort 1, 
Cohort 2 and overall);
o log10 parasite reduction ratio per 48 h 
(log10PRR48) (Cohort 1, Cohort 2 and 
overall);
o maximum log10PRR48 (log10PRR48,max)
(Cohort 1, Cohort 2 and overall); and
o parasite clearance half-life (PC½)
(Cohort 1, Cohort 2 and overall).


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OBJECTIVES
ENDPOINTS
For definitions of terms, see List of 
Abbreviations and Definitions of Terms
Exploratory
x
To characterise the individual 
variability of blood-stage parasite 
profile.
x
The individual variability of blood-stage 
parasite profile will be characterised by:
o the inter-individual variability of the 
parasite growth rate; and
o predicted time to reach parasitaemia 
threshold of first positive PCR, 
 parasites per mL blood, 
 parasites per mL blood 
including their 95% confidence 
interval (CI).
HYPOTHESIS: This study is exploratory in nature and therefore no hypothesis will be 
tested.


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3. STUDY DESIGN
3.1
OVERVIEW OF STUDY DESIGN
This is a single-centre, open-label, Phase Ib study designed to assess if intravenous bolus 
injection of approximately 3200 P. falciparum (NF54 strain) sporozoites can be safely 
administered to achieve blood-stage parasitaemia with a kinetics/PCR profile that will 
allow for the future characterisation of antimalarial blood-stage activity of NCEs in a 
relatively small number of participants during early drug development.
Up to 16 healthy, malaria-naïve males and females, aged 18-55 years, will be enrolled in 
a maximum of 2 cohorts (up to 8 participants per cohort; a participant may be enrolled in 
one cohort only). Enrolment into the cohorts will proceed sequentially, with two target 
levels of parasitaemia previously achieved in healthy participants enrolled in malaria VIS 
at other study sites (see Section 3.2), i.e., 5000 parasites/mL blood in Cohort 1 and 
10000 parasites/mL blood in Cohort 2.
Each participant will be admitted to the clinical unit in the morning of Day -1 and
inoculated with approximately 3200 P. falciparum sporozoites (NF54 strain) by DVI on 
Day 1. Participants will be discharged 2 h post inoculation on Day 1 and will be 
monitored daily via phone call from Day 2 until Day 6 to solicit any AEs. Participants
will come to the clinical unit daily from Day 7 until Day 9 and together with the malaria 
clinical score (see Attachment 1), the presence of parasites will be assessed once daily by 
a specific qPCR targeting the varATS (the acidic terminal segment in Plasmodium 
falciparum var genes) multigenic family; this to accurately describe parasite growth even 
in case PCR positivity, i.e., a qPCR RXWFRPHSDUDVLWHVSHUP/EORRG is confirmed 
this early (very low probability and with low densities). Participants will be confined to
the clinical unit from Day 10 in the morning. qPCR will be performed and malaria 
clinical score assessed twice daily and participants will be administered registered 
antimalarial therapy, i.e., Riamet® (see Section 5.1), when the following criteria are met:
1. &RKRUWSDUDVLWHVmL blood or earlier if a participant has a malaria 
clinical score >6 or at Investigator’s discretion.
2. &RKRUWSDUDVLWHVP/blood or earlier if a participant has a malaria 
clinical score >6 or at Investigator’s discretion.
The registered 3-day antimalarial therapy regimen will be further administered and 
monitored. qPCR assessments of parasitaemia will be carried out at multiple time points 
(2, 6, 8, 12, 16, 24, 36, 48 and 72 h) following initiation of Riamet® and malaria clinical 
score will be assessed twice daily during confinement in the clinical unit. Safety and 
tolerability will be monitored during the whole study duration, specific assessments will 
be done at periodic pre-specified time points from Day 10 and for at least 72 h after
initiating antimalarial therapy, i.e., during confinement in the clinical unit (see below).
Of note, all participants must consent to receiving antimalarial therapy, i.e., the registered 
3-day Riamet® regimen approved for treatment of uncomplicated malaria. Even in the 
case of withdrawal from the study, all participants administered the PfSPZ-DVI 
Challenge are to receive antimalarial therapy as soon as possible, and to have all 
appropriate visits and assessments as required. If an intolerance or contraindication to 
Riamet® develops, Malarone® will be administered (see Section 5.1).


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Upon parasite clearance (defined as a qPCR value of 0 parasites per mL blood after 
initiating antimalarial therapy) and at least 72 h after initiating antimalarial therapy
(estimated to occur on or before Day 19 and on or before Day 22 for Cohort 1 and 
Cohort 2, respectively), and if clinically well, participants will be discharged from the 
clinical unit and will be followed up for safety assessments, clinical evaluation and 
malaria qPCR in the clinical unit at the EOS visit on Day 28.
All participants who received antimalarial therapy will be asked non-leading questions to 
determine the occurrence of any AEs throughout the study and at the EOS visit.
All participants inoculated with PfSPZ-DVI Challenge will commence antimalarial 
therapy no later than Day 24 for both cohorts, regardless if they reach pre-defined 
cohort-specific PCR parasitaemia/malaria clinical score thresholds (i.e., 
5000 parasites/mL blood for Cohort 1 and 10000 parasites/mL blood for Cohort 2 and/or 
DPDODULDFOLQLFDOVFRUHIRU&RKRUWVDQGParticipants who start antimalarial 
therapy on Day 24 will only be discharged from confinement at the end of the EOS visit 
on Day 28.
Antimalarial therapy may be initiated whenever deemed necessary by the Investigators, 
e.g., if there is a concern regarding the safety of a study participant (see Section 5.1).
Therapy may be amended according to the treating physician if the participant does not 
respond to treatment or the condition worsens.
A sentinel strategy will be employed in Cohorts 1 and 2. Each cohort will consist of 
2 subgroups of participants, to be enrolled sequentially: Subgroup 1 will be composed of 
2 participants; Subgroup 2 will be composed of 6 participants. Participants in Subgroup 2 
will not be treated until the last participant in Subgroup 1 has completed antimalarial 
therapy and only upon decision of the PI, medical director and medical monitor after 
review of available safety and tolerability data (safety assessments, AEs and malaria 
clinical scores) and parasitaemia data, including clearance of parasitaemia, of 
Subgroup 1.
Review of available Cohort 1 safety/tolerability and parasitaemia data up to the last dose 
of Riamet® for all inoculated participants in Cohort 1 will be performed by an SRT 
before enrolment of Cohort 2 (see Section 3.4). 
A schematic overview of the study design is shown in Figure 1 for Cohort 1 and in 
Figure 2 for Cohort 2. The assessments to be performed are summarised per visit in the 
Time and Events Schedule for Cohort 1 and Cohort 2.


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Figure 1:
Schematic Overview of the Study for Cohort 1
Figure 2:
Schematic Overview of the Study for Cohort 2
3.2
DISCUSSION OF STUDY DESIGN AND DOSE SELECTION
Dose Selection
Currently, the validated inoculation method for drug and vaccine evaluation consists of 
direct venous inoculation (DVI) with an inoculum size of 3200 sporozoites which has 
been shown to induce subclinical malaria in 100% of inoculated healthy volunteers [18].
Based on published data in Phase I participants inoculated with malaria, the registered 
regimen of artemether-lumefantrine (Riamet®) will clear asexual parasitaemia in less 
than 48 h [15].


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Target PCR-Based Parasitaemia Thresholds Informing the Initiation of Antimalarial 
Therapy
The proposed PCR-based parasitaemia thresholds to initiate antimalarial therapy have 
been selected to maximise participant safety whilst ensuring study objectives are met 
through efficient conduct of the study as follows:
1. &RKRUWSDUDVLWHVP/EORRGRUHDUOLHULIDparticipant has a malaria 
clinical score >6 or at Investigator’s discretion.
2. &RKRUWSDUDVLWHVP/EORRGRUHDUOLHULIDparticipant has a malaria 
clinical score >6 or at Investigator’s discretion.
The aim of the proposed clinical study is the evaluation of the feasibility of PfSPZ-DVI 
Challenge to safely generate adequate levels of asexual blood-stage malaria parasitaemia 
for the evaluation of NCEs/drugs for acute treatment of blood-stage malaria. There is 
available evidence from published Phase I validation studies supporting the feasibility of 
this model for this purpose:
1. A Phase I PfSPZ-DVI Challenge study [7,18] was conducted in healthy 
volunteers, including inoculation of 3200 PfSPZ-DVI Challenge in 6 participants
resulting in:
-
Infectivity rate of 100%;
-
Geometric mean time to Thick Blood Smear (TBS)-positive asexual 
parasitaemia of 11.4 days (11.0, 10.4, 12.3, 10.9, 11.9, 12.2 days);
-
Geometric mean time to qPCR-positive asexual parasitaemia of 8.3 days (6.9, 
9.1, 8.0, 8.0, 9.0, 8.9 days);
-
Geometric mean parasite density at time of TBS-positivity (parasites/mL 
blood) of 6600 (5000, 1300, 10000, 8000, 12000, 14000 parasites/mL blood); 
and
-
PfSPZ-DVI Challenge was well tolerated with AEs occurring at the time of 
parasitaemia detection. AEs were mostly grade 1 (51/85) or grade 2 (28/85) in 
severity, with only a few grade 3 AEs reported (6/85). No SAEs occurred.
2. A Phase I study was conducted which assessed standardised VIS by DVI of 
3200 PfSPZ in healthy, adult, lifelong malaria–exposed volunteers [10]. The 
study included 25 participants in total, of which 5 were healthy and 
non-immune/malaria-naïve. Findings in these 5 participants are as follows:
-
Infectivity rate of 100% confirmed by TBS and qPCR;
-
Geometric mean time to TBS-positive parasitemia of 12.6 days 
(range:12-14 days);
-
Geometric mean time to qPCR-positive parasitemia of 7.9 days (range: 
7-9 days);
-
Geometric mean parasite density at first parasitemia of 5000 parasites/mL
blood (range: 2000-9000 mL); and 
-
PfSPZ-DVI Challenge was well tolerated and no serious AE occurred during 
the study. In the 5/5 healthy, malaria-naïve participants, majority of AEs were 
grade 1 (27/50) in severity. A total of 13/50 AEs were grade 2 and a further 
10/50 AEs were grade 3 in severity.


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3. In addition, the chemoprotection MMV_P218_17_01 study conducted in Belgium 
(EudraCT number: 2018-003004-39) [2] data indicate:
-
An infectivity rate of 100%, with asexual parasitaemia detected in 6 out of the 
6 inoculated participants administered placebo. Although the study protocol 
required administration of rescue treatment at the threshold of 
250 parasites/mL blood, 2/6 participants achieved parasite densities of 
1583 and 4432 parasites/mL blood at the time of rescue treatment 
administration; 
-
In Cohort 1 (2 x 1000 mg doses of P218 administered 48 h apart, no 
sporozoite inoculation): No SAEs or severe AEs were reported. A total of 
6 AEs occurred in 3/8 participants, all 6 were grade 1 AEs (mild). Only 
1/6 AEs (diarrhoea, grade 1) was assessed as being related/suspected to be 
due to P218 with the remaining 5/6 deemed not related to P218. In addition, 
no clinically significant findings were noted on vital signs, ECG (no clinically 
concerning prolongation in QT interval corrected according to Fridericia’s 
formula [QTcF] [5]) and laboratory investigations. These findings supported 
the Safety Review Committees’ decision after Cohort 1, to proceed with 
Cohort 2;
-
In Cohort 2 (sporozoite inoculation followed by 2 x 1000 mg doses of P218 
administered 48 h apart): No SAEs or severe AEs were reported. A total of 
26 AEs occurred in 11/12 participants, with 21/26 grade 1 AEs (mild) and 
5/26 grade 2 AEs (moderate). A total of 2/26 AEs in 1 participant (2 headache 
events, grade 1) was assessed as being related to P218 with the remaining 
24/26 AEs deemed not related to P218. A total of 4/26 AEs in 2 participants
(fatigue, malaise, flu-like symptoms and transaminase elevation) was assessed 
as being related to PfSPZ-DVI Challenge. In addition, no clinically significant 
findings were noted on vital signs, ECG (no clinically concerning QTc 
prolongation) and laboratory investigations. These findings supported the 
Safety Review Committees’ decision after Cohort 2, to proceed with 
Cohort 3;
-
In Cohort 3 (sporozoite inoculation followed by 2 x 100 mg doses of P218 
administered 48 h apart): No SAEs or severe AEs were reported. A total of 
7 AEs occurred in 4/12 participants, all were grade 1 AEs (mild). All AEs 
were considered not related to P218. A total of 2/7 AEs in two participants
(both flu-like symptoms) was assessed as being related to PfSPZ-DVI 
Challenge. In addition, no clinically significant findings were noted on vital 
signs, ECG (no clinically concerning QTc prolongation) and laboratory 
investigations; and
-
Of note was the occurrence of a transient, asymptomatic transaminase 
elevation (ALT) >3x the upper limit of normal (ULN) (with LQFUHDVHV[
ULN in AST and no effect on bilirubin) in the participant who achieved a 
peak parasitaemia of 4432 parasites/mL. ALT/AST values were back to 
normal range before study end without specific intervention.
Further indirect evidence in support of the safety rationale for the proposed 
PCR-thresholds is derived from completed MMV-sponsored IBSM studies conducted in 
Australia with the NCEs DSM265 [3] and MMV390048 [14]. The level of parasitaemia 


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to be observed in our proposed pilot study for both Cohorts 1 (5000 parasites/mL) and 2 
(10000 parasites/mL) is expected to be covered by the range of parasitaemia documented 
in these Australian Phase I IBSM studies:
1. The IBSM study with DSM265 [3] comprised of 8 healthy participants who 
developed asexual blood stage parasitaemia following inoculation with 
P. falciparum parasitised erythrocytes (IBSM model). Among the 7 participants 
who became parasitaemic, the geometric mean parasitaemia upon initial dosing 
with 400 mg DSM265 was 7,851 parasites/mL blood (95% CI, 2,245 to 
27,462 parasites/mL blood). No SAEs were reported. A total of 88 AEs which 
were mostly mild in severity (87.5%) were reported, and the majority were 
deemed related to malaria parasite infection (77.3%). Eleven AEs were moderate 
in severity, while none were classified as severe. The severity of the malaria 
symptoms and signs experienced by the participants during the study was 
generally mild, as assessed by use of a malaria clinical scoring tool. At the time 
the first dose of DSM265 was administered, 4 of the 7 participants who were 
parasitaemic had no malaria symptoms or signs (clinical score, 0), while the 
remaining 3 participants each had a score of 3. The peak malaria clinical score 
recorded during the study was 8; this was recorded for a single participant 
approximately 36 h after administration of the first dose of DSM265.
2. The IBSM study with MMV390048 [13] comprised of 15 healthy volunteers, 
who developed asexual blood stage parasitaemia following inoculation with 
P. falciparum parasitised erythrocytes (IBSM model). As the protocol was calling 
for the full cohort to be inoculated on the same study day, asexual blood stage 
parasitaemia densities prior to receiving any investigational medicinal product 
(IMP) was variable between participants and ranged from 1508 parasites/mL
blood to 95851 parasites/mL blood. Additionally, the malaria clinical score 
associated with the timing of this parasite density in each of these 15 participants, 
included a score of 0/42 (absence of malaria symptoms/signs) in 
10/15 participants, a score of 1/42 in 2/15 participants, a score of 2/42 in 
2/15 participants and a score of 3/42 in 1/15 participants.
3. Due to the mechanism of action of the test drug and evaluation of doses 
associated with suboptimal efficacy, peak asexual blood stage parasitaemia 
densities for these participants was observed after administration of the drug for 
the majority of the participants and ranged from 7946 parasites/mL to 
281387 parasites/mL. Additionally, the malaria clinical score associated with the 
timing of this parasite density in each of these 15 participants, included a score of 
1/42 in 1/15 participants, 2/42 in 6/15 participants, 4/42 in 2/15 participants, 6/42 
in 3/15 participants, 7/42 in 1/15 participants and 8/42 in 2/15 participants.
4. A total of 202 AEs occurred with 176 of these being assessed as 
inoculum-related. Most common AEs reflecting manifestations of blood stage 
malaria infection included: headache (57 cases in 15 participants), myalgia 
(25 cases in 12 participants), malaise (18 cases in 9 participants), reduction in 
lymphocyte count (11 cases in 8 participants), abdominal discomfort (7 cases in 
6 participants), fatigue (10 cases in 5 participants) and arthralgia (7 cases in 
5 participants). Most AEs were of mild severity (145/202). There were 52 AEs of 
moderate severity, which were predominantly signs and symptoms associated 
with malaria infection. There were 5 severe AEs recorded in 3 participants and all 


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considered to be inoculum related (1 participant with severe headache, 
1 participant with transient asymptomatic elevated ALT; elevated AST; and 
decreased lymphocyte count, 1 participant with decreased lymphocyte count). No 
SAEs were reported.
A review of data from 5 completed IBSM-Pf studies that collected both parasitaemia and 
malaria clinical score on first antimalarial treatment day, showed that only a small 
percentage of participants experienced malaria sign/symptoms. The majority had a low 
malaria clinical score of below 3 out of a maximum score of 42 (data on file at MMV and 
QIMR). For the total of 54 participants who were inoculated in these studies, the range of 
parasitaemia at first antimalarial treatment day was 634 to 107981 parasites/mL. At 
treatment initiation, 17 of 54 participants (31.5%) were symptomatic. Of those 
17 participants, 16 (94.1%) had a malaria clinical score ranging from 1-3 and the 
remaining participant had a score of 7. The parasitaemia associated with the clinical 
score of 7 was 31666 parasites/mL whereas the highest parasitaemia observed in this 
analysis (107981 parasites/mL) was observed in an asymptomatic participant
[3,4,6,13,14].
Lastly, it should be noted that from a general safety standpoint, the VIS studies in healthy 
volunteers achieve blood-stage parasitaemia levels that are approximately 1000-fold 
below those observed in patients with acute malaria infection.
Period for In-House Stays in the Clinical Unit
The period of in-house stays proposed for the current study is aimed at maximising 
participant safety and convenience, and ensuring efficient clinical study conduct. 
Participants will be discharged 2 h after inoculation. Experience from previous VIS 
Phase Ib studies with the DVI technique has shown that inoculation is not expected to 
induce inoculum-related AEs or laboratory tests changes (due to incubation period) 
[2,20,27]. Potential tolerability issue is limited to a possible haematoma or vasovagal 
reaction in relation with venepuncture and can be covered by the observation following 
injection.
In line with experience from previous VIS IBSM Phase Ib studies conducted by MMV at 
a Phase I Unit in Australia and the chemoprotection MMV_P218_17_01 study conducted 
in Belgium (EudraCT number: 2018-003004-39), safety will be assessed for both cohorts 
by daily monitoring via phone call from Day 2 until Day 6 and safety, parasitaemia and 
malaria signs and symptoms by daily visits to the clinical unit from Day 7 until Day 9, 
until start of second confinement in the unit on Day 10:
1. Experience with the MMV_P218_17_01 study:
-
Placebo participants developed protocol-defined PCR positivity 
 250 parasites/mL blood) on Day 10 (1/6) or Day 12 (5/6), aligned with a 
geometric mean time to positive parasitaemia of 10.615 (9.918; 11.360) days.
-
Malaria signs and symptoms were reported in 4 (66.7%) participants overall 
and there was a delay between detection of positive parasitaemia and malaria 
sign or symptom onset, with symptoms occurring after PCR positivity and 
starting on Day 12 in 1 out of the 4 participants and on Day 13 for each of the 
remaining 3 participants.


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-
For each of the 4/6 participants, a maximum individual symptom score of one 
(mild) was observed and no moderate or severe sign/symptom was reported. 
-
Total malaria clinical scores for the 4 participants were 2/42, 2/42, 3/42 and 
5/42.
2. Although occurring earlier than Day 10, previous studies [7,10,18] defined PCR 
positivity with a limit of detection between 20 and 30 parasites per mL blood, 
which is lower than our threshold of 250 parasites per mL blood.
Participants will be confined and closely monitored in the unit starting from Day 10 until 
the cohort-specific qPCR parasitaemia and/or malaria clinical scores thresholds for
initiation of registered antimalarial therapy (Riamet®/Malarone®) are reached.
At the time cohort-specific qPCR thresholds (i.e. 5000 parasites/mL blood for Cohort 1 
and 10000 parasites/mL blood for Cohort 2) and/or malaria clinical score (6/42 or more) 
are met, participants will be administered the registered antimalarial therapy. Participants 
will continue to be monitored at the clinical until complete parasite clearance and for a 
minimum of 72 h from initiating antimalarial therapy. Then, if clinically well, 
participants will be discharged and return for an ambulatory EOS visit.
All participants inoculated with PfSPZ-DVI Challenge will commence antimalarial 
therapy no later than Day 24 for both cohorts, regardless if they reach pre-defined 
cohort-specific PCR parasitaemia/malaria clinical score thresholds (i.e., 
5000 parasites/mL blood for Cohort 1 and 10000 parasites/mL blood for Cohort 2 and/or 
DPDODULDFOLQLFDOVFRUHIRU&RKRUWVDQG3DUWLFLSDQWVZKRVWDUWDQWLPDODULDO
therapy on Day 24 will only be discharged from confinement at the end of the EOS visit 
on Day 28.
The Applicant believes there are no further specific measures needed in this proposed 
study due to the use of the registered 3-day regimen of Riamet®/Malarone®.
3.3
END OF STUDY DEFINITION
A participant will be considered to have completed the study if he or she has completed 
all phases of the study including the required EOS visit.
The end of the study is defined as the date of the last EOS visit of the last participant in 
the study.
3.4
SAFETY REVIEW COMMITTEE (SRT)
The study will be overseen by an SRT.
The SRT members will include at least an independent Early Phase and Clinical 
Pharmacology MD expert experienced in malaria volunteer infection studies (SRT chair), 
the Medical Monitor, the Medical/Project Director, the PI and an independent infectious 
disease/malaria expert (or their delegates). The MMV Head of Experimental Medicine 
and Clinical Pharmacology or further internal or external experts such as a clinical lead 
and/or a statistician may be consulted by the SRT as necessary.
The SRT will review safety/tolerability, parasitaemia and malaria signs and symptoms 
data during the study. SRT meetings will be scheduled at one prespecified time (see 
Section 3.4.1) and ad-hoc if deemed necessary. The required data for SRT review will be 


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detailed in a separate study specific SRT Charter and will be sent to the SRT at least 24 h
prior to an SRT meeting. 
The decision of the SRT will be taken in consensus between the members of the SRT. If
consensus cannot be reached, then the most cautious approach will proceed. The SRT 
decision and decision-making will be documented in the SRT meeting minutes, which 
will be provided to the attendees after the meeting.
Safety will be continuously monitored by the Investigators, the Sponsor’s medical 
monitor, and study personnel.
Criteria for discontinuation of dosing in individual participants are listed in Section 8.
The SRT will not review the data from the sentinel groups in Cohort 1 and Cohort 2.
Progression from Subgroup 1 to Subgroup 2 in both Cohorts 1 and 2 will occur upon 
decision of the PI, medical director and medical monitor only (see Section 3.1).
3.4.1
Toxicity Criteria and Progression From Cohort 1 to Cohort 2
An SRT meeting is scheduled to occur at least a week after the conclusion of malaria 
therapy of Cohort 1, prior to commencing Cohort 2. The SRT will review available 
Cohort 1 safety/tolerability and parasitaemia data up to the last dose of Riamet® for all 
inoculated participants in Cohort 1 before enrolment of Cohort 2 and determine whether 
progression to Cohort 2 is indicated. If no safety concerns are identified during SRT 
review, progression to Cohort 2 will take place. Initiation of Cohort 2 will be put on hold 
and further review will be conducted by the SRT, if any of the following toxicity criteria 
are observed in Cohort 1:
-
PfSPZ-DVI Challenge-related or Riamet®-related SAE; or
-
any other critical PfSPZ-DVI Challenge-related finding that may place 
participants at risk within the same cohort or in the next cohort; or
-
two or more Riamet®-related severe (grade 3 or higher) AEs, independent of 
within or not within the same system organ class.
If after data review the SRT confirms that any of the above has been met, including a 
relationship with the PfSPZ and/or Riamet®, progression to Cohort 2 with higher target 
levels of parasitaemia might not be conducted.
3.4.2
Final SRT Review at Study End
The SRT will also meet at the end of the study when data from Cohort 2 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 participant 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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4. SELECTION OF STUDY POPULATION
Screening for eligible participants will be performed within approximately 4 weeks prior 
to first confinement and up to Day -2.
Approximately 16 participants are planned to be enrolled sequentially in 2 cohorts of up
to 8 participants per cohort. A participant may be enrolled in one cohort only. 
For details on the sample size calculation, please refer to Section 9.2.
4.1
INCLUSION CRITERIA
Participants 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 participant understands the purpose of and 
procedures required for the study and is willing to participate in the study, 
including administration of registered antimalarial therapy;
2. Male or female, between 18 and 55 years old (extremes included) at screening;
3. Body weight of at least 50 kg and a body mass index (BMI) of 19.0 to 30.0 kg/m2
(extremes included);
4. Good general health without clinically relevant medical illness, physical exam 
findings including vital signs, and laboratory abnormalities (e.g., without liver 
transaminases >1x ULN and according to the clinically acceptable ranges for 
study inclusion laboratory tests in Attachment 4) as determined by the 
Investigator;
5. Willing to adhere to the prohibitions and restrictions specified in this protocol
(see Section 4.3), including willingness to stay confined to the inpatient unit for 
the required duration and willingness to avoid travelling outside of Benelux 
during the study period;
6. Female participants should fulfil one of the following criteria:
a. At least 1 year postmenopausal (amenorrhea >12 months and 
follicle-stimulating hormone [FSH] >30 mIU/mL) prior to screening;
b. Surgically sterile (bilateral oophorectomy, hysterectomy or bilateral 
salpingectomy);
c.
Will use contraceptives as outlined in inclusion criterion 7;
7. Female participants of childbearing potential (excluding females with female 
partners) must agree to the use of a highly effective method of birth control from 
the screening visit until 40 days after the EOS visit at Day 28 (covering a full 
menstrual cycle of 30 days starting after 5 half-lives of last dose of Riamet®);
Note: Highly effective birth control methods include: combined (oestrogen- and 
progestogen-containing) oral/intravaginal/transdermal hormonal contraception associated with 
inhibition of ovulation, progestogen-only oral/injectable/implantable hormonal contraception 
associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing 
system, bilateral tubal occlusion, vasectomised partner or sexual abstinence from heterosexual 
intercourse.


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8. Female participant has a negative pregnancy test at screening and upon admission 
in the clinical unit;
1RWH3UHJQDQF\WHVWLQJZLOOFRQVLVWRIVHUXPȕ-KXPDQFKRULRQLFJRQDGRWURSLQȕ-HCG) tests at 
screening and at the EOS visit and a XULQHȕ-HCG tests on Day -1, in all women.
9. 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
Participants 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 
5 half-lives for drugs) preceding the day of PfSPZ-DVI Challenge (whichever is 
longer), or plans to participate in other investigational drug or vaccine research
during the study period;
3. Participants who took standard vaccinations within 3 months before the start of 
the study or are planning to take standard vaccinations during the study period up 
to 8 weeks after PfSPZ-DVI Challenge;
4. 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 on Day -1;
5. Mean ECG outside normal range and deemed clinically relevant by the 
Investigator. Examples of clinically significant ECG abnormalities for this study 
include:
-
PR-interval >220 ms;
-
QRS-complex >120 ms;
-
Absolute QT greater than >500 ms;
-
QT interval corrected according to Bazett’s formula (QTcB) or QTcF 
>450 ms for male participants, >470 ms for female participants;
-
Pathologic Q wave;
-
Significant ST-T wave changes;
-
Left or right ventricular hypertrophy;
-
Non-sinus rhythm except isolated premature atrial contractions and 
ventricular extrasystole <2 per 10 s ECG lead;
-
Incomplete left bundle branch block, or complete or intermittent right or left 
bundle branch block;
-
Second or third degree A-V heart block.
6. Seropositive human immunodeficiency virus (HIV), hepatitis A 
immunoglobulin M (IgM) antibody, hepatitis B virus (HBV) (hepatitis B surface 
antigen [HBsAg]), hepatitis C virus (HCV) (antibody), hepatitis D antibody, 
hepatitis E IgM antibody, cytomegalovirus (CMV) IgM antibody or Epstein Barr 
Virus (EBV) IgM antibody;


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7. Previous or current diagnosis of hepatitis including but not limited to viral 
hepatitis, auto-immune hepatitis, non-alcoholic steatohepatitis (NASH), 
alpha-1-antitrypsin deficiency, alcoholic liver disease, primary biliary cholangitis 
(PBC), primary sclerosing cholangitis (PSC), hemochromatosis, Wilson disease 
or suspected hepatocellular carcinoma (HCC).
8. History or presence of diagnosed food or known drug allergies (including but not 
limited to allergy to any of the antimalarial medications to be used in the study, 
see Section 5.1), or history of anaphylaxis or other severe allergic reactions;
Note: Participants 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.
9. History of convulsion or severe head trauma, excluding fever convulsion under 
5 years of age;
Note: A medical history of a single febrile convulsion during childhood is not an exclusion criterion.
10. 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, participants 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. Participants 
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.
11. 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 defined as 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%).
12. Participants 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. Participants must agree to abstain from smoking 
while in the unit;


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13. Use of any prescription drugs, herbal supplements (e.g., St John’s Wort) or 
over-the-counter medication within 7 days or 5 half-lives (whichever is longer) 
prior to the PfSPZ-DVI Challenge, 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) and
paracetamol (2 g/day, 10 g/week) may be acceptable at the Investigator’s discretion 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 participant safety nor the overall results of the study, 
may be permitted on a case-by-case basis by the Investigator.
14. Any surgical or medical condition possibly affecting drug absorption (e.g., 
cholecystectomy, gastrectomy, bowel disease), distribution, metabolism or 
excretion;
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 jeopardise the safety 
or rights of a person participating in the study or would render the person unable 
to comply with the protocol;
17. Personal history of malaria;
18. Volunteer has travelled to or lived in a malaria-endemic area within 6 months 
prior to planned study enrolment;
19. Plans to travel to malaria-endemic region during the study period up to last 
follow-up visit;
20. Previous participation in any malaria vaccine or CHMI study/VIS;
21. Falling in moderate or higher risk category for a fatal or non-fatal cardiovascular 
event within 5 years (> 5%) determined by a validated risk estimation system,
e.g., SCORE [21];
22. Use of systemic antibiotics with known antimalarial activity within 5 half-lives of 
PfSPZ-DVI Challenge (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);
23. Receipt of blood or blood-derived products (including immunoglobulin) within 
3 months prior to screening. Receipt of packed RBCs given for an emergent 
indication in an otherwise healthy person, and not required as ongoing treatment 
is not exclusionary (for example packed RBCs emergently given during an 
elective surgery).
24. Participants who test positive for severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2).
Note: In case of an out-of-range clinical laboratory test (according to the clinically acceptable 
ranges for study inclusion laboratory tests in Attachment 4), vital sign or ECG value that will
determine a participant’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 participant eligibility at the Investigator’s discretion. 
Participants can be rescreened at the discretion of the Investigator.


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4.3
LIFESTYLE CONSIDERATIONS
No blood donation will be allowed until 24 weeks after the end of the study.
Female participants of childbearing potential (excluding females with female partners) 
must agree to the use of an effective method of contraception from the screening visit 
until 40 days after the EOS visit at Day 28, as outlined in Section 4.1. For details on the 
existing data regarding the reproductive toxicity of the PfSPZ-DVI Challenge, Riamet®
and Malarone®, please see the current Investigator’s Brochure [9] and SmPCs [22] and 
[12].
Information on prohibited therapies can be found in Section 6.
Participants will be confined from Day -1 in the morning until 2 h post inoculation on 
Day 1 and from Day 10 in the morning until the day of parasite clearance and at least 
72 h after initiating antimalarial therapy (estimated to occur on or before Day 19 and on 
or before Day 22 for Cohort 1 and Cohort 2, respectively) or from Day 10 in the morning 
until Day 28 for participants that start antimalarial therapy on Day 24, unless they are 
withdrawn from the study.
Authorisation to leave the clinical unit will be given by the Investigator.
4.3.1
Meals and Dietary Restrictions
1. Safety clinical laboratory blood tests will be performed in a fasted state, i.e., after 
overnight fast for at least 8 h, except for the ones taken during antimalarial 
therapy for troponin T measurements, and except for the ones on Day of first PCR 
SDUDVLWHVP/LQ&RKRUWRUSDUDVLWHVP/LQ&RKRUWDQGSULRUWR
initiating antimalarial therapy, where a non-fasted state is allowed.
2. The first dose of antimalarial drug should be taken as soon as possible according 
to the pre-defined cohort-specific PCR parasitemia/malaria clinical score 
thresholds (i.e., 5000 parasites/mL blood for Cohort 1 and 10000 parasites/mL
EORRGIRU&RKRUWDQGRUDPDODULDFOLQLFDOVFRUHIRU&RKRUWVDQGRURQ
reaching Day 24. Antimalarial drug administration should be immediately 
followed by a meal or drinks rich in fat (e.g., milk). 
3. Participants will abstain from eating or drinking grapefruit or grapefruit-related 
citrus fruits (e.g., Seville oranges, pomelos) from 2 weeks prior to the first 
Riamet® administration and for the whole duration of the study.
4. Participants should not consume poppy-seeds within 24 h before screening and 
before each urine drug screening because this can falsify the results of the opiate 
urine drug test.
4.3.2
Caffeine, Alcohol, and Tobacco
5. Participants will abstain from smoking a tobacco product or marijuana in the unit.
Participants are non-smokers or ex-smokers for more than 90 days prior to 
screening, or smoke no more than 5 cigarettes per day (see Section 4.2).
6. Participants will not be allowed to take any alcohol-containing food or beverages 
and energy drinks containing taurine or glucuronolactone (such as Red Bull) from 


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24 h prior to screening and from 24 h prior to admission to the clinical unit on 
Day 10 until discharge.
4.3.3
Activity
7. Participants will abstain from any strenuous activity (e.g., weight lifting, aerobics, 
football, endurance training sessions) or unaccustomed physical exercise during 
the whole study (from 48 h prior to screening and from 48 h prior to admission to 
the unit on Day -1 until EOS).
4.3.4
Other
8. Transplantation is not permitted until successful antimalarial treatment will be 
given.
4.4
SCREEN FAILURES
Unscheduled visits may be planned to assess, confirm, and follow-up on out-of-range
clinical laboratory test, vital sign, or ECG values that determine a participant’s eligibility, 
or in case of a positive urine drug screen. The result of the retest must be considered for 
participant eligibility and must be available prior to inoculation (Day 1). Findings made 
during unscheduled visits should be reported in the eSource system.
If a participant does not meet all selection criteria (is a screen failure) but at some point 
in the future is expected to meet the eligibility criteria, the participant may be rescreened 
on 1 occasion only. Participants who are rescreened will undergo the informed consent 
process, be assigned a new participant number, and then restart a new screening phase.


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5. STUDY INTERVENTIONS
5.1
STUDY INTERVENTIONS ADMINISTERED
Manufacturing, packaging, and labelling of PfSPZ-DVI Challenge inoculum will be done 
under the responsibility of the biotechnology company Sanaria (USA) [9].
The clinical unit will be responsible for acquiring the registered antimalarial drugs 
artemether-lumefantrine (Riamet®) and atovaquone-proguanil (Malarone®):
-
Participants will be prescribed with Riamet® according to the pre-defined 
cohort-specific PCR parasitaemia/malaria clinical score thresholds (i.e., 
5000 parasites/mL blood for Cohort 1 and 10000 parasites/mL blood for Cohort 2 
and/or a malaria clinical sFRUHIRU&RKRUWs 1 and 2) to ensure parasite 
clearance prior to the end-of-study evaluation. In addition, participants will also 
be administered with Riamet®:
o
if they experience  inoculum-related SAE, irrespective of severity; or
o
if they experience  Common Terminology Criteria for Adverse Events 
(CTCAE) JUDGH3 (severe) AE deemed related to malaria and not 
self-resolved or relieved with concomitant medications; or
o
if the PI or delegate considers it necessary for participant safety. In this 
situation, the PI or delegate will consult with the independent infectious 
disease/malaria expert (Prof. Jean-Pierre Van geertruyden). However, 
antimalarial medication may be administered prior to consultation if
immediate treatment is deemed necessary for participant safety.
-
If an intolerance or contraindication to Riamet® develops, Malarone® will be 
administered. 
All participants inoculated with PfSPZ-DVI Challenge will commence antimalarial 
therapy no later than Day 24 for both cohorts, regardless if they reach pre-defined 
cohort-specific PCR parasitaemia/malaria clinical score thresholds (i.e., 
5000 parasites/mL blood for Cohort 1 and 10000 parasites/mL blood for Cohort 2 and/or 
DPDODULDFOLQLFDOVFRUHIRU&RKRUWVDQG
All participants must consent to receiving antimalarial therapy. Even in the case of 
withdrawal from the study, all participants administered the PfSPZ-DVI Challenge are to 
receive antimalarial therapy as soon as possible, and to have all appropriate visits and 
assessments as required.
The PfSPZ-DVI Challenge agent consists of a strain of P. falciparum NF54 sporozoites 
used for CHMI/VIS studies that is known to be sensitive to the registered antimalarial 
therapy treatments described above.


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Table 2:
Description of Study Interventions
Intervention Name
PfSPZ-DVI
Challenge
artemether-lumefantrine 
(Riamet®)
atovaquone-proguanil 
(Malarone®); only to be 
used if an intolerance or 
contraindication to 
Riamet® develops
Intervention Type
inoculum
drug
Dose Formulation
cryovial
tablet
Unit Dose 
Strength(s)
15000 or 
50000 aseptic, 
cryopreserved 
P. falciparum 
sporozoites
20 mg artemether and 
120 mg lumefantrine
250 mg atovaquone and 
100 mg proguanil 
hydrochloride
Dosage Level
3200 P. falciparum
sporozoites once
6 doses of 4 tablets over 
a period of 3 days at 
approximately 0, 8, 24, 
36, 48 and 60 h
4 tablets as a single daily 
dose for 3 consecutive 
days
Route of 
Administration
intravenously by 
DVI
oral
Meals in Relation 
to Dosing
Not applicable
see Section 4.3.1
Use
challenge agent
antimalarial medication
Sourcing
provided by 
Sanaria (USA)
provided locally by the clinical unit
Packaging and 
Labeling
dispensed into 
screw-cap vials 
containing 
15000 or 
50000 sporozoites 
in a 20 μL-aliquot
light yellow, round 
tablet with ‘NC’
debossed on one side 
and ‘CG’ on the other
round, biconvex, pink 
film-coated tablets 
engraved 'GX CM3' on 
one side
Any deviation from the treatment regimen defined in the protocol must be documented in 
the eSource system.
5.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
The Investigator (or his/her designee) is responsible for the safe storage of PfSPZ-DVI 
Challenge and all antimalarial drugs assigned to/acquired by the clinical site, in a locked, 
secure storage facility with access limited to those individuals authorized to dispense the 
PfSPZ-DVI Challenge and antimalarial drugs, and maintained within the appropriate 
ranges of temperature. PfSPZ-DVI Challenge and all antimalarial drugs must be stored as 
specified at delivery and in the original packaging. 
Regular temperature logging of the PfSPZ-DVI Challenge and antimalarial drug storage 
room at the clinical site should be performed. In case a deviation in storage conditions 
should occur, the clinical site must not further dispense the affected PfSPZ-DVI
Challenge and antimalarial drugs and notify the Sponsor.


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The Investigator (or his/her designee) is responsible for ensuring that PfSPZ-DVI
Challenge and all antimalarial drugs received at the clinical site are inventoried and 
accounted for throughout the study.
PfSPZ-DVI Challenge and antimalarial 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 PfSPZ-DVI Challenge and drugs supplied to whom and by who. PfSPZ-DVI
Challenge and antimalarial drugs will be supplied only to participants participating in the 
study.
The Sponsor’s designated site monitor will periodically check the supplies of PfSPZ-DVI
Challenge and antimalarial drugs held by the Investigator or pharmacist to ensure 
accountability and appropriate storage conditions of all products used.
Unused products must be available for verification by the site monitor during on-site 
monitoring visits. 
After the last visit of the last participant in the study (LPLV), any unused PfSPZ-DVI 
Challenge will be returned to Sanaria. Any unused antimalarial medication will be
destroyed at the clinical site (via Emergency waste and chemical services [EWACS])
after Sponsor’s approval (in this case a certificate of destruction will be provided and 
filed in the Trial Master File [TMF])
Hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will 
not be retained for drug accountability purposes.
5.2.1
PfSPZ-DVI Challenge
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 
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-DVI Challenge agent.


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The diluent for PfSPZ-DVI 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-DVI Challenge). 
PBS that is manufactured in compliance with Good Manufacturing Practice (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-DVI Challenge agent is dispensed into screw-cap vials containing 15000 or 
50000 sporozoites in a 20 μL aliquot. The PfSPZ-DVI Challenge is stored in liquid 
nitrogen vapour phase at -140°C to -196°C until it is shipped to the clinical 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.
Transfer of PfSPZ-DVI 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-DVI Challenge will be documented on a tracking log by study staff.
Immediately prior to use, the PfSPZ-DVI Challenge in cryovials will be thawed 
individually by partial submersion of the vials for 30 s in a 37°C ± 1°C water bath. 
Designated, trained study staff will then prepare, dilute (if necessary) and dispense the 
PfSPZ-DVI 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-DVI Challenge (3200 P. falciparum sporozoites per participant) will be 
administered intravenously by DVI. The study staff administering the PfSPZ-DVI
Challenge will wear gloves and eye protection. Advanced life support drugs and 
resuscitation equipment will be immediately available in the event of any participants
experiencing an anaphylactic reaction to the challenge.
5.2.2
Registered Antimalarial Therapy
Riamet® and Malarone® must be stored at ambient conditions (15-30°C or 59-86°F),
should not be exposed to freezing temperatures, and should be protected from light
during storage at the clinical site.
Procedures for handling and storage are detailed on the study-specific labels [22,12].


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5.3
RANDOMISATION AND BLINDING
Participants are not randomised. As participants are confirmed to be eligible for the 
study, they will be assigned a single unique identifier across the study and will be 
enrolled sequentially in 1 of the 2 cohorts.
All participants will be inoculated with PfSPZ-DVI Challenge and receive antimalarial 
therapy. PfSPZ-DVI Challenge will be packaged and labelled by Sanaria in line with 
local labelling regulations. The antimalarial drugs (Riamet® and Malarone®) will be 
labelled by the clinical unit pharmacy with an appropriate study label in line with local 
labelling regulations. The pharmacist or appropriate qualified member of the study staff, 
assigned by the PI, will prepare the PfSPZ-DVI Challenge and antimalarial drugs 
identifying the products with the correct participant unique identifier according to the 
applicable procedures.
As this is an open-label study, blinding is not applicable.
5.4
DOSE MODIFICATION
No dose modification is allowed.
5.5
TREATMENT COMPLIANCE
To ensure treatment compliance, PfSPZ-DVI Challenge and Riamet®/Malarone® will be 
administered/intakes will be supervised by the Investigator or his/her designee.
Any deviation from the treatment regimen defined in the protocol must be documented in 
the eSource system.


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6. PRIOR AND CONCOMITANT THERAPY
All therapies (prescriptions and over-the-counter medications, including herbal 
preparations/treatments) other than the antimalarial medication administered from the 
time of informed consent until the last study visit must be recorded in the eSource system 
(name of the drug, dosage, route and dates of administration).
Medications taken during the 28 days prior to PfSPZ-DVI Challenge will be recorded in 
the eSource system as previous medications. Medications taken after this time will be 
recorded as concomitant medications.
Female participants of childbearing potential (excluding females with female partners) 
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
Participants will abstain from using any medications (prescription or over-the-counter) or 
herbal remedies from 7 days or 5 half-lives (whichever is longer) prior to PfSPZ-DVI 
Challenge, as described in the exclusion criteria of this protocol (see Section 4.2). If 
necessary, the incidental use of NSAIDs and paracetamol (2 g/day, 10 g/week), and the 
use of nutritional supplements may be acceptable at the Investigator’s discretion.
Except for the antimalarial medication and medication considered essential to treat AEs, 
all medications (prescription and non-prescription), herbal remedies and nutritional 
supplements should be avoided within 7 days or 5 half-lives (whichever is longer) prior 
to the PfSPZ-DVI Challenge until after the EOS visit on Day 28. Incidental and limited 
use of medications not believed to affect participant 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 transient asymptomatic ALT and 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. In the case paracetamol is used, 
the recommended dose should not exceed 2 g/day.
6.2
PROHIBITED CONCOMITANT THERAPIES
The following medications are not allowed during the study and should be washed-out 
within 5 half-lives of PfSPZ-DVI Challenge:
-
Drugs with known antimalarial activity (trimethoprim-sulfamethoxazole, 
tetracycline, doxycycline, erythromycin, clarithromycin, azithromycin, 
clindamycin, rifampicin, or newer quinolones, benzodiazepines, flunarizine, 
fluoxetine, methotrexate, chloroquine and hydroxychloroquine);
-
Any drug susceptible to interaction with breast cancer resistance proteins (BCRP)
(cyclosporin, 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 (except for urinalysis assessments, morning void allowed).
The following time-related windows for parasitaemia assessments will be acceptable 
based on logistical and operational considerations:
-
± 60 min on Days 7, 8 and 9;
-
± 10 min during confinement;
-
± 1 day at the EOS visit.
The following time-related windows for blood pressure, pulse rate, ECG, haematology, 
blood chemistry and urinalysis assessments will be acceptable based on logistical and 
operational considerations:
-
pre-inoculation observations within 3 h prior to inoculation;
-
a 5% deviation from theoretical post inoculation times will be allowed for all 
other post inoculation assessments.
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 case-by-case 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 Visit
Screening for eligible and consenting participants will be performed within 
approximately 4 weeks prior to first confinement.
Participants 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.


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At screening, participants will be asked to attend the clinical unit to have assessments 
performed as indicated in the Time and Events Schedule.
All results from the screening procedure needed to evaluate eligibility, including the 
clinical laboratory results, must be available before PfSPZ-DVI Challenge on Day 1. Any 
abnormal assessment at the screening visit will be assessed according to its clinical 
relevance, and if found relevant, the participant will not be included in the study (see also 
Section 4.4).
Up until Day -2, testing for SARS-CoV-2 using real-time reverse transcription PCR 
(rRT-PCR) on nasopharyngeal swabs will also be performed for participants who 
completed the rest of the screening procedure and are still eligible to be enrolled in the 
study. The rRT-PCR test will be performed by ZNA Middelheim or by SGS Clinical 
Pharmacology Unit, depending on the availability of appropriate equipment.
Unscheduled visits may be planned to assess, confirm and follow-up on out-of-range 
clinical laboratory test, vital sign or ECG values that determine a participant’s eligibility, 
or in case of a positive urine drug screen. The result of the retest will be considered for 
participant eligibility. Findings made during unscheduled visits should be reported in the 
eSource system.
Pre-treatment Day -1
Participants will be admitted to the clinical unit in the morning of Day -1 (the day before 
PfSPZ-DVI Challenge) and participants will remain at the clinical unit until 2 h post 
inoculation on Day 1.
Eligibility of the participants will be confirmed and assessments will be performed as 
indicated in the Time and Events Schedule. All assessments must be completed and 
safety assessment outcomes must be available before PfSPZ-DVI Challenge on Day 1.
7.1.2
Treatment Period
Day 1
On Day 1, assessments begin as of 3 h before PfSPZ-DVI Challenge (except for 
urinalysis assessments, morning void allowed) and will be performed as indicated in the 
Time and Events Schedule. All assessments must be completed and safety assessment 
outcomes must be available before inoculation with approximately 3200 P. falciparum
sporozoites (NF54 strain) by DVI. After assessments are performed as indicated in the 
Time and Events Schedule, participants will be discharged 2 h post inoculation.
Day 2 Until Day 6
Participants will be monitored daily via phone call from Day 2 until Day 6 to solicit any 
AEs.
Day 7 Until Day 9
Participants will come to the clinical unit daily from Day 7 until Day 9 and the presence 
of parasites will be assessed once daily by qPCR.
Before confinement to the study site (on Day 10), participants will be tested again for 
SARS-CoV-2 using rRT-PCR on nasopharyngeal swabs. If a participant tests positive for 
SARS-CoV-2, he or she will be withdrawn from the study and will be administered 


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registered antimalarial therapy (i.e., Riamet®) immediately. The SARS-CoV-2 infection 
will be managed further according to national laws.
Day 10 Until Day of Pre-Defined Cohort-Specific Thresholds (Including Day of First 
3&53DUDVLWHVP/)
Participants will be confined to the clinical unit from Day 10 in the morning and the 
presence of parasites will be assessed twice daily by qPCR until Day of first PCR 
 parasites/mL blood IRU&RKRUWRUXQWLO'D\RIILUVW3&5 parasites/mL 
blood for Cohort 2.
Assessments will be performed as indicated in the Time and Events Schedule.
Day of Pre-Defined Cohort-Specific Thresholds Until K$IWHU,QLWLDWLQJ
Antimalarial Therapy
Participants will be administered registered antimalarial therapy, i.e., Riamet®, as soon as 
possible when the pre-defined cohort-specific PCR parasitaemia/malaria clinical score 
thresholds (i.e., 5000 parasites/mL blood for Cohort 1 and 10000 parasites/mL blood for 
&RKRUWDQGRUDPDODULDFOLQLFDOVFRUHIRU&RKRUWV 1 and 2) are reached or at the 
Investigator’s discretion (see Section 5.1).
All participants inoculated with PfSPZ-DVI Challenge will commence antimalarial 
therapy no later than Day 24 for both cohorts, regardless if they reach pre-defined 
cohort-specific PCR parasitaemia/malaria clinical score thresholds (i.e., 
5000 parasites/mL blood for Cohort 1 and 10000 parasites/mL blood for Cohort 2 and/or 
DPDODULDFOLQLFDOVFRUHIRU&RKRUWVDQG
Antimalarial therapy will be further administered and monitored. qPCR assessments of 
parasitaemia will be carried out at multiple time points (2, 6, 8, 12, 16, 24, 36, 48 and 
72 h) following initiation of Riamet®.
Assessments will be performed as indicated in the Time and Events Schedule.
'D\RI3DUDVLWH&OHDUDQFH$QGK$IWHU,QLWLDWLQJ$QWLPDODULDO7KHUDS\
Upon parasite clearance and at least 72 h after initiating antimalarial therapy (estimated 
to occur on or before Day 19 and on or before Day 22 for Cohort 1 and Cohort 2,
respectively), and if clinically well, participants will be discharged from the clinical unit.
Participants who start antimalarial therapy on Day 24 will only be discharged from 
confinement at the end of the EOS visit on Day 28.
Assessments will be performed as indicated in the Time and Events Schedule.
7.1.3
Follow-up Period
After discharge from the clinical unit, or after confinement until the EOS on Day 28 in 
case antimalarial therapy was initiated on Day 24, all participants will be followed up for 
safety assessments, clinical evaluation and malaria qPCR in the clinical unit at the EOS 
visit on Day 28.
All participants will be assessed for parasitaemia and will be asked non-leading questions 
to determine the occurrence of any AEs at the EOS visit on Day 28. In order to provide 
some flexibility for the participants regarding the site visit and to maintain the integrity 


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of the study design, a time window of ±1 day is permitted, in case of time conflict or 
unforeseen circumstances. 
Assessments will be performed as indicated in the Time and Events Schedule.
7.1.4
Unscheduled Visits
Unscheduled visits can be planned for instance:
-
to obtain additional information to ensure safety to the participant. 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 participant’s eligibility, or in case of a 
positive drug screen. The result of the retest will be considered for participant
eligibility.
Findings made during unscheduled visits should be reported in the eSource system.
7.2
PHARMACODYNAMIC ASSESSMENTS
For an overview of pharmacodynamic endpoints, see Section 2.
7.2.1
Parasitaemia
A blood sample will be collected via direct venepuncture from each participant at time 
points where parasitological assessments are scheduled (Time and Events Schedule). The 
assessment of malaria parasitology by qPCR will be as follows: varATS multigenic 
family targeted qPCR assay of parasite load will be performed in accordance with the 
centre of excellence for tropical medicine (ITM) standard operating procedure and the 
Laboratory Manual. Given the high sensitivity of qPCR, this method will be used to 
confirm parasite clearance after definitive antimalarial therapy for all participants. The 
results of the PCR at the ITM will be available in approximately 6 h from arrival of 
samples at the ITM. A participant will be considered cured following completion of the 
course of antimalarial therapy and after qPCR indicates 0 parasites per mL blood.
7.3
SAFETY ASSESSMENTS
The safety assessment in this study will be based on AEs, the malaria clinical score, 
clinical laboratory tests, vital signs, ECG, physical examination and Beck Depression 
Inventory (screening only) as described in the following sections.
7.3.1
Adverse Events
Adverse events will be monitored continuously from informed consent until the last 
study-related activity. At regular intervals during the study, participants 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.
For detailed definitions and reporting procedures of AEs, see Section 10.
Close monitoring of expected signs and symptoms associated with malaria infection 
(listed in Attachment 1) form part of the safety evaluation of the study and will be used 
as part of the decision criteria to administer registered antimalarial therapy (see 


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Section 5.1 and Section 7.3.2). These events will be classified as AEs, and may also be 
further sub-classified as inoculum-related AEs:
An inoculum-related AE is a sign or symptom associated with malaria infection, i.e., 
confirmed by a protocol-defined PCR positivity (defined for the purpose of this study as 
a qPCR outcome  parasites per mL blood) at
-
the onset of the event; or
-
if the event started within 1 day of parasite clearance (defined as a qPCR value of 
0 parasites per mL blood after initiating antimalarial therapy) or 
laboratory-defined PCR positivity (a qPCR outcome of 50-249 parasites per mL 
blood).
If the presence of P. falciparum malaria is confirmed (see above), then these AEs will be 
further sub-classified as inoculum-related AEs, following the guidelines on AE reporting, 
i.e., followed-up until resolution with the same causality assessment (see Section 10), and 
reported as such in the final clinical study report.
If the PCR results for P. falciparum are between 0 and <250 parasites per mL blood at 
the time of the onset of the event and the day before, usual AE/SAE reporting procedures 
and criteria will apply (see Section 10), but the event will not be classified as an 
inoculum-related AE.
Final classification of signs and symptoms as AE and inoculum-related AE, or as AE 
only, will occur after PCR results are available.
7.3.2
Malaria Clinical Score
The malaria clinical score, which assesses malaria signs and symptoms (see 
Attachment 1) at the time points indicated in the Time and Events Schedule, will be part 
of the close monitoring for known/identified risks related to PfSPZ-DVI 
Challenge/malaria. The malaria clinical score has been widely used in the conduct of 
IBSM CHMI/VIS studies in Australia and also implemented in the recently conducted 
PfSPZ-DVI Chemoprotection Challenge study with P218 (MMV_P218_17_01 study 
[EudraCT number: 2018-003004-39]) at the SGS Clinical Pharmacology Unit in 
Antwerp, Belgium [2]. This quantitative tool will be used as part of the decision criteria 
to administer registered antimalarial therapy along with the level of parasitaemia (see 
Section 5.1).
The following 14 signs/symptoms frequently associated with malaria will be graded 
using a 4-point scale (absent: 0; mild: 1; moderate: 2; severe: 3) and summed to generate 
a total malaria clinical score (maximum score possible is 42): headache, 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 and hypotension. To determine severity of the 
14 signs/symptoms we use the CTCAE grading scale grade 1 - 5. Mild (1) equates to 
CTCAE grade 1, Moderate (2) equates to CTCAE grade 2 and Severe (3) equates to 
CTCAE grade 3 or above. Individual scores for each symptom as well as the total score 
will be recorded.
For the grading of fever, the vital sign parameter body temperature (sublingual) will be 
assessed (see Section 7.3.4).


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7.3.3
Clinical Laboratory Tests
Blood samples will be collected by venepuncture 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 viral serology testing (hepatitis A IgM 
antibody, HbsAg, anti-HCV antibody, hepatitis D antibody [only in subjects positive for 
HbsAg], hepatitis E IgM antibody, CMV IgM antibody, EBV IgM antibody and HIV) on 
the sample from screening. In all female participantVDOVRVHUXPȕ-HCG assessments at 
screening and at the EOS visit and a XULQHȕ-HCG assessment on Day-1 will be 
performed. FSH will be measured at screening in all women.
All blood samples for safety assessments should be taken in a fasted state (after overnight 
fast for at least 8 h for unbiased glucose determination), except for the ones taken during 
antimalarial therapy for troponin T measurements, and except for the one on Day of first 
PCR SDUDVLWHVP/LQ&RKRUWRUSDUDVLWHVP/LQ&RKRUWDQGSULRUWR
initiating antimalarial therapy, where a non-fasted state is allowed.
Standard laboratory tests will be performed by ZNA Middelheim.
The following biochemistry and haematology tests will be performed on the safety blood 
samples: 
-
Liver biochemistry: albumin, AST, ALT, alkaline phosphatase (ALP), gamma 
glutamylaminotransferase (GGT), total and direct bilirubin and total serum 
proteins;
-
Biochemistry other than liver: sodium, potassium, chloride, bicarbonate, urate, 
inorganic phosphate, creatinine, estimated glomerular filtration rate (eGFR), 
glucose, lactate dehydrogenase (LDH), blood urea nitrogen (BUN) and creatine 
phosphokinase (CPK);
-
High sensitive troponin T and;
-
C-reactive protein (CRP);
-
Haematology: haemoglobin, haematocrit, 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) and activated partial thromboplastin time 
(aPTT) (at screening and on Day -1 only), and international normalized ratio 
(INR).
A midstream urine sample will be collected for urinalysis by dipstick for glucose, 
protein, nitrite, pH and occult blood at the time points for biochemistry other than liver 
indicated in the Time and Events Schedule. 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 


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eSource system. Laboratory values outside the normal range will be flagged and their 
clinical relevance will be assessed by the Investigator.
7.3.4
Vital Signs
Vital sign parameters will be assessed after at least 10 min 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)
and pulse rate. Body temperature (sublingual) will also be assessed, and this whenever 
the malaria clinical score will be evaluated (see Section 7.3.2). Orthostatic changes to BP 
and pulse rate will also be assessed at screening: participants will be requested to stand 
after completion of the supine measurements and blood pressure and pulse rate will be 
recorded after at least 2 min 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.
7.3.5
Electrocardiogram
Twelve-lead ECG recordings will be recorded in triplicate after at least 10 min in supine 
position at the time points indicated in the Time and Events Schedule.
Paper speed will be 25 mm/s, so that the different ECG intervals can be measured 
manually.
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.
7.3.6
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, 
participants must be weighed lightly clothed.
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.
Full physical examination will be conducted at screening, on Day -1, within ±24 h after 
ILUVW3&5SDUDVLWHVP/EORRGDQGDWWKHEOS visit on Day 28. Targeted, 
symptom-driven physical examination will be performed in case malaria clinical 
score >6 on Day 10 (upon confinement to the clinical unit), within 24 h after first PCR 
&RKRUWRU&RKRUW parasites/mL blood and at pre-discharge from 
clinical unit; and will be focused on changes since the previous examination, but will 


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always include at least: chest/respiratory, general appearance, heart/cardiovascular, 
abdomen, neurological and skin/mucous membranes examination.
7.3.7
Beck Depression Inventory
The Beck Depression Inventory is performed at screening only (see Attachment 2).
The questionnaire is scored by the participant. The inventory completed by the 
participant will be reviewed/checked for completeness and the total score calculated by 
the study personnel.
7.4
PARASITE TRANSCRIPTOMICS
Different environmental conditions that occur during a human infection (such as the 
presence of drugs) can select for parasites with different expression patterns [16,17]. We 
aim to evaluate the effect of in-host factors on parasite transcriptional/epigenetic 
responses during experimental infections. 
To this aim, blood samples will be collected via direct venepuncture at the time points 
indicated in the Time and Events Schedule. Sample aliquots will be stored in Trizol for 
RNA preservation and cryopreserved for parasite culture in case higher parasite densities 
are needed to increase starting material for transcriptomic analysis of parasite isolates.
Protocols for transcriptomic analysis of parasite isolates have been validated and are 
currently in use at the Malariology Unit at the ITM.
7.5
TREATMENT OF OVERDOSE
In this study, all dosing will be supervised by study personnel and consequently the risk 
of overdose will be minimal.
7.6
TOTAL VOLUME OF BLOOD SAMPLING
The total volume of blood drawn per the Time and Events Schedule from each 
participant will not exceed the maximum allowable volume of approximately 460 mL.
7.7
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. PARTICIPANT WITHDRAWAL FROM THE STUDY
8.1
WITHDRAWAL OF PARTICIPANTS FROM STUDY
Participants may be withdrawn from the study following inoculation with PfSPZ-DVI 
Challenge in the event of:
-
a severe AE or a SAE considered related to the PfSPZ-DVI Challenge.
Participants may be withdrawn from the study following inoculation with PfSPZ-DVI 
Challenge and administration of Riamet® in the event of:
-
a severe AE or a SAE considered related to either Riamet® or the PfSPZ-DVI 
Challenge.
Participants must be withdrawn from the study in the event of:
-
withdrawal of consent;
-
safety reasons, it being in the best interest of the participant that he/she be 
withdrawn, in the Investigator’s opinion or in the opinion of the SRT (see 
Section 3.4);
-
a positive pregnancy test (the participant or, in case of a male participant, his 
female partner), or if the participant/partner is non-compliant with the 
contraception requirements (see Section 4.1);
-
a positive SARS-CoV-2 test (see Section 7.1.2);
-
development of a medical condition that requires concomitant treatment with a 
prohibited therapy (see Section 6.2);
-
failure of the participant to comply with the protocol requirements or to cooperate 
with the Investigator resulting in a significant risk to the participant’s safety.
In the event a participant has to discontinue Riamet®, 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 h; 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 participant will remain under the 
supervision of the Investigator until satisfactory health has returned.
All participants must consent to receiving antimalarial therapy if inoculated with the 
PfSPZ-DVI Challenge agent, i.e., the registered 3-day Riamet® regimen approved for 
treatment of uncomplicated malaria. Even in the case of withdrawal from the study, all 
participants administered the PfSPZ-DVI Challenge are to receive antimalarial therapy as 
soon as possible (see Section 5.1), and to have all appropriate visits and assessments as 
required (see Time and Events Schedule). Participants will be followed up for safety 
assessments, clinical evaluation and malaria qPCR in the clinical unit at the EOS visit on 
Day 28. Participants who fail to return for visits will be traced as described in 
Section 8.2.
Participants who have to discontinue Riamet® prior to completion of the scheduled study 
procedures for safety reasons/due to intolerance must complete antimalarial therapy with 
Malarone® and should be invited to complete the assessments as much as possible: as 


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long as the participant consents, all relevant assessments of the day on which the 
participant discontinued should be completed, at least those related to safety, and the 
participant should come for a safety follow-up visit 4 weeks after the last administration 
of antimalarial drug. In the event of discontinuation due to an AE, the appropriate 
follow-up will be done.
Participants have the right to withdraw from the study at any time for any reason, 
including personal reasons. A participant can withdraw without giving a reason. This will 
not affect his/her future care. The Investigator should however try to find out why a 
participant withdraws from the study and document the reason for withdrawal in the 
source documents and in the eSource system.
If the participant withdraws consent for disclosure of future information, the Sponsor 
may retain and continue to use any data collected before such a withdrawal of consent.
Participants 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 
PfSPZ-DVI Challenge and antimalarial drugs assigned to a participant who withdraws 
must not be assigned to another participant.
8.2
LOST TO FOLLOW-UP
Before a participant is considered lost to follow-up, every reasonable effort must be made 
by the study site personnel to contact the participant, if only to determine the reason for 
discontinuation. The measures taken to follow up must be documented.
The following measures will be taken to assure traceability of the participants:
-
Following daily contact from Day 2 to 9 and scheduled, in-house confinement 
within the clinical unit, participants will be followed up for safety assessments, 
clinical evaluation and malaria qPCR in the clinical unit at the EOS visit on 
Day 28.
-
All participants will commit to remaining contactable 24/7 throughout the study 
and this will be recorded on the Informed Consent Form (ICF).
-
Participants 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 participant not be contactable by the unit, all alternative methods 
possible (e.g., sending someone to home address of participant) will be used to 
locate and communicate with the participant.
-
Should a participant 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.
Should the participant remain unreachable, he/she will be considered to have 
discontinued the study.


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9. STATISTICAL METHODS
9.1
STATISTICAL ANALYSIS
All statistical analysis will be performed by SGS Life Sciences, under the supervision 
and responsibility of the Sponsor, using SAS® (SAS Institute Inc., Cary, NC, USA; 
version 9.4 or higher) software for statistical computations. 
All statistical methods shall be detailed in a Statistical Analysis Plan (SAP) that will be 
finalised before database lock.
The final analysis will be performed once all participants have completed the follow-up
visit or have discontinued earlier. 
Data from all participants enrolled and inoculated with PfSPZ-DVI Challenge will be 
included in the data analysis. The following analysis populations will be defined:
-
Inoculation Set: all participants who were inoculated with PfSPZ-DVI Challenge;
-
PD Analysis Set: all inoculated participants with at least one available PD data 
who received all Riamet® doses and who experienced no protocol deviations with 
relevant impact on PD data;
-
Safety Analysis Set: all inoculated participants who received any treatment.
Unless specified otherwise, the Inoculation Set will be used for analysis of 
demographics, the PD analysis set will be used for pharmacodynamic statistical analysis 
and the Safety Analysis Set will be used for safety/tolerability analysis.
9.1.1
Initial Characteristics Data of the Participant Sample
For all participants who receive PfSPZ-DVI Challenge, descriptive statistics will be 
provided for demographic (e.g., age, height, weight, BMI, race, gender) and other initial 
participant characteristics (alcohol and drug screening tests, pregnancy test, orthostatic 
changes to blood pressure and pulse rate, serology, medical and social history, 
concomitant diseases, Beck Depression Inventory). Standard descriptive statistics for 
continuous variables are the number of participants (N), mean, standard deviation (SD), 
median, minimum and maximum values. The standard descriptive statistics for 
categorical variables are the number of participants in the category and the proportion 
expressed as a percentage.
Prior and concomitant medications will be coded using the WHO_DRUG Dictionary.


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9.1.2
Pharmacodynamic Data
Parasitaemia
Primary endpoints:
To characterise key stages in the parasite growth:
-
first PCR positivity;
-
threshold of 5000 parasites/mL for Cohort 1 and threshold of 10000 parasites/mL 
for Cohort 2; and
-
parasitaemia levels at drug administration.
This will be done by calculating:
-
Descriptive statistics (geometric mean, SD, 95% CI, range) of time to first PCR 
positivity. In the absence of positive PCR, the duration will be set to a maximum 
of 28 days;
-
Descriptive statistics (N, geometric mean, SD, 95% CI, range) of parasitaemia at 
first PCR positivity;
-
Descriptive statistics (geometric mean, SD, 95% CI, range) of time to 
SDUDVLWDHPLDRISDUDVLWHVSHUP/EORRG&RKRUWs 1 and 2);
-
Descriptive statistics (geometric mean, SD, 95% CI, range) of parasitaemia at the 
time parasitaHPLDSDUDVLWHVSHUP/EORRG&RKRUWs 1 and 2);
-
Descriptive statistics (geometric mean, SD, 95% CI, range) of time to 
SDUDVLWDHPLDRISDUDVLWHVSHUP/EORRG&RKRUW
-
Descriptive statistics (geometric mean, SD, 95% CI, range) of parasitaemia at the 
time parasitaHPLDSDUDVLWHVSHUP/EORRG&RKRUW
-
Descriptive statistics per cohort (geometric mean, SD, 95% CI, range) of time to 
first dose of treatment with Riamet® (Cohorts 1 and 2); and
-
Descriptive statistics per cohort (geometric mean, SD, 95% CI, range) of 
parasitaemia at first dose of treatment with Riamet® (Cohorts 1 and 2).
The number and proportion of participants with presence of positive PCR and 
SDUDVLWDHPLDRIRUSDUDVLWHVSHUP/EORRGEHWZHHQLQRFXODWLRQZLWK
PfSPZ-DVI Challenge and Day 28 will be summarised per cohort. Corresponding 
two-sided 90% Exact Clopper-Pearson confidence limits will be presented as well.
Secondary endpoints:
To characterise the blood-stage parasite profile, a model will be fitted to the measured 
parasitaemia data prior to Riamet® administration to be able to predict the growth of 
parasites as a function of time. This model may be a log-linear model or, if the 
parasitaemia profile shows a cyclic behaviour due to synchronicity of the parasites and 
their sequestration during the late stages of their lifecycle, it may include a sinus 
function. The latter will allow the estimation of the period of the observed waves in 


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addition to the parasite growth. The following parameters will be calculated from the 
individual fits of the data:
-
Descriptive statistics per cohort and overall (geometric mean, SD, 95% CI, range) 
of parasite growth rate expressed as the PMR48;
-
If cycles are observed and if their estimated period is not 48 h, descriptive 
statistics per cohort and overall (geometric mean, SD, 95% CI, range) of parasite 
growth rate expressed as the PMRLC; and
-
Descriptive statistics (geometric mean, SD, 95% CI, range) of predicted time to 
UHDFKSDUDVLWDHPLDWKUHVKROGRIILUVWSRVLWLYH3&5SDUDVLWHVSHUP/EORRG
SDUDVLWHVSHUP/EORRGIRUCohorts 1 and 2.
To characterise the blood-stage parasite clearance profile of Riamet® in malaria infection 
in naïve healthy participants after PfSPZ-DVI Challenge; by calculating:
-
Descriptive statistics per cohort and overall (geometric mean, SD, 95% CI, range) 
of time to parasite clearance, i.e., time between drug administration and first PCR 
below the limit of quantification;
-
Descriptive statistics per cohort and overall (geometric mean, SD, 95% CI, range) 
of log10PRR48;
-
Descriptive statistics per cohort and overall (geometric mean, SD, 95% CI, range) 
of log10PRR48,max; and
-
Descriptive statistics per cohort and overall (geometric mean, SD, 95% CI range) 
of PC½.
The parasite reduction ratios (PRRs) and the clearance half-life will be estimated from a 
log-linear model that will be fitted to the parasitaemia data observed from the 
administration of the treatment onwards. The PRR48, PRR48,max and PC½ will be 
calculated from the individual parameters and summarised by cohort.
Exploratory endpoints:
To characterise the individual variability of blood-stage parasite profile: 
-
Obtain the inter-individual variability of the parasite growth rate; and
-
5th, 50th and 95th percentiles of predicted time to reach parasitaemia threshold of 
ILUVWSRVLWLYH3&5SDUDVLWHVSHUP/EORRGSDUDVLWHVSHUP/EORRG
including their 95% CI.
Both these estimates will be based on the mixed model on parasite growth data described 
above.
9.1.3
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).


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The reported AEs will be allocated to phases based on their start date. All AEs will be 
listed. All AEs with onset after PfSPZ-DVI Challenge will be summarised by cohort.
Summaries will be made per MedDRA primary system organ class, MedDRA preferred 
term, severity, with the number and percentage of participants and the number of events. 
Similar summaries will be prepared for AEs considered to be related to Riamet® and AEs 
considered to be related to the PfSPZ-DVI Challenge, for serious AEs and AEs of special 
interest.
Special attention will be paid to those participants who died, discontinued the 
investigational products 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.
Malaria Clinical Score 
For the malaria clinical score that will be administered by the PI or his/her trained 
delegate, actual values and changes from baseline will be evaluated by means of 
descriptive statistics. Additionally, expected signs and symptoms (see Attachment 1) will 
be summarised by score.
Clinical Laboratory Tests
Each continuous biochemistry and haematology laboratory test will be evaluated by 
means of descriptive statistics on the actual values, at each assessment time point and by 
cohort. Changes from baseline will also be summarised using descriptive statistics by 
assessment time point and by cohort.
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 participants with clinical laboratory test 
abnormalities will be summarised by cohort.
The number and percentage of participants with liver enzyme elevations after inoculation 
with the PfSPZ-DVI Challenge 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 participants with any clinical laboratory test result outside the reference 
ranges will be provided.
Vital Signs
Vital signs parameters will be assessed after at least 10 min in supine position at the time 
points indicated in the Time and Events Schedule. Pulse rate, SBP and DBP will be 
evaluated by means of descriptive statistics (actual values and changes from baseline). 
The percentage of participants with vital signs abnormalities will be summarised by 
cohort in a cross-tabulation of post-baseline versus baseline abnormalities to the normal 
ranges (as defined in Attachment 3).


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Electrocardiogram
Twelve-lead ECG recordings will be performed in triplicate after participants remained 
in a supine position for at least 10 min.
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 cohort.
The percentage of participants with ECG abnormalities will be summarised by cohort 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.
Physical Examination
Abnormal findings in physical examination will be listed.
9.2
DETERMINATION OF SAMPLE SIZE
Up to 16 participants will be enrolled in 2 cohorts of 8 participants per cohort. In 
agreement with the Sponsor, additional participants may be recruited in each cohort, to 
replace discontinuations for non-safety reasons and achieve the required cohort size.
This is an exploratory study focusing on the methodology of malaria inoculation in 
healthy participants, thus no formal sample size calculation is performed.


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10.
ADVERSE EVENT REPORTING
10.1
DEFINITIONS
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant 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 participant 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 
hospitalisation:
Hospitalisation refers to an overnight admission into hospital for the purpose of 
investigating and/or treating the AE. Hospitalisation 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 
participant’s general condition, is not an SAE; 
-
results in persistent or significant disability/incapacity, i.e., causing substantial 
disruption of the participant’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 hospitalisation but may jeopardise the participant’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 hospitalisation or 
development of drug dependency or drug abuse.
-
Constitutes a possible Hy’s Law case (defined as a participant with any value of 
ALT or AST greater than or equal to 3x the Upper Limit of Normal (ULN)


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together with an increase in bilirubin to a value greater than 2xULN [>35% 
direct] and NOT associated with an ALP value greater than 2xULN).
Adverse Events of Special Interest (AESIs)
An AESI (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
o
Total bilirubin level (TBL) >1.5x ULN OR
o
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 count above the ULN).
Cardiac
-
Chest pain
-
High sensitive troponin T 12 ng/L;
-
QTcB or QTcF at any time >480 ms;
-
Bundle branch block (except right bundle branch block that was present prior to 
Riamet® 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. 


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Haematological
-
Haemoglobin drop >2 g/dL and under lower limit of normal from baseline prior 
to inoculation; 
-
Absolute neutrophil count <1000/μL;
-
Platelet count <100000/mm3.
Dermatological:*
-
Any suspected cutaneous AE, e.g., rash
* if one of these cutaneous reactions is observed and when feasible, pictures of the 
lesions should be obtained.
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 an unapproved IMP or 
SmPC or approved Package Insert for an authorized product).
For this protocol, the reference documents for the assessment of expectedness for 
PfSPZ-DVI Challenge is the Investigator’s Brochure [9]. Expected reactions to the 
antimalarial therapies are described in the product’s prescribing information [22,12]:
-
PfSPZ-DVI Challenge can be associated with itching, pain and swelling at the site 
of inoculation. This usually resolves within 24-48 hours.
-
Riamet® (artemether and lumefantrine) may be associated with the following 
AEs; these may occur with a varying periodicity:


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Frequency of Undesirable Effects of Riamet®
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® (antimalarial therapy if an intolerance or contraindication to Riamet®
develops: atovaquone and proguanil hydrochloride) may be associated with the 
following AEs; 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 


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An Inoculum-Related AE is a sign or symptom associated with malaria infection, i.e., 
confirmed by a protocol-defined PCR positivity (defined for the purpose of this study as 
DT3&5RXWFRPH parasites per mL blood) at
-
the onset of the event; or
-
if the event started within 1 day of parasite clearance (defined as a qPCR value of 
0 parasites per mL blood after initiating antimalarial therapy) or 
laboratory-defined PCR positivity (a qPCR outcome of 50-249 parasites per mL 
blood).
Close monitoring of expected signs and symptoms associated with malaria infection 
(listed in Attachment 1) form part of the safety evaluation of the study and will be used 
as part of the decision criteria to administer registered antimalarial therapy. These events 
will be classified as AEs, and may also be further sub-classified as inoculum-related AEs 
(see Section 5.1, Section 7.3.1, Section 7.3.2 and Section 9.1.3).
An Antimalarial Therapy-Related AE is a sign or symptom associated with the 
antimalarial drugs. Expected reactions to the antimalarial drugs are described in the 
product’s prescribing information [22,12].
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 5.0:
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; hospitalisation or 
prolongation of hospitalisation 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 PfSPZ-DVI Challenge
agent and the antimalarial treatments (separately) and decide whether, in his or her 


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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 PfSPZ-DVI Challenge agent and the antimalarial 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 
participant’s source document and eSource system.
The following may guide this assessment:
-
Related – the temporal relationship between the event and the administration of 
the PfSPZ-DVI Challenge agent and/or antimalarial treatment is compelling 
and/or follows a known or suspected response pattern to that product, and the 
event cannot be explained by the participant’s medical condition, other therapies 
or accident;
-
Not related – the event can be readily explained by other factors such as the 
participant’s underlying medical condition, concomitant therapy or accident and 
no plausible temporal or biologic relationship exists between the PfSPZ-DVI 
Challenge agent and/or antimalarial treatment 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 AE is related to the study participation of the participant (study procedures etc.).
10.4
ACTION TAKEN REGARDING THE INVESTIGATIONAL PRODUCTS
The action taken towards the investigational products 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.


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10.6
RECORDING OF ADVERSE EVENTS
All (S)AEs occurring during the clinical investigation (i.e., monitored continuously from 
informed consent until the last study-related activity at the EOS on Day 28) 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 investigational products 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.
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 stabilisation or until final database lock. If necessary, in order to obtain 
additional information to ensure safety to the participant, 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 and AESIs, independent of the circumstances or suspected cause, must be 
reported on a Serious Adverse Event Form by the investigator to PrimeVigilance Ltd.
within 24 h 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 participants 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 participant’s subsequent course must be 
submitted to PrimeVigilance Ltd. until the event has subsided or, in case of permanent 
impairment, until the condition stabilises.
10.8
PREGNANCY
All initial reports of pregnancy in participants or in partners of male participants must be 
reported by the Investigator to PrimeVigilance Ltd. within 24 h of his/her knowledge of 
the event using a Pregnancy Form. Any participant who becomes pregnant during the 
study must be promptly withdrawn from the study (cfr. Section 8).


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The Investigator will contact the participant at the expected time of delivery for follow-
up. Abnormal pregnancy outcomes (e.g., spontaneous 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 
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 risk-benefit analysis and is likely to have an impact on the 
participants 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 participants 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, participants 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 
participants 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 Harmonization 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 participants. Compliance with this standard provides public assurance that the 
rights, safety, and well-being of study participants 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 participants. 
Special attention should be paid to studies that may include vulnerable participants.
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 ICF (and any updates or any other written materials to be 
provided to the participants);
-
Investigator’s Brochure (or equivalent information) and addenda;
-
available safety information;


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-
information on compensation for study-related injuries or payment to participants
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 participants;
-
any other documents that the IEC/IRB may require to fulfill 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 participants,
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 
participants;
-
revisions to compensation for study-related injuries or payment to participants 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 participants or the 
conduct of the study;
-
deviations from or changes to the protocol to eliminate immediate hazards to the 
participants;
-
report of death of any participants under the Investigator’s care;
-
notification if a new Investigator is responsible for the study at the clinical site;
-
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 participants, 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 participants. If a deviation from or a change to the protocol was implemented 
to eliminate an immediate hazard to study participants, 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.


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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).
11.2.3
Informed Consent
Each participant 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 authorised member of the clinical 
staff must explain to potential participants the aims, methods, reasonably anticipated 
benefits and potential hazards of the study, and any discomfort participation in the study 
may entail. Participants 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 participant was entitled. Finally, they will be told that the 
Investigator will maintain a participant identification register for the purposes of long-
term follow-up if needed and that their records may be accessed by health authorities and 
authorised Sponsor staff without violating the confidentiality of the participant, to the 
extent permitted by the applicable law(s) or regulations. By signing the ICF the 
participant is authorising such access, and agrees to allow his or her study physician to 
recontact the participant 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 participant (or 
the participant’s legally acceptable representative). The participant 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 participant's personally dated signature. After having obtained consent, a 
copy of the ICF must be given to the participant.
If a participant (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 participants, is 
read and explained to the participant (or legally acceptable representative), and after the 
participant (or legally acceptable representative) has orally consented to the participant’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 participant (or legally 
acceptable representative), and that informed consent was freely given by the participant
(or legally acceptable representative).


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11.2.4
Privacy of Personal Data
The collection and processing of personal data from participants 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 
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 participants confidential.
During the informed consent process the participants will be informed that, if they 
participate in this study, the Investigator may be required to allow direct access to 
participants’ original medical records for study-related monitoring, audit, IEC/IRB 
review, and regulatory inspection. The participants will also be informed of possible 
transfer of the collected personal data to other entities and to other countries and that 
should such transfer take place, the Sponsor will ensure that technical and organisational 
measures are put in place to protect the data.


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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 
participants, 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
PARTICIPANT IDENTIFICATION, ENROLMENT AND SCREENING 
LOGS
The Investigator agrees to complete a participant identification and enrolment log to 
permit easy identification of each participant during and after the study. This document 
will be reviewed by the Sponsor site contact for completeness.
The participant identification and enrolment log will be treated as confidential and will 
be filed by the Investigator in the study file. To ensure participant confidentiality, no 
copies will be made. All reports and communications related to the study will identify 
participants by initials and/or assigned number only.
The Investigator must also complete a participant screening log which reports on all 
participants who were seen to determine eligibility for inclusion in the study.
12.3
SOURCE DOCUMENTATION
The Clinspark 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 Clinspark. 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 site. The Investigator will ensure that the data 
collected are accurate, complete and legible. Data will be monitored within Clinspark 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 Clinspark.
At a minimum, source documentation must be available for the following: participant
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, 
investigational product administration information, laboratory and ECG printouts (if not 
available digitally), date of study completion and reason for early discontinuation of 
investigational products or withdrawal from the study, if applicable.


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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 site. 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. Data must be entered in English. 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. The Investigator must verify that all data entries in the eSource system are 
accurate and correct.
12.5
MONITORING
Medical and clinical monitoring of the study will be done under the responsibility of the 
Sponsor by ICON Clinical Research and IQVIA RDS & Integrated Services Belgium 
NV/SA, 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 site visit log that will be kept at the 
clinical site. 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 (e)Source 
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.


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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. Computerised data 
cleaning rules will be used in addition to manual review to 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 authorised 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 participant data handed over by the 
Investigator to the data management department and during inspections against 
disclosure to unauthorised third parties. Participant 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 is 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 site 
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. Participant 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 


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Sponsor if they have been contacted by a regulatory agency concerning an upcoming 
inspection.
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 
participant, 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 


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information only to accomplish this study, and not to use it for other purposes without the 
Sponsor’s prior written consent.
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 investigational 
product, 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 sites 
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 investigational products;
-
All discontinuations of the investigational products 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 recognise the integrity of a multicentre study by not 
publishing data derived from an individual clinical site 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 sites, 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 


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study or analysis and interpretation of the data, provided critical review of the paper, and 
given final approval of the final version.
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 participants’ anonymity will be maintained. The 
Investigator will keep a separate list with at least the initials, the participants’ 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. Chughlay MF, El Gaaloul M, Donini C, et al. A randomised, double-blind, 
placebo-controlled, Phase Ib study to evaluate the safety, tolerability and 
chemoprotective antimalarial activity of P218 against controlled human malaria 
infection by direct venous inoculation (DVI) of Plasmodium falciparum 
sporozoite (PfSPZ-DVI) in non-immune healthy adult volunteers. 68th Meeting, 
American Society for Tropical Medicine and Hygiene. November 20-24th, 2019. 
Gaylord National Resort and Convention Center National Harbor, MD, USA.
3. Collins KA, Rückle T, Elliott S, et al. DSM265 400 mg clears asexual stage 
parasites but not mature gametocytes from the blood of healthy participants
experimentally infected with Plasmodium falciparum. Antimicrobial Agents and 
Chemotherapy 2019;63:1-11.
4. Collins KA, Wang C, Adams M, et al. Human to mosquito transmission during 
controlled human malaria infection: a model to evaluate transmission blocking 
interventions. J Clin Invest 2018;128:1551-1562.
5. Fridericia LS. The duration of systole in the electrocardiogram of normal 
participants and of patients with heart disease. Acta Med Scand. 1920;53:469–
486.
6. Gaur A, McCarthy JS, Panetta JC, et al. Safety, tolerability, pharmacokinetics, 
and antimalarial efficacy of a novel Plasmodium falciparum ATP4 inhibitor 
(SJ733): a first-in-human and induced blood stage malaria phase 1a/ 1b study. 
Lancet ID 2019; accepted for publication.
7. 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. 
8. 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. 
9. Investigational Brochure PfSPZ Challenge (NF54). Sanaria Incorporated, 
Edition 13, 7 March 2019. 
10. 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.


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11. 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.
12. Malarone Summary of Product Characteristics (May 2017). GlaxoSmithKline 
Pharmaceuticals SA/NV. Wavre, Belgium. (bijsluiters.fagg-
afmps.be/registrationSearchServlet?key=BE186821&leafletType=skp). Accessed 
November 2019.
13. McCarthy JS, Donini C, Chalon S, et al. Defining the antimalarial activity of the 
novel Plasmodium phosphatidylinositol 4-kinase inhibitor MMV390048 in 
healthy volunteers. In preparation.
14. McCarthy J, Donini C, Chalon S, et al. Antimalarial activity of the Plasmodium 
phosphatidylinositol 4-kinase inhibitor MMV048 in the human Induced Blood 
Stage Malaria model. 28th European Congress of Clinical Microbiology and 
Infectious Diseases. April 21-24, 2018. Madrid, Spain.
15. McCarthy JS, Sekuloski S, Griffin PM, et al. A Pilot Randomised Trial of 
Induced Blood-Stage Plasmodium falciparum Infections in Healthy Volunteers 
for Testing Efficacy of New Antimalarial Drugs. PlOS One. 2011,6(8):e21914.
16. Mira-Martinez S, van Schuppen E, Amambua-Ngwa A, et al.Expression of the 
Plasmodium falciparum Clonally Variant clag3 Genes in Human Infections. J 
Infect Dis. 2017,215(6):938-945.
17. Mira-Martinez S, Pickford AK, Rovira-Graells N, et al. Identification of 
Antimalarial Compounds That Require CLAG3 for Their Uptake by Plasmodium 
falciparum-Infected Erythrocytes. Antimicrob Agents Chemother. 2019,63(5).
18. Mordmüller B, Supan C, Sim K L, et al. Direct venous inoculation of
Plasmodium falciparum sporozoites for controlled human malaria infection: a 
dose-finding trial in two centres Malar J. 2015 Mar 18; 14:117.
19. 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. 
20. Murphy SC, Duke E, Shipman KJ, et al. A randomized trial evaluating the 
prophylactic activity of DSM265 against pre-erythrocytic Plasmodium falciparum 
controlled human malaria infection by mosquito bites and direct venous 
inoculation. J Inf Dis 2018; 217: 693-702.
21. Piepoli MF, Hoes AW, Agewall S, 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 & Rehabilitation (EACPR). Eur Heart 
J. 2016;37(29):2315–2381.
22. Riamet Summary of Product Characteristics (May 2017). Novartis Pharma 
NV/SA. Vilvoorde, Belgium (bijsluiters.fagg-
afmps.be/registrationSearchServlet?key=BE223562&leafletType=skp). Accessed 
November 2019. 


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23. 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.
24. 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. 
25. 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.
26. 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.
27. Sulyok M, Rückle T, Roth A, et al. DSM265 for Plasmodium falciparum 
chemoprophylaxis in adults: a randomised, double blinded, Proof of concept 
Phase 1b trial with controlled human malaria infection. Lancet Infect Dis 2017; 
17: 636-644.
28. Woodrow CJ, White NJ. The clinical impact of artemisinin resistance in 
Southeast Asia and the potential for future spread. FEMS Microbiol Rev. 2017
Jan;41(1):34-48.
29. World Malaria Report 2018. World Health Organization. Geneva, Switzerland 
(http://www.who.int/malaria/publications/world-malaria-report-2018/en/). 
Accessed July 2019.


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ATTACHMENT 1: CLINICAL SCORE FOR MALARIA
Grading of the signs and symptoms specified in the table beneath according to the 
CTCAE grading scale will be performed at all relevant protocol-specified time points,
during the previous 24 h (continuously) if once daily assessments are required or during 
the previous 12 h (continuously) if assessments are performed twice daily, in accordance 
with the following:
-
Absent = 0
-
Mild = 1; equates to CTCAE grade 1
-
Moderate = 2; equates to CTCAE grade 2
-
Severe = 3; equates to CTCAE grade 3 or above
Participant 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
TOTAL SCORE
…/42


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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)
6%3
'%3
SXOVH
W
These normal ranges are applicable in supine and sitting position (after at least 10 min) 
and in the standing position (after at least 2 min in the standing position).
NORMAL RANGES FOR ECG PARAMETERS
PR
(ms)
QRS
(ms)
QTc F
(ms)
Heart rate
(bpm)
120d PR d220
QRS d120
QTc d450 for males, d470
for females.
+5
These normal ranges are applicable in supine and sitting position (after at least 10 min).


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ATTACHMENT 4: CLINICALLY ACCEPTABLE RANGES 
FOR CLINICALLY IMPORTANT STUDY INCLUSION
LABORATORY TESTS
Test
Unit
Acceptable Inclusion Range
Low
High
Sodium
mmol/L
130
150
Potassium
mmol/L
3.0
5.5
Chloride
mmol/L
85
120
Calcium (Corrected)
mg/dL
0.95 x LLN 
1.05 x ULN 
Phosphate
mmol/l
0.95 x LLN 
1.05 x ULN 
Bicarbonate
mmol/l
0.95 x LLN
1.05 x ULN
Glucose Fasted
mg/dL
N/A
1.0 x ULN 
Urea
mg/dL
N/A
1.75 x ULN
Uric acid
mg/dL
N/A
1.75 x ULN
Creatinine
mg/dL
N/A
1.0 x ULN 
Creatine kinase
U/L
N/A
< 2.5 x ULN
*eGFR
mL/min/1.73m2
60
N/A
Total Protein
g/L
[//1
[8/1
Albumin
g/L
[//1
[8/1
Total Bilirubin
mg/dL
N/A
1.25 x ULN
Direct Bilirubin
mg/dL
N/A
1.25x ULN
ALP
U/L
N/A 
1.5 x ULN
AST
U/L
N/A
1 x ULN
ALT
U/L
N/A
1 x ULN
GGT
U/L
N/A
1.5 x ULN
Lactate Dehydrogenase
U/L
0.9x LLN
1.1 x ULN
Prothrombin time INR
INR
1.0 x LLN 
1.0 x ULN 
Cholesterol
mg/dL
N/A
1.2 x ULN 


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Test
Unit
Acceptable Inclusion Range
Low
High
HDL Cholesterol
mg/dL
0.9x LLN 
N/A
LDL Cholesterol
mg/dL
N/A
1.25 x ULN 
Haemoglobin
g/dL
0.9x LLN
1.1.x ULN
Platelets 
10E9/L
0.9x LLN 
1.1 x ULN 
White Blood Cells
10E9/L
0.9x LLN 
1.1 x ULN 
Neutrophils 
10E9/L
1.0 x LLN 
1.0x ULN 
Lymphocytes
10E9/L
1.1 x LLN 
1.1 x ULN 
Monocytes
10E9/L
N/A
1.2 x ULN 
Eosinophils
10E9/L
N/A
1.0 x ULN 
Basophils
10E9/L
N/A
2.0 x ULN 
C-reactive protein (CRP)
mg/L
N/A
1.0 x ULN
Troponin-T 
(high 
sensitivity)
ng/L
N/A
< 12
Protein (dipstick)
N/A
Trace
Ketones (dipstick)
N/A
Positive
Red Blood Cells (MCS)
μL
N/A
<19
White Blood Cells (MCS)
μL
N/A
<15
Hyaline Casts (MCS)
N/A
1+

SAP_001.pdf: 
 
 
 
 
Page 1 of 50 
 
STATISTICAL ANALYSIS PLAN 
 
A single centre, open label, pilot phase Ib study to investigate 
blood stage malaria infection after Direct Venous Inoculation of 
cryopreserved Plasmodium falciparum (NF54 strain) Sporozoites 
(PfSPZ-DVI) in malaria naïve healthy adult volunteers 
 
Protocol: MMV_PfSPZ-DVI Blood Stage_19_01 
SGS LS number: BE-80-1914715 
Development phase: Ib 
Sponsor: Medicines for Malaria Venture (MMV) 
SAP version number: Final 1.0 
SAP version date: 11FEB2021  
 


 
Statistical Analysis Plan 
 
MMV_PfSPZ-DVI Blood 
Stage_19_01 
 
Final 1.0 of 11FEB2021
 
Page 2 of 50 
SIGNATURE PAGE 
Name and function 
Date 
(ddMMMyyyy) 
Signature 
SGS LS author(s) and reviewer(s): 
Daniel Izquierdo 
Juncàs, Biostatistician 
11FEB2021 
 
 
 
Bastiaan Jansen, 
Biostatistical 
Coordinator 
11FEB2021 
 
 
 
Sponsor’s approval: 
The approver agrees the statistical analysis will be performed according to this 
statistical analysis plan. 
Farouk Chughlay, 
Project and Medical 
Director 
 
 
 
 
Myriam El Gaaloul 
Director, Clinical 
Sciences 
 
 
 
 


 
Statistical Analysis Plan 
 
MMV_PfSPZ-DVI Blood 
Stage_19_01 
 
Final 1.0 of 11FEB2021 
 
Page 3 of 50 
PROTOCOL HISTORY 
Protocol: 
Version or ID 
Date 
(ddMMMyyyy) 
Impact of the changes on the statistical 
analysis 
Final 1.0 
17DEC2019 
NAP 
Final 2.0 
27JAN2020 
Including substantial amendment 1: no 
impact on the statistical analysis. 
Final 3.0 
24JUN2020 
Including substantial amendment 2: no 
impact on the statistical analysis. 
This statistical analysis plan (SAP) only considers the last version of the protocol, and 
of the protocol amendments, as listed above. 
 
 


 
Statistical Analysis Plan 
 
MMV_PfSPZ-DVI Blood 
Stage_19_01 
 
Final 1.0 of 11FEB2021 
 
Page 4 of 50 
LIST OF ABBREVIATIONS 
ADaM 
analysis data model 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate transaminase 
β-HCG 
β-human chorionic gonadotropin 
BMI 
body mass index 
bpm 
beats per minute 
CI 
confidence interval 
CMV 
cytomegalovirus 
CRF 
case report form 
CRP 
C-reactive protein 
DBP 
diastolic blood pressure 
DVI 
direct venous inoculation 
DY 
relative day 
EBV 
Epstein Barr Virus 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
FSH 
follicle stimulating hormone 
GGT 
gamma-glutamyl transferase 
HbsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IgM 
immunoglobulin M 
INR 
international normalised ratio 
LDH 
lactate dehydrogenase 
log10PRR48 
log10 parasite reduction ratio per 48 h 


 
Statistical Analysis Plan 
 
MMV_PfSPZ-DVI Blood 
Stage_19_01 
 
Final 1.0 of 11FEB2021 
 
Page 5 of 50 
log10PRR48,max maximum log10 parasite reduction ratio per 48 h 
MCH 
mean corpuscular haemoglobin 
MCHC 
mean corpuscular haemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAP 
not applicable 
NCE 
new chemical entities 
PC50 
parasite clearance half-life 
PC99 
predicted time to reach parasite clearance of 99% 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic 
PfSPZ 
P. falciparum sporozoites 
PfSPZ-DVI 
Challenge 
inoculation of P. falciparum sporozoites through direct venous 
inoculation 
PMR 
parasite multiplication rate 
PMR48 
parasite multiplication rate standardised to 48 h 
PMRLC 
parasite multiplication rate per life cycle (if not 48 h) 
PRR 
parasite reduction ratio 
PT 
prothrombin time 
QTc 
corrected QT interval 
QTcB 
Bazett’s corrected QT interval 
QTcF 
Fridericia’s corrected QT interval 
RBC 
red blood cell 
rRT-PCR 
real-time reverse transcription polymerase chain reaction 
SAP 
statistical analysis plan 
SAF 
safety analysis set 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SBP 
systolic blood pressure 
SCR 
all screened subject's analysis set 
SD 
standard deviation 
SE 
standard error 
SGS LS 
SGS Life Sciences 
SOP 
standard operating procedure 
STAT 
statistics 


 
Statistical Analysis Plan 
 
MMV_PfSPZ-DVI Blood 
Stage_19_01 
 
Final 1.0 of 11FEB2021 
 
Page 6 of 50 
TLF 
tables, listings and figures 
ULN 
upper limit of normal 
varATS 
the acidic terminal segment in Plasmodium falciparum var 
genes 
VIS 
volunteer infection study 
VS 
vital signs 
WBC 
white blood cell 
WHO 
World Health Organisation 
WI 
work instruction 


 
Statistical Analysis Plan 
 
MMV_PfSPZ-DVI Blood 
Stage_19_01 
 
Final 1.0 of 11FEB2021 
 
Page 7 of 50 
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. 
 
 
post-
baseline-
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. 
 
 
 


 
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TABLE OF CONTENTS 
Signature page .............................................................................................................. 2 
Protocol history ............................................................................................................ 3 
List of abbreviations .................................................................................................... 4 
Definition of terms ....................................................................................................... 7 
Table of contents .......................................................................................................... 8 
1. 
Introduction ....................................................................................................... 11 
1.1 
Study objectives............................................................................................. 11 
1.2 
Study design .................................................................................................. 11 
1.3 
Expected sample size ..................................................................................... 13 
1.4 
Randomisation and blinding .......................................................................... 13 
1.5 
Interim analysis ............................................................................................. 13 
1.6 
Software ......................................................................................................... 13 
1.7 
Validation model ........................................................................................... 13 
2. 
Pharmacodynamic analyses .............................................................................. 14 
2.1 
Pharmacodynamics ........................................................................................ 14 
2.1.1 
Available data .................................................................................. 14 
2.1.2 
Endpoints and derivation rules ........................................................ 14 
2.1.3 
Inferential statistics ......................................................................... 15 
2.1.3.1 
Secondary endpoints: ............................................................................... 15 
2.1.3.2 
Exploratory endpoints: ............................................................................. 17 
2.1.4 
Presentation of results ..................................................................... 18 
3. 
Safety analyses ................................................................................................... 20 
3.1 
Adverse events............................................................................................... 20 
3.1.1 
Available data .................................................................................. 20 
3.1.2 
Derivation rules ............................................................................... 20 
3.1.3 
Presentation of results ..................................................................... 21 
3.2 
Clinical laboratory evaluation ....................................................................... 22 
3.2.1 
Available data .................................................................................. 22 
3.2.2 
Derivation rules ............................................................................... 23 
3.2.3 
Presentation of results ..................................................................... 23 
3.3 
Vital signs ...................................................................................................... 24 
3.3.1 
Available data .................................................................................. 24 
3.3.2 
Derivation rules ............................................................................... 24 
3.3.3 
Presentation of results ..................................................................... 24 


 
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3.4 
Electrocardiograms ........................................................................................ 25 
3.4.1 
Available data .................................................................................. 25 
3.4.2 
Derivation rules ............................................................................... 25 
3.4.3 
Presentation of results ..................................................................... 25 
3.5 
Malaria clinical score .................................................................................... 26 
3.5.1 
Available data .................................................................................. 26 
3.5.2 
Derivation rules ............................................................................... 26 
3.5.3 
Presentation of results ..................................................................... 26 
3.6 
Physical examinations ................................................................................... 27 
4. 
General characteristics analyses ...................................................................... 28 
4.1 
Subject disposition......................................................................................... 28 
4.2 
Protocol deviations and eligibility ................................................................. 28 
4.3 
Demographic and other baseline characteristics ........................................... 28 
4.3.1 
Available data .................................................................................. 28 
4.3.2 
Derivation rules ............................................................................... 29 
4.3.3 
Presentation of results ..................................................................... 29 
4.4 
Medical history and concomitant diseases .................................................... 29 
4.4.1 
Available data .................................................................................. 29 
4.4.2 
Derivation rules ............................................................................... 29 
4.4.3 
Presentation of results ..................................................................... 30 
4.5 
Prior and concomitant therapies .................................................................... 30 
4.5.1 
Available data .................................................................................. 30 
4.5.2 
Derivation rules ............................................................................... 30 
4.5.3 
Presentation of results ..................................................................... 30 
4.6 
Exposure to challenge agent .......................................................................... 30 
4.6.1 
Available data .................................................................................. 30 
4.6.2 
Derivation rules ............................................................................... 31 
4.6.3 
Presentation of results ..................................................................... 31 
5. 
General methodology......................................................................................... 32 
5.1 
Analysis sets .................................................................................................. 32 
5.1.1 
Analysis sets .................................................................................... 32 
5.1.2 
As planned versus as actual analysis ............................................... 32 
5.2 
Phases and time points................................................................................... 32 
5.2.1 
Phases .............................................................................................. 32 


 
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5.2.2 
Baseline and change from baseline ................................................. 33 
5.2.3 
Relative day ..................................................................................... 33 
5.2.4 
Analysis visits ................................................................................. 33 
5.2.5 
Worst-case ....................................................................................... 34 
5.3 
Imputation and rounding rules ....................................................................... 34 
5.3.1 
Missing values ................................................................................. 34 
5.3.2 
Handling partially or completely missing dates in calculations ...... 34 
5.3.3 
Values below or above a threshold ................................................. 34 
5.3.4 
Rounding of derived variables ........................................................ 35 
5.3.5 
Outliers ............................................................................................ 35 
5.4 
Presentation of results.................................................................................... 35 
5.4.1 
Calculation of descriptive statistics and percentages ...................... 35 
5.4.2 
Presentation of treatments ............................................................... 36 
5.4.3 
Ordering in tables, figures and listings ............................................ 36 
6. 
Changes to the planned analysis ....................................................................... 37 
6.1 
Changes not covered by protocol amendments before database lock ........... 37 
6.2 
Changes not covered by protocol amendments after database lock .............. 37 
6.3 
Changes to the final statistical analysis plan ................................................. 37 
7. 
References ........................................................................................................... 38 
8. 
List of tables, listings and figures ..................................................................... 39 
8.1 
Tables ............................................................................................................ 39 
8.2 
Listings .......................................................................................................... 41 
8.3 
Figures ........................................................................................................... 42 
9. 
Appendices ......................................................................................................... 44 
9.1 
SAS code ....................................................................................................... 44 
9.2 
Schedule of assessments ................................................................................ 45 
 


 
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1. 
INTRODUCTION 
This SAP describes the final statistical analysis to be performed for the 
MMV_PfSPZ-DVI Blood Stage_19_01 (BE-80-1914715) study. 
This SAP covers the pharmacodynamic (PD), 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 parasite transcriptomics analysis is not in the 
scope of this SAP but will be described by the Institute of Tropical Medicine and 
reported separately. 
The statistical analysis will process and present the results following the International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) standards, in particular the ICH-E3, ICH-E6, and ICH-E9 
guidelines. 
1.1 
STUDY OBJECTIVES 
According to the protocol, the primary objectives of this study are: 
x To evaluate the safety and tolerability associated with blood-stage malaria 
infection in naïve healthy participants after PfSPZ-DVI Challenge. 
x To characterise key stages in the blood-stage parasite growth profile in 
malaria infection in naïve healthy participants after PfSPZ-DVI Challenge. 
According to the protocol, the secondary objectives of this study are: 
x To determine the safety and tolerability of Riamet® in blood-stage malaria 
infection in naïve healthy participants after PfSPZ-DVI Challenge. 
x To characterise the blood-stage parasite profile in malaria infection in naïve 
healthy participants after PfSPZ-DVI Challenge before Riamet® 
administration. 
x To characterise the blood-stage parasite clearance profile of Riamet® in 
malaria infection in naïve healthy participants after PfSPZ-DVI Challenge. 
According to the protocol, the exploratory objective of this study is to characterise the 
individual variability of blood-stage parasite profile. 
1.2 
STUDY DESIGN 
This is a single-centre, open-label, Phase Ib study designed to assess if intravenous 
bolus injection of approximately 3200 P. falciparum (NF54 strain) sporozoites can be 
safely administered to achieve blood-stage parasitaemia with a kinetics/PCR profile 
that will allow for the future characterisation of antimalarial blood-stage activity of 
NCEs in a relatively small number of participants during early drug development. 
Up to 16 healthy, malaria-naïve males and females, aged 18-55 years, will be enrolled 
in a maximum of 2 cohorts (up to 8 participants per cohort; a participant may be 
enrolled in one cohort only). Enrolment into the cohorts will proceed sequentially, 
with two target levels of parasitaemia previously achieved in healthy participants 
enrolled in malaria VIS at other study sites, i.e., 5000 parasites/mL blood in Cohort 1 
and 10000 parasites/mL blood in Cohort 2. 


 
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Each participant will be admitted to the clinical unit in the morning of Day -1 and 
inoculated with approximately 3200 P. falciparum sporozoites (NF54 strain) by DVI 
on Day 1. Participants will be discharged 2 h post inoculation on Day 1 and will be 
monitored daily via phone call from Day 2 until Day 6 to solicit any AEs. Participants 
will come to the clinical unit daily from Day 7 until Day 9 and together with the 
malaria clinical score, the presence of parasites will be assessed once daily by a 
specific qPCR targeting the varATS (the acidic terminal segment in Plasmodium 
falciparum var genes) multigenic family; this to accurately describe parasite growth 
even in case PCR positivity, i.e., a qPCR outcome ≥250 parasites per mL blood, is 
confirmed this early (very low probability and with low densities). Participants will 
be confined to the clinical unit from Day 10 in the morning. qPCR will be performed 
and malaria clinical score assessed twice daily and participants will be administered 
registered antimalarial therapy, i.e., Riamet®, when the following criteria are met: 
1. Cohort 1: ≥5000 parasites/mL blood or earlier if a participant has a malaria clinical 
score >6 or at Investigator’s discretion. 
2. Cohort 2: ≥10000 parasites/mL blood or earlier if a participant has a malaria 
clinical score >6 or at Investigator’s discretion. 
The registered 3-day antimalarial therapy regimen will be further administered and 
monitored. qPCR assessments of parasitaemia will be carried out at multiple time 
points (2, 6, 8, 12, 16, 24, 36, 48 and 72 h) following initiation of Riamet® and 
malaria clinical score will be assessed twice daily during confinement in the clinical 
unit. Safety and tolerability will be monitored during the whole study duration, 
specific assessments will be done at periodic pre-specified time points from Day 10 
and for at least 72 h after initiating antimalarial therapy, i.e., during confinement in 
the clinical unit. If an intolerance or contraindication to Riamet® develops, 
Malarone® will be administered. 
Upon parasite clearance (defined as a qPCR value below the limit of quantification of 
50 parasites per mL blood after initiating antimalarial therapy) and at least 72 h after 
initiating antimalarial therapy (estimated to occur on or before Day 19 and on or 
before Day 22 for Cohort 1 and Cohort 2, respectively), and if clinically well, 
participants will be discharged from the clinical unit and will be followed up for 
safety assessments, clinical evaluation and malaria qPCR in the clinical unit at the 
EOS visit on Day 28. 
All participants inoculated with PfSPZ-DVI Challenge will commence antimalarial 
therapy no later than Day 24 for both cohorts, regardless if they reach pre-defined 
cohort-specific PCR parasitaemia/malaria clinical score thresholds. Participants who 
start antimalarial therapy on Day 24 will only be discharged from confinement at the 
end of the EOS visit on Day 28. 
The schedule of assessments is in appendix 9.2. 
After evaluation of data from Cohort 1, the Safety Review Team decided to continue 
with Cohort 2 (8 participants) using a threshold of 5000 parasites/mL. 
 


 
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1.3 
EXPECTED SAMPLE SIZE 
Up to 16 participants will be enrolled in 2 cohorts of 8 participants per cohort. In 
agreement with the Sponsor, additional participants may be recruited in each cohort, 
to replace discontinuations for non-safety reasons and achieve the required cohort 
size. 
This is an exploratory study focusing on the methodology of malaria inoculation in 
healthy participants, thus no formal sample size calculation is performed. 
1.4 
RANDOMISATION AND BLINDING 
Participants are not randomised. As participants are confirmed to be eligible for the 
study, they will be assigned a single unique identifier across the study and will be 
enrolled sequentially in one of the two cohorts. 
All participants will be inoculated with PfSPZ-DVI Challenge and receive registered 
antimalarial therapy, i.e. Riamet® (Malarone® if an intolerance or contraindication to 
Riamet® develops). 
As this is an open-label study, blinding is not applicable. 
1.5 
INTERIM ANALYSIS 
No interim analyses are foreseen. 
1.6 
SOFTWARE 
SAS version 9.4 or later will be used for programming. 
Monolix for modelling parasite growth. 
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, provided the applicable regulatory 
requirements are still met. 
ADaMs and TLFs related to the time to first PCR positivity and time to parasitaemia 
of ≥5000 parasites per mL blood will be validated according to model C. All other 
tables/figures/listings follow validation model B (see SOP.STAT.020): 
x Model B: review by an independent person 
x Model C: review by an independent person and independent programming 
of the parameters indicated in this SAP 


 
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2. 
PHARMACODYNAMIC ANALYSES 
2.1 
PHARMACODYNAMICS 
2.1.1 
Available data 
Parasitaemia is assessed by qPCR at the time points indicated in appendix 9.2. 
2.1.2 
Endpoints and derivation rules 
The following primary endpoint parameters will be derived: 
x Time to first PCR positivity in days: (datetime in seconds of first positive 
parasitaemia - datetime in seconds of inoculation) / (24*60*60) 
o Positive parasitaemia is defined as qPCR outcome (MBTESTCD = 
PARADENS) ≥ 250 asexual parasites per mL. 
o Subjects with absence of positive parasitaemia will be excluded.  
x Parasitaemia at first PCR positivity defined as qPCR outcome ≥ 250 asexual 
parasites per mL 
x Time to parasitaemia of ≥5000 parasites per mL blood in days: (datetime in 
seconds of first parasitaemia of ≥5000 parasites per mL blood - datetime in 
seconds of inoculation) / (24*60*60) 
o In the absence of parasitaemia of ≥5000 parasites per mL blood, the 
duration will be censored. The censoring datetime will be set to the 
datetime of first administration of antimalarial treatment. If the date of 
antimalarial treatment is (partially) missing the censored duration will 
be set to 28 days. 
x Parasitaemia at the first time of ≥5000 parasites per mL blood 
x Time to first dose of treatment with Riamet®: (datetime of first dose of 
Riamet® - datetime of inoculation) / (24*60*60) 
x Parasitaemia at first dose of treatment with Riamet® 
The following secondary endpoint parameter will be derived: 
x Time to parasite clearance: (datetime of first PCR below the limit of 
quantification - datetime of first dose of Riamet®) / (24*60*60) 
o PCR below the limit of quantification is defined as (MBTESTCD = 
PARADENS) < 50 asexual parasites per mL. 
(Partially) missing times will be imputed as specified in section 5.3.2. 
For the creation of the graphs of parasitaemia by time point, the individual subject 
assessments will be mapped as follows: 
x Time from first PCR positivity (days) = (datetime of assessment - datetime 
of first PCR positivity) / (24*60*60) 
o  (Partially) missing times will be imputed as specified in section 5.3.2. 


 
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2.1.3 
Inferential statistics 
2.1.3.1 
SECONDARY ENDPOINTS: 
Blood-stage parasite profile before treatment with Riamet® 
To characterise the blood-stage parasite profile before treatment with Riamet® is 
initiated, first, a log-linear mixed effect model will be fitted to the measured 
parasitaemia (in count/mL, transformed on natural log scale) data prior to Riamet® 
administration.  In this model, for each individual ݅: 
ቐ
݀ ݈݋݃ܲܽݎܽݏ݅ݐܽ݁݉݅ܽ௜
݀ݐ
= ܩܴ௜
݈݋݃ܲܽݎܽݏ݅ݐܽ݁݉݅ܽ଴,௜= ݈݋݃ܨ௜௡௢௖,௜+ ݈݋݃ܲ௜௡௢௖−݈݋ܸ݃௕௟௢௢ௗ
 
where ݐ is the time in hours since inoculation, ܩܴ௜ is the individual parasitaemia 
growth rate (measured in 1/hour) , Parasitaemiao,i is the individual parasitaemia at 
time of inoculation (ݐ= 0), ܨ௜௡௢௖,௜ is the individual inoculum viability, ܲ௜௡௢௖ is the  
inoculum size, which is fixed to 3200 parasites, and ܸ௕௟௢௢ௗ  is the blood volume (in 
mL units) which is fixed to 5000 mL for all individuals:  
If the measured parasitaemia profile shows a cyclic behaviour due to synchronicity of 
the parasites and their sequestration during the late stages of their lifecycle, an 
attempt will be made to model this behaviour using the following extended version of 
the log-linear model: 
⎩
⎪
⎨
⎪
⎧
݀ ݈݋݃ܲܽݎܽݏ݅ݐܽ݁݉݅ܽ௜
݀ݐ
= ܩܴ௜
݈݋݃ ܲܽݎܽݏ݅ݐܽ݁݉݅ܽ଴,௜= ݈݋݃ܨ௜௡௢௖,௜+ ݈݋݃ܲ௜௡௢௖−݈݋ܸ݃௕௟௢௢ௗ
݈݋݃ܲܽݎܽݏ݅ݐܽ݁݉݅ܽ௩௜௦௜௕௟௘,௜= ݈݋݃ܲܽݎܽݏ݅ݐܽ݁݉݅ܽ௜+ ݈݋݃ቊ1 −0.5ܨ௠௔௫,௜ቈ1 −cos ቆ2ߨ(ݐ/24 −D௧,௜)
ܲ௟௘௡,௜
ቇ቉ቋ
 
where ܲܽݎܽݏ݅ݐܽ݁݉݅ܽ௩௜௦௜௕௟௘,௜ denotes the measured parasitaemia, D௧,௜= ߶௜ܲ௟௘௡,௜ , 
ܨ௠௔௫,௜ denotes the individual maximum fraction of hidden parasites, ܲ௟௘௡,௜ denotes the 
individual period length of the oscillation (in hours), and ߶௜ denotes the individual 
oscillation phase.   
Parameter estimation will be performed using Monolix (Antony, France: Lixoft 
SAS).  By default, all of the model parameters described above will be estimated, 
including their inter-individual variability (IIV) distributions. If, due to limited data 
size, the relative standard error (RSE) of the estimates exceeds 40%, the modeler may 
decide to fix the IIV for some of the parameters to previous estimates based on 
pooled data from induced blood-stage malaria VIS studies. By default, the models 
should assume independence of the parameters in their uncertainty and IIV 
distributions. If, during the model exploration, indications appear of a strong 
correlation between specific pairs of parameters, both, in their uncertainty and/or IIV 
distributions, the modeler may attempt to explicitly estimate such parameter 
correlations. Data below the limit of quantification will be included in the dataset and 
flagged as censored observations. 
The following parameters will be determined from the population fits of the data: 


 
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x Parasite growth rate expressed as the parasite multiplication rate (PMR) 
standardised to 48 h (PMR48), i.e., ratio of the parasite density at a specific 
time point to the parasite density 48 h earlier. Based on the population 
estimates for the GR parameter in the log-linear mixed effect model, PMR48 
will be reported in log10 units: , i.e. ܲܯܴସ଼=
ସ଼ீோ
୪୭୥ (ଵ଴)  
x If cycles are observed and if their estimated period is not 48 h, parasite 
growth rate expressed as the PMR per life cycle (PMRLC). Based on the 
population estimates for the GR and ܲ௟௘௡ parameters in the extended log-
linear mixed effect model, PMRLC will be reported in log10 units: ܲܯܴ௅஼=
௉೗೐೙ீோ
୪୭୥ (ଵ଴). 
x Predicted time to reach parasitaemia thresholds of first positive PCR, ≥5000 
parasites per mL blood for Cohorts 1 and 2. All these quantities should be 
calculated at the population level by solving for ݐ the linear equations 
݈݋݃ܺ= ݈݋݃ܲܽݎܽݏ݅ݐܽ݁݉݅ܽ଴+ ܩܴ× ݐ 
where ܺ∈{250, 5000} and logଵ଴ܲܽݎܽݏ݅ݐܽ݁݉݅ܽ଴ and GR are the 
population estimates for parasitaemia at time of inoculation and 
parasitaemia growth rates respectively. 
To determine confidence intervals for the population mean, parameters will be 
sampled from uncertainty.  
Blood-stage parasite clearance profile after treatment with Riamet® 
To characterise the blood-stage parasite clearance profile of Riamet® in malaria 
infection in naïve healthy participants after PfSPZ-DVI challenge; a log-linear model 
will be fitted to the parasitaemia data observed from the administration of the 
treatment onwards.  
For each participant ݅: 
logଵ଴ܲܽݎܽݏ݅ݐܽ݁݉݅ܽ௜௝= ߚ଴,௜+ ߚଵ,௜ݐ௜௝+ ߝ௜௝ 
Where ݐ௜௝ is the time in hours since administration of antimalarial treatment, ߚ଴,௜ and 
ߚଵ,௜ are the participant's intercept and slope, respectively, and ߝ௜௝ the error terms. For 
each participant ݅, ߚ଴,௜ is the logଵ଴(Parasitaemia at initiation of antimalarial treatment) 
and −ߚଵ,௜ is the clearance rate constant. 
The following algorithm will be used to remove potential lag and/or tail phases of the 
parasitaemia clearance profile, in order to determine the optimal log-linear decay 
regression (Marquart et al, 2015 see section 7). The algorithm considers removing 
parasitaemia data points in an iterative process from both ends of the parasitaemia 
curve, i.e. a combination of removing values from the tail phase and removing values 
from the lag phase. 
The optimal log-linear regression model for a participant is deemed an appropriate fit 
if the overall model p-value < 0.001.  
Iteration process to determine the optimal log-linear decay curve: 
For each participant: 


 
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x Step 1: Fit the full model - fit a linear regression (as defined by the previous 
equation) to all ݉ parasitaemia values of participant ݅ 
x Step 2: Fit two models: 
o Fit linear regression model to ݉ − 1 parasitaemia values, removing 
the first observation 
o Fit linear regression model to ݉ − 1 parasitaemia values, removing 
the last observation 
x Step 3: Determine the best model of Step 2a and Step 2b, defined as the 
model corresponding to the minimum overall model p-value 
x Step 4: Of the best model defined in Step 3, repeat Step 2 and Step 3 in an 
iterative process until a minimum of four observations remain. 
x Step 5: Of the ݉ − 3 best models selected per iteration (including the full 
model [Step 1]), the optimal model is defined by the minimum overall 
model p-value. 
The following parameters will be calculated from the estimates of the optimal linear 
regression model for participant ݅: 
x log10 parasite reduction ratio per 48 h (log10PRR48), i.e., ratio of the parasite 
density at a specific time point to the parasite density 48 h later and 
expressed in log10 
o logଵ଴PRRସ଼௜= −48ߚଵ,௜ 
x Parasite clearance half-life (PC50), i.e., time taken for the parasite density to 
be reduced by 50% after the first dose administration of Riamet® 
o ܲܥ50௜= logଵ଴(2) ൬
ସ଼ ௛௢௨௥௦
୪୭୥భబ୔ୖୖరఴ೔൰=
୪୭୥భబ(ଶ)
ିఉభ,೔ 
x Predicted time to reach parasite clearance of 99% (PC99) is calculated 
solving for ݐ the linear equation 
logଵ଴ܺ= ߚመ଴,௜+ ߚመଵ,௜× ݐ 
where ߚመ଴,௜ is the participant's estimated logଵ଴(Parasitaemia at initiation of 
Riamet®), ߚመଵ,௜ the opposite of clearance rate constant, and ܺ the 
Parasitaemia at initiation of Riamet®  / 100. Thus: 
ܲܥ99௜= logଵ଴(100)
−ߚଵ,௜
 
Note: when computing descriptive statistics per cohort and overall of the above 
estimated parameters, the summary statistics will be estimated by using the inverse-
variance method to calculate the weighted average linear regression slope (ߚ̅ଵ) and 
corresponding standard error [SE(ߚ̅ଵ)] (Hartung et al, 2008 see section 7). Descriptive 
statistics are based only on the participants whose optimal regression model overall p-
value < 0.001. 
2.1.3.2 
EXPLORATORY ENDPOINTS: 
To characterise the individual variability the results of modelling the blood-stage 
parasite profile with a log-linear or cyclic growth model whichever best describes the 
data (Section 2.1.3.1) will be used. Based on the individual parameter estimates from 


 
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the NLME model the inter-individual variability of the parasite growth rate and the 
predicted time to reach parasitaemia threshold of first positive PCR, ≥5000 parasites 
per mL blood for Cohorts 1 and 2 will be calculated according to corresponding 
equations from Section 2.1.3.1. In case that the IIV can be estimated for all 
parameters, prediction intervals for these variables will be determined based on 1000 
samples of individual parameters from the estimated IIV.  
2.1.4 
Presentation of results 
All parasitaemia tables, listings and figures will be presented for the PD set. As a 
sensitivity analysis the tables and figures will also be presented for the modified PD 
set. In this set subjects with a PCR assessment below the limit of quantification (<50 
parasites per mL) after first PCR positivity (>250 parasites per mL) but before first 
antimalarial treatment administration will be excluded. 
All parasitaemia data will be listed, including all derived parameters. The onset date 
of antimalarial treatment administration will be added to the listing. 
Primary endpoints: 
Descriptive statistics (N, geometric mean, geometric SD, 95% CI, minimum, 
maximum) will be provided for the following primary endpoints per cohort and 
overall:  
x Time to first PCR positivity 
x Parasitaemia at first PCR positivity 
x Parasitaemia at the time of ≥5000 parasites per mL blood 
x Time to first dose of treatment with Riamet® 
x Parasitaemia at first dose of treatment with Riamet® 
Time to parasitaemia of ≥5000 parasites per mL blood will be analysed using Kaplan-
Meier time to event analysis per cohort and overall. The number of events, number of 
censored observations, 25th percentile, median and 75th percentile with 95% CI will 
be presented. 
The number and proportion of participants with presence of positive PCR and 
parasitaemia of ≥5000 parasites per mL blood between inoculation with PfSPZ-DVI 
Challenge and Day 28 will be summarised per cohort. Corresponding two-sided 90% 
Exact Clopper-Pearson confidence limits will be presented as well. 
Parasitaemia actual values in the base-10 logarithmic scale will be summarised by 
means of descriptive statistics at each analysis visit. The visits will be grouped by 
analysis phase. 
Graphs of the median actual values over time and spaghetti plots of the individual 
participants will be prepared for parasitaemia in the base-10 logarithmic scale. The 
median plot will be shown from the Day 7 assessment to the assessment 72 h 
following initiation of Riamet®. The spaghetti plots will be shown from the subject's 
first PCR positivity to parasite clearance. For the spaghetti plots, different plotting 
symbols will be used on the first assessment when antimalarial treatment was given.  
For all time to event parameters, Kaplan-Meier plots per cohort and overall will be 
presented. 


 
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Secondary endpoints: 
Blood-stage parasite profile before treatment with Riamet® 
Parameter estimates for fixed (mean parameter value) and random (inter-individual 
and residual variability) effects values will be tabulated including their standard 
error and shrinkage for the inter-individual variability. 
To characterise the blood-stage parasite profile the mean, 90%-CI will be provided 
for: 
x PMR48 
x PMRLC (if cycles are observed and their estimated period is not 48 h) 
x Predicted time to reach parasitaemia threshold of first positive PCR, ≥5000 
parasites per mL blood for Cohorts 1 and 2 
 
Blood-stage parasite clearance profile after treatment with Riamet® 
The model estimates and derived parameters resulting from the optimal log-linear 
decay regression model of each subject will be tabulated. 
To characterise the blood-stage parasite clearance profile of Riamet® descriptive 
statistics (N, geometric mean, geometric SD, 95% CI, minimum, maximum) will be 
provided for time to parasite clearance per cohort and overall. 
The following cohort parameters will be estimated based on the weighted average 
slope and standard error of the subjects with the optimal regression model having a p-
value <0.001. N, mean, 95% CI, minimum and maximum will be shown. 
x log10 parasite reduction ratio per 48 h (log10PRR48) 
x Parasite clearance half-life (PC50) 
x Predicted time to reach parasite clearance of 99% (PC99) 
For each subject, the regression slope with 95% CI, log10PRR48 with 95% CI and 
overall model p-value of all the fitted models leading to the selection of the optimal 
log-linear model will be listed. The optimal model of each subject will be flagged.  
A Kaplan-Meier plot per cohort and overall will be presented for the time to parasite 
clearance.  
Exploratory endpoints: 
Summary statistics of all individual parameters (cohort 1 and cohort 2) of the log-
linear growth model will be tabulated to show the inter-individual variability of the 
parasite growth rate of predicted time to reach parasitaemia threshold of first positive 
PCR, ≥5000 parasites per mL blood by geometric mean, standard deviation 
(including their 95% CI), and the range. In case that the IIV could be estimated for all 
parameters, the 90% prediction interval and the median will be reported.  


 
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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 grade, severity, a seriousness flag, 
relatedness to PfSPZ inoculum, relatedness to Riamet®, relatedness to Malarone®, 
action taken towards PfSPZ inoculum, action taken towards Riamet®, action taken 
towards Malarone®, outcome and a flag for AEs of special interest. 
To determine severity of Adverse Events, including the 14 signs/symptoms as part of 
the Malaria Clinical Score, we use the CTCAE grading scale grade 1 - 5. 
3.1.2 
Derivation rules 
Based on their start date(time), AEs will be allocated to the phase during which they 
started. Each AE will therefore be reported in only one phase. Phases are defined in 
section 5.2.1. In case the AE start date(time) is incomplete or missing and the AE 
could consequently be allocated to more than one phase, a worst-case allocation will 
be done as detailed below: 
x Screening phase vs. challenge phase: AE will be allocated to the challenge 
phase unless the available parts of the AE start or stop date(time) provide 
evidence for allocating to the screening phase. 
x Challenge phase vs. rescue phase: AE will be allocated to the rescue phase 
unless the available parts of the AE start or stop date(time) provide evidence 
for allocating to the challenge phase. 
A fatal AE is defined as an AE with outcome ‘fatal’. 
An AE for which the antimalarial treatment was discontinued is defined as an AE 
with action taken ‘Permanently discontinued’ towards Riamet® or Malarone®.  
Treatment-relatedness will be assessed for PfSPZ inoculum, Riamet® and 
Malarone®. It will be dichotomised as follows in tables: 
x Treatment-related: Related/Suspected or missing. 
x Not treatment-related: Not related/Not suspected or Not Applicable. 
AE onset and duration will be calculated as follows when start and stop dates are 
fully known: 
x AE onset day / hour (vs. first PfSPZ Challenge administration) = 
o AE start date > date of first inoculation: AE start date – date of first 
inoculation + 1 day 
o AE start date < date of first inoculation: AE start date – date of first 
inoculation 
o AE start date = date of first inoculation (AE start datetime – datetime 
of first inoculation)/(60*60) 


 
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x AE onset day / hour (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) 
x AE duration (days) =  
o AE end date – AE start date + 1 day 
o study discontinuation date – AE start date + 1 day (when the AE start 
date is fully known but the AE is not resolved at the end of the study) 
In this case the duration will be presented as “>x days”. 
(Partially) missing times will be imputed as specified in section 5.3.2. 
3.1.3 
Presentation of results 
Tables will present only AEs that start after the PfSPZ Challenge inoculation. Pre-
inoculation AEs will only be listed. Unless stated otherwise, tables will not be shown 
by phase.  
An overview table will show the number and percentage of subjects with at least one 
event and the number of events for the following: 
x AEs 
x Serious AEs 
x Grade ≥ 3 AEs 
x Fatal AEs 
x AEs related to PfSPZ inoculum 
x AEs related to antimalarial treatment 
x AEs related to Riamet® 
x AEs related to Malarone® 
x Serious AEs related to PfSPZ inoculum 
x AEs for which the study was discontinued 
x AEs for which the antimalarial treatment was discontinued 
x AEs for which Riamet® was discontinued  
x AEs for which Malarone® was discontinued 
x AEs of special interest 
x AEs of special interest related to PfSPZ inoculum 
x AEs of special interest related to antimalarial treatment 
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 AEs will 
additionally show the number of events.  


 
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Separate tables will be prepared for the following: 
x AEs 
x Serious AEs 
x Grade ≥ 3 AEs 
x AEs related to PfSPZ inoculum 
x AEs related to antimalarial treatment (overall, related to Riamet® and 
related to Malarone®) 
x Serious AEs related to PfSPZ inoculum 
x AEs for which the antimalarial treatment was discontinued (overall, 
Riamet® discontinued and Malarone® discontinued) 
x AEs of special interest related to PfSPZ inoculum 
x AEs of special interest related to antimalarial treatment (overall, related to 
Riamet® and related to Malarone®) 
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 total group). 
All AEs, including pre-inoculation events will be listed. Separate listings will be 
prepared for serious AEs, AEs after antimalarial treatment administration, AEs for 
which the study was discontinued, AEs for which the antimalarial treatment was 
discontinued (Riamet® or Malarone®), fatal AEs and AEs for which another action is 
taken. A listing showing all 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: 
x Biochemistry: Liver biochemistry: albumin, AST, ALT, alkaline 
phosphatase (ALP), gamma glutamyl aminotransferase (GGT), total and 
direct bilirubin and total serum proteins; Biochemistry other than liver: 
sodium, potassium, chloride, bicarbonate, urate, inorganic phosphate, 
creatinine, estimated glomerular filtration rate (eGFR), glucose, lactate 
dehydrogenase (LDH), blood urea nitrogen (BUN) and creatine 
phosphokinase (CPK); C-reactive protein (CRP); High sensitive troponin T; 
x Haematology: haemoglobin, haematocrit, 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; 
x Coagulation: prothrombin time (PT), international normalised ratio (INR), 
activated partial thromboplastin time (aPTT); 
x Urinalysis: dipstick for glucose, protein, nitrite, pH and occult blood; 
microscopic examination for WBC, RBC and casts. 


 
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Normal ranges are available as provided by the laboratory. Based on the Regulatory 
Agency’s recommendation, the Clinically Acceptable Ranges for Clinically Important 
Study Inclusion Laboratory Tests (including total and conjugated bilirubin) have been 
added in Attachment 4 of the protocol to guide inclusion/exclusion of study 
participants. 
3.2.2 
Derivation rules 
The following abnormality categories will be defined: 
x Low: value < lower limit of normal range 
x Normal: lower limit of normal range ≤ value ≤ upper limit of normal range 
x High: value > upper limit of normal range 
Note: 
x Classification will be done in standardised units, using non-imputed values 
and limits. 
x 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. 
x If not straightforward how to categorise urinalysis results, a worst-case 
approach will be used. A value of ‘4 to 6’ with normal range ‘0 to 5’ will 
thus be classified as normal for predose assessments but as high for post-
dose assessments. 
Additionally, for liver enzymes, the following elevation categories will be defined: 
x ALT or AST >3 x Upper Limit of Normal (ULN); 
x ALT or AST >5 x ULN; 
x ALT or AST >8 x ULN; 
x 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. Categorical 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 post-baseline-emergent abnormalities 
will also be shown. 
Additionally, a frequency table showing the liver enzyme elevation categories for the 
highest post-inoculation values will be prepared. 
All laboratory data will be listed, but only for subjects with any post-baseline 
abnormality or clinically significant value.  


 
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Spaghetti plots of the individual subjects' actual values over time will be prepared for 
liver biochemistry parameters, CRP and haemoglobin. For the spaghetti plots, the 
median will also be plotted. 
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 body weight. 
3.3.2 
Derivation rules 
Abnormalities are defined in below table. 
 
Heart 
rate 
(bpm) 
SBP 
(mmHg) 
DBP 
(mmHg) 
Temperature 
(°C) 
Weight 
(kg) 
Low 
<40 
<90 
<45 
<35.0 
<50 
Normal 40-100 
90-150 
45-90 
35.0-37.5 
50-120 
High 
>100 
>150 
>90 
>37.5 
>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 the figures, the median assessment of first antimalarial treatment administration 
will be calculated starting from the individual vital signs first assessments which 
follow the first administration. In case the median is found to be between two 
assessments the first of the two will be selected. 
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. 
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 
post-baseline-emergent abnormalities will also be shown. 
All vital signs data will be listed, but only for subjects with any post-baseline 
abnormality or clinically significant value. 
Spaghetti plots of the individual subjects' actual values over time will be prepared for 
heart rate and body temperature. For the spaghetti plots, the median will also be 
plotted. The median time to first antimalarial treatment administration will be shown. 


 
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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). 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, PR and QTc interval are defined in below table. 
 
HR (bpm) 
PR (ms) 
QRS (ms) 
QTc (ms) 
Low 
<40 
<120 
- 
- 
Normal 40-100 
120-220 
≤120 
≤450 for males, ≤470 for females 
High 
>100 
>220 
>120 
>450 for males, >470 for females 
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 changes (ms), the following categories are defined: 
x ≤ 30 (normal) 
x >30; ≤ 60 
x > 60 
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. 
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 of subjects with post-baseline-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, but only for subjects with any post-baseline abnormality 
or clinically significant value or change.  
Spaghetti plots of the individual subjects' actual values over time will be prepared for 
QTcF and QTcB. For the spaghetti plots, the median will also be plotted. 


 
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3.5 
MALARIA CLINICAL SCORE 
3.5.1 
Available data 
The following 14 signs/symptoms frequently associated with malaria will be graded 
using a 4-point scale (absent: 0; mild: 1; moderate: 2; severe: 3): headache, 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 and hypotension. 
3.5.2 
Derivation rules 
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 malaria clinical score and individual signs and symptoms, a worst-case analysis 
visit, as defined in section  5.2.5 will be derived. 
For the creation of the graphs of malaria clinical score and parasitaemia/C-reactive 
protein together, the individual subject assessments will be mapped as follows: 
x Time from PfSPZ inoculation (days) = (datetime of assessment - datetime of 
inoculation) / (24*60*60) 
o  (Partially) missing times will be imputed as specified in section 5.3.2. 
For the figures, the median assessment of first antimalarial treatment administration 
will be calculated starting from the individual MCS first assessments which follow 
the first administration. In case the median is found to be between two assessments 
the first of the two will be selected. 
3.5.3 
Presentation of results 
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 (by phase and overall). 
Individual malaria signs and symptoms scores will be presented as frequency 
tabulations at the worst-case analysis visit (by phase and overall). Numbers and 
percentage of subjects with any post-baseline non-zero score will also be shown. 
Malaria signs and symptoms and clinical score will be listed. The onset date of 
antimalarial treatment administration will be added to the listing. 
Malaria clinical scores of more than 6 will be listed. The baseline score value, the 
corresponding parasitaemia values at those analysis visits and the onset date of 
antimalarial treatment administration will be added to the listing. 
Spaghetti plots of the individual subjects' actual values over time will be prepared for 
malaria clinical score. For the spaghetti plots, the median will also be plotted and 
different plotting symbols will be used at the time point of first antimalarial treatment 
administration and at the time point of peak parasitaemia. The median time to first 
antimalarial treatment administration will be shown. 
Spaghetti plots of the individual subjects' actual values over time will be prepared for 
malaria clinical score and parasitaemia together. These plots will be shown per cohort 


 
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and per individual subject. The same type of plot will be prepared for malaria clinical 
score and C-reactive protein together. 
3.6 
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: 
x The number of subjects in each analysis set 
x Dates of first signed informed consent, last visit and last contact (overall 
only) 
x 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, study discontinuation, 
antimalarial treatment discontinuation and information on phases will be listed. The 
phases listing will also include the start and stop dates of antimalarial treatment 
administration. 
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 inoculated with PfSPZ-DVI Challenge will be 
listed. 
4.3 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
4.3.1 
Available data 
The following parameters will be available: 
x Demographics: sex, age, race, ethnicity, height, body weight at screening, 
date of signing informed consent form (ICF), smoking habits 
x Screening laboratory tests: Viral serology: hepatitis A IgM antibody, 
HbsAg, anti-HCV antibody, hepatitis D antibody (only in subjects positive 
for HbsAg), hepatitis E IgM antibody, CMV IgM antibody, EBV IgM 
antibody and HIV; Urine drug screen (amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine and opiates) and alcohol breath test. 
In all female participants, serum β-HCG at screening and at the EOS visit, 
urine β-HCG on Day-1 and FSH at screening. rRT-PCR test on 
nasopharyngeal swab to screen for infection with SARS-CoV-2 at screening 
and prior to confinement to the study site on Day 10 
x Standing and supine heart rate, standing and supine systolic (SBP) and 
diastolic blood pressure (DBP) 
x Beck depression inventory (question 9 - suicidal thoughts - and total score) 


 
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4.3.2 
Derivation rules 
The following parameters will be derived: 
x Body mass index (BMI) at screening (kg/m²) = (body weight at screening 
(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. 
x Smoking status: 
o Non-smoker: SUOCCUR = N 
o Ex-smoker: SUOCCUR = Y and non-missing smoking end date 
o Smoker: SUOCCUR = Y and missing smoking end date 
x Orthostatic change = value in supine position – value in standing position 
x 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, body 
weight and BMI and frequency tabulations for sex, race, ethnicity and smoking status. 
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 smoking 
history, orthostatic changes, Beck depression inventory, screening laboratory tests, 
pregnancy tests (including EOS result) and rRT-PCR tests. 
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: 
x Medical history finding: not ongoing at screening (MHENRTPT 
=BEFORE) 
x Concomitant disease finding: still ongoing at screening (MHENRTPT = 
ONGOING) 


 
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4.4.3 
Presentation of results 
Medical history and concomitant diseases will be tabulated separately. Each table will 
show: 
x The number and percentage of subjects with and without findings 
x 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. 
4.5 
PRIOR AND CONCOMITANT THERAPIES 
4.5.1 
Available data 
All therapies (excluding antimalarial treatment) 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 or prior flag and stop date or ongoing flag are collected. 
For antimalarial treatment 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 therapies and the number 
and percentage of subjects with therapies by ATC class (level 4) and generic term 
will be tabulated by phase and overall. Blank ATC levels, if any, will be shown as 
‘not available’ in the tables. 
A frequency table will be prepared showing the timing of antimalarial treatment 
administration (prior to day 24 / on day 24) and the generic name (Riamet®  / 
Malarone®). 
The number and percentage of subjects who completed or discontinued the 
antimalarial treatment as documented on the treatment termination page and the 
number and percentage of subjects for each discontinuation reason will be tabulated. 
All prior and concomitant therapies data will be listed. A separate listing will be 
prepared for antimalarial treatment administration. 
4.6 
EXPOSURE TO CHALLENGE AGENT 
4.6.1 
Available data 
For the challenge agent (PfSPZ-DVI) the administration date(time) and the dose will 
be recorded. 


 
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4.6.2 
Derivation rules 
Not applicable. 
4.6.3 
Presentation of results 
All exposure to challenge agent 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): 
subjects who signed an informed consent to participate 
in this study 
Safety analysis set 
(SAF): 
subjects who were inoculated with PfSPZ-DVI 
Challenge 
PD analysis set: 
subjects from the safety analysis set with at least one 
available PD data who received all Riamet® doses and 
who experienced no major protocol deviations with 
relevant impact on PD data  
Modified PD analysis 
set (m-PD): 
subjects from the PD analysis set excluding subjects 
with a PCR assessment below the limit of quantification 
(<50 parasites per mL) after first PCR positivity (>250 
parasites per mL) but before first antimalarial treatment 
administration 
Notes: 
x Having signed an informed consent is defined as having a complete 
informed consent signature date in the database. 
x Being inoculated with PfSPZ-DVI Challenge is defined as having an 
exposure date of PfSPZ-DVI Challenge or any information confirming this 
exposure present in the database. 
x Major protocol deviations with impact on PD data will be identified with 
DVSCAT. DVSCAT = 'MISSING DATA EXPECTED PER PROTOCOL' 
indicates no impact on PD. 
Unless specified otherwise, the safety analysis set will be used for the analysis of 
demographics and other general characteristics and for the safety/tolerability analysis. 
The PD analysis set will be used for pharmacodynamic statistical analysis. The 
modified PD analysis set will be used as a sensitivity analysis for the 
pharmacodynamic statistical analysis. 
Protocol deviations will be reviewed and exclusion of subjects from the analysis sets 
will be decided during final data review prior to database lock. 
5.1.2 
As planned versus as actual analysis 
Not applicable. 
5.2 
PHASES AND TIME POINTS 
5.2.1 
Phases 
All events and assessments will be allocated to phases. Seconds in the time part will 
be ignored. 


 
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Phase 
Start 
End 
Screening 
Date of signing the ICF, with 
00:00 added as time part 
First inoculation date(time) – 1 
minute 
Challenge 
First inoculation date(time) 
First antimalarial treatment 
administration date(time) – 1 
minute 
Rescue 
First antimalarial treatment 
administration date(time) 
Date of last contact, with 23:59 
added as time part 
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 therapies 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 handled as follows: 
x Screening phase vs. challenge phase: assessments will be allocated to the 
challenge phase unless the available parts of the assessments start or stop 
date(time) provide evidence for allocating to the screening phase. 
x Challenge phase vs. rescue phase: assessments will be allocated to the 
rescue phase unless the available parts of the assessments start or stop 
date(time) provide evidence for allocating to the challenge phase. 
5.2.2 
Baseline and change from baseline 
The baseline value is the last available and non-missing value before the inoculation 
of PfSPZ-DVI Challenge. If all values are missing, the baseline will be reported as 
missing. 
Change from baseline is defined as: 
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: 
x Concerned date < reference date: DY = concerned date – reference date 
x Concerned date ≥ reference date: DY = concerned date – reference date + 1 
The reference date is the date of inoculation of PfSPZ-DVI Challenge.  
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. 


 
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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. 
The day -1 value is the last available and non-missing value performed on the date of 
day -1. 
Baseline is defined in section 5.2.2. 
5.2.5 
Worst-case 
A worst-case analysis visit will be created for parameters for which abnormalities are 
defined 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. 
All non-missing post-baseline values, including unscheduled assessments and follow-
up will be considered when deriving the worst-case analysis visit.  
Worst-case will be derived both by phase (challenge/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. 
No other imputation will be done of missing values. 
5.3.2 
Handling partially or completely missing dates in 
calculations 
For the time to event parasitaemia parameters, assessment datetimes used in the 
figures and AE onset hours, partially missing time parts will be imputed with zero 
(e.g. if minutes and seconds are missing time will be set to hh:00:00). 
Note: If imputation of the start datetime results in a start datetime posterior to the stop 
datetime, the start datetime will be imputed with the stop datetime. If imputation of 
the stop datetime results in a stop datetime anterior to the start datetime, the stop 
datetime will be imputed with the start datetime. 
No other date(time) imputation will be performed. 
5.3.3 
Values below or above a threshold 
Safety values expressed as below (or above) the limit of quantification will be 
imputed by the value of the quantification limit itself. 
Parasitaemia values below the limit of quantification (50 parasites/mL) will be 
imputed by 1 parasite per mL blood, which is equivalent to zero in the logarithmic 
scale. 
Listings will always show the non-imputed values. 


 
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5.3.4 
Rounding of derived variables 
Derived variables will be rounded to the appropriate number of significant digits (see 
Definition of terms) at display level:  
x Malaria clinical score will be rounded to 1 decimal. 
x Mean of triplicates, mean scores and BMI will be rounded to 1 decimal. 
x AE onset hour will be rounded to 1 decimal. 
x Time to event parameters and log10(parasitaemia) will be rounded to 1 
decimal. 
x Other derived PD parameters will be rounded to 2 decimals. 
Rounding will be done using the round half to up rule (see Definition of terms). 
5.3.5 
Outliers 
There will be no outlier detection. All measured values will be included in the 
analyses. 
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 of the general and safety parameters 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 pharmacodynamic endpoints will include the number of 
non-missing data points, the arithmetic or geometric mean and SD, the corresponding 
95% confidence interval (CI), minimum and maximum. Geometric mean, geometric 
SD and CI are calculated as the exponentials of the arithmetic mean, SD and 
corresponding CI (based on t-distribution, without continuity correction) of the log-
transformed data. 
Mean, geometric mean, median, SD, geometric SD and CI will be presented with one 
more decimal place than the individual values. Minimum and maximum will be 
presented with the same number of decimal places than the individual values. 
P-values will be presented with four decimal places, ratios with three decimal places 
and test statistics with two decimal places. 
For event-type data, the denominator will be all subjects in the analysis set and phase. 
All cohorts 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. 
Percentages will be shown with one decimal place. 


 
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5.4.2 
Presentation of treatments 
The following labels will be used in the tables, listings and figures: 
x Cohort 1 
x Cohort 2 
In the analysis, a grand total will be added to summarise all subjects over cohorts 
except for parameters defined only for cohort 2. Grand totals will be shown last. 
5.4.3 
Ordering in tables, figures and listings 
All tables and figures will be presented per cohort, unless specified otherwise. 
All listings will be ordered by cohort, subject, analysis visit and time point, unless 
specified otherwise. 
Tables will be sorted first by cohort, then by time point. 
In tables and figures showing several parameters, each parameter will begin on a new 
page and parameters will be sorted alphabetically, within the parameter category if 
applicable. 
 
 


 
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6. 
CHANGES TO THE PLANNED ANALYSIS 
6.1 
CHANGES NOT COVERED BY PROTOCOL AMENDMENTS BEFORE 
DATABASE LOCK 
x The inoculation set is renamed as safety analysis set and will be used for the 
general and safety analyses instead of the safety analysis set defined in the 
protocol as “all inoculated participants who received any treatment” (see 
protocol section 9.1). 
x Time to first PCR positivity (defined as qPCR outcome ≥ 250 asexual 
parasites per mL blood): in the absence of positive PCR, the endpoint will 
not be derived instead of imputing the duration by 28 days.  
x Time to parasitaemia of >= 5000 parasites per mL blood: summarised using 
Kaplan Meier estimates instead of geometric mean (95% CI), SD and range.  
x Endpoints related to the 10000 parasites per mL blood are removed from the 
analysis since the threshold for Cohort 2 was modified to 5000 parasites per 
mL blood. 
x log10PRR48, PC50 and PC99 are estimated using the weighted average 
slope and standard error of the subjects with the optimal regression model 
having a p-value <0.001. 
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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Page 38 of 50 
7. 
REFERENCES 
ICH Topic E6(R2) Guideline for Good Clinical Practice – Step 4, 9 November 2016. 
ICH guideline E14: the clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs (R3) – questions and answers, 
January 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. 
Hartung J, Knapp G, Sinha B. 2008. Statistical meta-analysis with applications, p 35–
41. John Wiley & Sons, Inc, Hoboken, NJ. 
Leesa F Wockner, Isabell Hoffmann, Lachlan Webb, Benjamin Mordmüller, Sean C 
Murphy, James G Kublin, Peter O’Rourke, James S McCarthy, Louise Marquart, 
Growth Rate of Plasmodium falciparum: Analysis of Parasite Growth Data From 
Malaria Volunteer Infection Studies, The Journal of Infectious Diseases, Volume 221, 
Issue 6, 15 March 2020, Pages 963–972, https://doi.org/10.1093/infdis/jiz557 .  
Marquart, L.C., Baker, M., O'Rourke, P., & McCarthy, J.S. (2015). Evaluating the 
pharmacodynamic effect of antimalarial drugs in clinical trials by quantitative PCR. 
Antimicrobial agents and chemotherapy, 59 7, 4249-59 . 
 


 
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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 
Major 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 
Antimalarial Treatment  
SAF 
14.1.2.8 
Antimalarial Treatment Discontinuation 
SAF 
PHARMACODYNAMICS 
14.2.3.1.1 
Time to First PCR Positivity (days): Descriptive Statistics 
PD 
14.2.3.1.2 
Time to First PCR Positivity (days): Descriptive Statistics 
m-PD 
14.2.3.2.1 
Parasitaemia at First PCR Positivity (parasites/mL): Descriptive Statistics 
PD 
14.2.3.2.2 
Parasitaemia at First PCR Positivity (parasites/mL): Descriptive Statistics 
m-PD 
14.2.3.3.1 
Time to Parasitaemia of ≥5000 Parasites per mL Blood (days): Kaplan 
Meier Estimates 
PD 
14.2.3.3.2 
Time to Parasitaemia of ≥5000 Parasites per mL Blood (days): Kaplan 
Meier Estimates 
m-PD 
14.2.3.4.1 
Parasitaemia at the Time of ≥5000 Parasites per mL Blood (parasites/mL): 
Descriptive Statistics 
PD 
14.2.3.4.2 
Parasitaemia at the Time of ≥5000 Parasites per mL Blood (parasites/mL): 
Descriptive Statistics 
m-PD 
14.2.3.5.1 
Time to First Dose of Treatment with Riamet (days): Descriptive Statistics 
PD 
14.2.3.5.2 
Time to First Dose of Treatment with Riamet (days): Descriptive Statistics 
m-PD 
14.2.3.6.1 
Parasitaemia at First Dose of Treatment with Riamet (Parasites/mL): 
Descriptive Statistics 
PD 
14.2.3.6.2 
Parasitaemia at First Dose of Treatment with Riamet (Parasites/mL): 
Descriptive Statistics 
m-PD 
14.2.3.7.1 
Incidence of Parasitaemia 
PD 
14.2.3.7.2 
Incidence of Parasitaemia 
m-PD 
14.2.3.8.1 
Blood-Stage Parasite Profile: Log-Linear Mixed Model Estimates 
PD 
14.2.3.8.2 
Blood-Stage Parasite Profile: Log-Linear Mixed Model Estimates 
m-PD 


 
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Final 1.0 of 11FEB2021 
 
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14.2.3.9.1 
Blood-Stage Parasite Profile: Extended Log-Linear Mixed Model 
Estimates 
PD 
14.2.3.9.2 
Blood-Stage Parasite Profile: Extended Log-Linear Mixed Model 
Estimates 
m-PD 
14.2.3.10.1 
Blood-Stage Parasite Profile: Model Derived Population Parameters 
PD 
14.2.3.10.2 
Blood-Stage Parasite Profile: Model Derived Population Parameters 
m-PD 
14.2.3.11.1 
Blood-Stage Parasite Profile: Model Derived Parameters Based on 
Individual Parameter Estimates 
PD 
14.2.3.11.2 
Blood-Stage Parasite Profile: Model Derived Parameters Based on 
Individual Parameter Estimates 
m-PD 
14.2.3.12.1 
Blood-Stage Parasite Profile: Model Derived Parameters Based on 
Simulated Individual Parameter Values 
PD 
14.2.3.12.2 
Blood-Stage Parasite Profile: Model Derived Parameters Based on 
Simulated Individual Parameter Values 
m-PD 
14.2.3.13.1 
Blood-Stage Parasite Clearance Profile: Individual Log-Linear Model 
Estimates 
PD 
14.2.3.13.2 
Blood-Stage Parasite Clearance Profile: Individual Log-Linear Model 
Estimates 
m-PD 
14.2.3.14.1 
Blood-Stage Parasite Clearance Profile: Descriptive Statistics 
PD 
14.2.3.14.2 
Blood-Stage Parasite Clearance Profile: Descriptive Statistics 
m-PD 
14.2.3.15.1 
Descriptive Statistics of log10(Parasitaemia) Actual Values 
PD 
14.2.3.15.2 
Descriptive Statistics of log10(Parasitaemia) Actual Values 
m-PD 
SAFETY 
ADVERSE EVENTS 
14.3.1.1 
Adverse Events Overview 
SAF 
14.3.1.2 
Adverse Events by MedDRA System Organ Class and Preferred Term 
SAF 
14.3.1.3 
Adverse Events by MedDRA Preferred Term by Descending Order of 
Frequency 
SAF 
14.3.1.4 
Serious Adverse Events by MedDRA System Organ Class and Preferred 
Term 
SAF 
14.3.1.5 
Grade 3 or More Adverse Events by MedDRA System Organ Class and 
Preferred Term 
SAF 
14.3.1.6 
PfSPZ Inoculum Related Adverse Events by MedDRA System Organ 
Class and Preferred Term 
SAF 
14.3.1.7 
Antimalarial Treatment Related Adverse Events by MedDRA System 
Organ Class and Preferred Term 
SAF 
14.3.1.8 
Serious PfSPZ Inoculum Related Adverse Events by MedDRA System 
Organ Class and Preferred Term 
SAF 
14.3.1.9 
Adverse Events for which the Antimalarial Treatment Was Discontinued 
by MedDRA System Organ Class and Preferred Term 
SAF 
14.3.1.10 
Adverse Events of Special Interest Related to PfSPZ Inoculum by 
MedDRA System Organ Class and Preferred Term 
SAF 
14.3.1.11 
Adverse Events of Special Interest Related to Antimalarial Treatment by 
MedDRA System Organ Class and Preferred Term 
SAF 


 
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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 
MALARIA CLINICAL SCORE 
14.3.5.1 
Descriptive Statistics of Malaria Clinical Score 
SAF 
14.3.5.2 
Frequency Table of the Worst-Case Individual Malaria Signs and 
Symptoms 
SAF 
8.2 
LISTINGS 
GENERAL CHARACTERISTICS 
16.2.1.1 
Allocation 
SCR 
16.2.1.2 
Analysis Phases 
SAF 
16.2.1.3 
Study and Antimalarial Treatment Discontinuation 
SAF 
16.2.2.1 
Major Protocol Deviations 
SAF 
16.2.2.2 
Violations on Eligibility Criteria 
SAF 
16.2.2.3 
No-Inoculated Subjects 
SCR 
minus 
SAF 
16.2.4.1 
Demographic Data 
SAF 
16.2.4.2 
Smoking History 
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 Laboratory Tests 
SAF 
16.2.4.6 
Pregnancy Tests 
SAF 
16.2.4.7 
rRT-PCR Tests for SARS-CoV-2 Infection 
SAF 
16.2.4.8 
Medical History 
SAF 
16.2.4.9 
Concomitant Diseases 
SAF 
16.2.4.10 
Prior and Concomitant Therapies  
SAF 
16.2.4.11 
Antimalarial Treatment 
SAF 
16.2.4.12 
Comments 
SAF 
16.2.5.1 
Exposure to Challenge Agent 
SAF 


 
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Final 1.0 of 11FEB2021 
 
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PHARMACODYNAMICS 
16.2.6.1 
Parasitaemia 
PD 
16.2.6.2 
Parasitaemia Endpoints 
PD 
16.2.6.3 
Blood-Stage Parasite Clearance Profile: Iteration Process to Determine the 
Optimal Log-Linear Model 
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 
Adverse Events for Which the Study Was Discontinued  
SAF 
16.2.7.5 
Adverse Events for Which the Antimalarial Treatment Was Discontinued  
SAF 
16.2.7.6 
Adverse Events after Administration of Antimalarial Treatment 
SAF 
16.2.7.7 
Adverse Events for Which Another Action Is Taken 
SAF 
16.2.7.8 
Adverse Events: Coding Information 
SAF 
16.2.7.9 
Physical Examinations Abnormalities 
SAF 
LABORATORY DATA 
16.2.8.1 
Laboratory Test Results for Subjects with Abnormal Values 
SAF 
VITAL SIGNS 
16.2.9.1 
Vital Signs Results for Subjects with Abnormal Values 
SAF 
ECG 
16.2.10.1 
ECG Results for Subjects with Abnormal Values 
SAF 
16.2.10.2 
ECG Interpretation and Morphology for Subjects with any Abnormal 
Interpretation 
SAF 
MALARIA CLINICAL SCORE 
16.2.11.1 
Malaria Signs and Symptoms 
SAF 
16.2.11.2 
Malaria Clinical Scores > 6 and Parasitaemia 
SAF 
8.3 
FIGURES 
PHARMACODYNAMICS 
14.2.3.1.1 
Blood-Stage Parasite Profile: Median Parasitaemia Actual Values over 
Time 
PD 
14.2.3.1.2 
Blood-Stage Parasite Profile: Median Parasitaemia Actual Values over 
Time 
m-PD 
14.2.3.2.1 
Blood-Stage Parasite Profile: Individual Parasitaemia Actual Values over 
Time 
PD 
14.2.3.2.2 
Blood-Stage Parasite Profile: Individual Parasitaemia Actual Values over 
Time 
m-PD 
14.2.3.3.1 
Time to first PCR positivity: Kaplan Meier Plot 
PD 
14.2.3.3.2 
Time to first PCR positivity: Kaplan Meier Plot 
m-PD 


 
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Final 1.0 of 11FEB2021 
 
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14.2.3.4.1 
Time to parasitaemia of ≥5000 parasites per mL blood: Kaplan Meier Plot 
PD 
14.2.3.4.2 
Time to parasitaemia of ≥5000 parasites per mL blood: Kaplan Meier Plot 
m-PD 
14.2.3.5.1 
Time to First Dose of Treatment with Riamet: Kaplan Meier Plot 
PD 
14.2.3.5.2 
Time to First Dose of Treatment with Riamet: Kaplan Meier Plot 
m-PD 
14.2.3.6.1 
Time to Parasite Clearance: Kaplan Meier Plot 
PD 
14.2.3.6.2 
Time to Parasite Clearance: Kaplan Meier Plot 
m-PD 
LABORATORY DATA 
14.3.2.1 
Individual Laboratory Test Actual Values over Time 
SAF 
VITAL SIGNS 
14.3.3.1 
Individual Vital Signs Actual Values over Time 
SAF 
ECG 
14.3.4.1 
Individual ECG Actual Values over Time 
SAF 
MALARIA CLINICAL SCORE 
14.3.5.1 
Individual Malaria Clinical Score Actual Values over Time 
SAF 
14.3.5.2 
Individual Malaria Clinical Score and Parasitaemia Actual Values over 
Time 
SAF 
14.3.5.3 
Individual Malaria Clinical Score and CRP Actual Values over Time 
SAF 


 
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Final 1.0 of 11FEB2021 
 
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9. 
APPENDICES 
9.1 
SAS CODE 
Blood-stage parasite clearance profile: 
 
data ds; 
   set ...; 
   laval = log10(aval); 
run; 
 
proc glm data = ds alpha = 0.05; 
   by usubjid; 
   model laval = areltm / clparm; 
run; 
 
 


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9.2 
SCHEDULE OF ASSESSMENTS 
 
Assessments 
Screening Visit 
Day -28 to Day -2 
 
Challenge, treatment and follow-up 
EOS Visit 
Day 28Error! Reference source not found. 
Study Day/Event 
Day -1Er
ror! 
Reference 
source not 
found. 
Day 1 
Day 2-6 
Day 7-9 
Day 10: Start of 
Confinement in 
Clinical Unit 
Day of First PCR 
≥250 Parasites/mL Until 
Day of First PCR 
≥5000 Parasites/mL 
Day of First PCR 
≥5000 Parasites/mL Until ≥72 h 
After Initiating Antimalarial 
Therapy 
Day of Discharge From 
Confinement: Day of 
Parasite Clearance 
(0 Parasites/mL) AND ≥72 
h After Initiating 
Antimalarial Therapy 
Time point (h) in 
relation to 
PfSPZ-DVI 
Challenge 
 
0Error! 
Reference 
source not 
found. 
2 
 
 
 
 
 
Estimated On or Before 
Day 19 
Ambulatory visit 
X 
 
 
 
 
X 
 
 
 
 
X 
Ambulatory visit 
(SARS-CoV-2 test) 
X 
 
 
 
 
X 
 
 
 
 
 
Confinement in 
clinical unitError! 
Reference source not found. 
 
X 
X 
 
 
 
X 
X 
X 
(X) 
 
Discharge from 
clinical unit 
 
 
 
X 
 
 
 
 
 
X 
(X) 
Telephonic 
Monitoring for AEs 
 
 
 
 
X 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Informed consentError! 
Reference source not found. 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical and social 
history 
X 
 
 
 
 
 
 
 
 
 
 
Beck Depression 
Inventory 
X 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
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Final 1.0 of 11FEB2021 
 
Page 46 of 50 
 
Assessments 
Screening Visit 
Day -28 to Day -2 
 
Challenge, treatment and follow-up 
EOS Visit 
Day 28Error! Reference source not found. 
Study Day/Event 
Day -1Er
ror! 
Reference 
source not 
found. 
Day 1 
Day 2-6 
Day 7-9 
Day 10: Start of 
Confinement in 
Clinical Unit 
Day of First PCR 
≥250 Parasites/mL Until 
Day of First PCR 
≥5000 Parasites/mL 
Day of First PCR 
≥5000 Parasites/mL Until ≥72 h 
After Initiating Antimalarial 
Therapy 
Day of Discharge From 
Confinement: Day of 
Parasite Clearance 
(0 Parasites/mL) AND ≥72 
h After Initiating 
Antimalarial Therapy 
Time point (h) in 
relation to 
PfSPZ-DVI 
Challenge 
 
0Error! 
Reference 
source not 
found. 
2 
 
 
 
 
 
Estimated On or Before 
Day 19 
Alcohol & drug 
screenError! Reference 
source not found. 
X 
X 
 
 
 
 
 
 
 
 
 
Height & weightError! 
Reference source not found. 
X 
X 
 
 
 
 
 
 
 
 
X 
Physical 
examinationError! 
Reference source not found. 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
Vital signsError! 
Reference source not found. 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
12-lead ECGError! 
Reference source not found. 
X 
 
 
 
 
 
 
 
X 
 
 
Viral serologyError! 
Reference source not found. 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy testError! 
Reference source not found. 
X 
X 
 
 
 
 
 
 
 
 
X 
DVI of PfSPZ 
Challenge 
 
 
X 
 
 
 
 
 
 
 
 
Riamet®Error! Reference 
source not found.  
 
 
 
 
 
 
 
 
XError! Reference source not found. 
 
 
Malaria Clinical 
ScoreError! Reference source 
not found. 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Haematology & liver 
biochemistryError! 
Reference source not found. 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 


Statistical Analysis Plan 
 
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Stage_19_01 
 
Final 1.0 of 11FEB2021 
 
Page 47 of 50 
 
Assessments 
Screening Visit 
Day -28 to Day -2 
 
Challenge, treatment and follow-up 
EOS Visit 
Day 28Error! Reference source not found. 
Study Day/Event 
Day -1Er
ror! 
Reference 
source not 
found. 
Day 1 
Day 2-6 
Day 7-9 
Day 10: Start of 
Confinement in 
Clinical Unit 
Day of First PCR 
≥250 Parasites/mL Until 
Day of First PCR 
≥5000 Parasites/mL 
Day of First PCR 
≥5000 Parasites/mL Until ≥72 h 
After Initiating Antimalarial 
Therapy 
Day of Discharge From 
Confinement: Day of 
Parasite Clearance 
(0 Parasites/mL) AND ≥72 
h After Initiating 
Antimalarial Therapy 
Time point (h) in 
relation to 
PfSPZ-DVI 
Challenge 
 
0Error! 
Reference 
source not 
found. 
2 
 
 
 
 
 
Estimated On or Before 
Day 19 
Biochemistry other 
than liverError! Reference 
source not found. 
X 
X 
 
 
 
 
X 
 
X 
 
X 
CRP analysisError! 
Reference source not found. 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Coagulation 
parametersError! 
Reference source not found. 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
rRT-PCR for SARS-
CoV-2 
Xr 
 
 
 
 
Xs 
 
 
 
 
 
qPCR for 
parasitesError! Reference 
source not found. 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Parasite 
TranscriptomicsError! 
Reference source not found. 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Previous medications 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
AEs 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
SAE reporting 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
β-HCG: β-human chorionic gonadotropin, AE: adverse event, aPTT: activated partial thromboplastin time, CMV: cytomegalovirus, CRP: C-reactive protein, DVI: direct venous inoculation, EBV: 
Epstein Barr Virus, ECG: electrocardiogram, EOS: end of study, FSH: follicle stimulating hormone, HbsAg: hepatitis B surface antigen , HCV: hepatitis C virus, HIV: human immunodeficiency 
virus, IgM: immunoglobulin M, INR: international normalized ratio, PfSPZ: Plasmodium falciparum sporozoites, PT: prothrombin time, qPCR: quantitative polymerase chain reaction, rRT-PCR: 
real-time reverse transcription polymerase chain reaction,  SAE: serious adverse event, SARS-CoV-2: severe acute respiratory syndrome coronavirus 2 


Statistical Analysis Plan 
 
MMV_PfSPZ-DVI Blood 
Stage_19_01 
 
Final 1.0 of 11FEB2021 
 
Page 48 of 50 
 
a. Assessments begin as of participant confinement in the clinical unit and must be completed and safety assessment outcomes must be available before PfSPZ-DVI Challenge on Day 1. 
b. On Day 1, assessments begin as of 3 h before challenge (except for urinalysis assessments, morning void allowed). The assessments indicated must be completed and safety assessment outcomes 
must be available before PfSPZ-DVI Challenge inoculation. 
c. Confinement to the clinical unit will occur as follows: 
x 
Participants will be admitted to the clinical unit in the morning of Day -1 and discharged from confinement 2 h post PfSPZ-DVI Challenge on Day 1. 
x 
Participants will be admitted to the clinical unit in the morning of Day 10 and discharged on Day of discharge from confinement (Day of parasite clearance AND ≥72 h after initiating 
antimalarial therapy), estimated to occur on or before Day 19. Of note, participants who commence antimalarial therapy on Day 24 (see Error! Reference source not found.) will only be 
discharged from confinement at the end of the EOS visit on Day 28. 
d. No study-related procedure is to be performed before voluntarily signing of the informed consent form. 
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, at admission on Day -1 and at the EOS visit. 
g. Physical examination will be conducted: 
x 
once at screening and once on Day -1; 
x 
once on Day 10 (upon admission to clinical unit for confinement);  
x 
once within 24 h after first PCR ≥250 parasites/mL; 
x 
once within 24 h after first PCR ≥5000 parasites/mL; 
x 
once at pre-discharge from clinical unit on Day of discharge from confinement (Day of parasite clearance AND ≥72 h after initiating antimalarial therapy); and 
x 
once at the EOS. 
Full physical examination will be conducted at screening, on Day -1, within ±24 h after first PCR ≥250 parasites/mL and at the EOS visit on Day 28. Targeted (symptom-driven) physical 
examination will be performed on the other time points in case malaria clinical score >6. 
h. Vital signs (blood pressure and pulse) will be measured after remaining in a supine position for at least 10 min. All measurements will be performed as follows: 
x 
once at screening and once on Day -1; 
x 
on Day 1 (pre and post PfSPZ-DVI Challenge); 
x 
twice daily from Day 10 (admission to clinical unit for confinement) onwards until Day of discharge from confinement (Day of parasite clearance AND ≥72 h after initiating antimalarial 
therapy); and 
x 
once at the EOS. 
Body temperature (sublingual) will also be assessed, and this whenever the malaria clinical score will be evaluated (see Error! Reference source not found.). 
At screening, orthostatic changes to blood pressure and pulse rate will also be assessed: participants will be requested to stand after completion of the supine measurements and blood pressure 
and pulse rate will be recorded after at least 2 min in the standing position. 


Statistical Analysis Plan 
 
MMV_PfSPZ-DVI Blood 
Stage_19_01 
 
Final 1.0 of 11FEB2021 
 
Page 49 of 50 
 
i. 12-lead ECGs recordings will be performed in triplicate after participants have remained in a supine position for at least 10 min. All recordings will be performed as follows: 
x 
once at screening; and 
x 
once on Days 2 and 3 of antimalarial therapy. 
j. Serological testing for HIV, hepatitis A IgM antibody, HbsAg, anti-HCV antibody, hepatitis D antibody (only in subjects positive for HbsAg), hepatitis E IgM antibody, CMV IgM antibody and 
EBV IgM antibody, to determine eligibility for the study. 
k. Pregnancy testing consists of serum β-HCG assessments at screening and at the EOS visit and a urine β-HCG assessment on Day-1.  
l. Every participant will be prescribed a 3-day oral course of Riamet® (20 mg artemether and 120 mg lumefantrine tablets) (see Protocol Section 5.1). The first dose should be taken as soon as 
possible when a PCR threshold of 5000 parasites/mL is achieved or earlier if a participant has a malaria clinical score >6 or at Investigator’s discretion. Of note, all participants inoculated with 
PfSPZ-DVI Challenge will commence antimalarial therapy no later than Day 24, regardless if they reach the pre-defined cohort-specific PCR parasitaemia/malaria clinical score thresholds (i.e., 
5000 parasites/mL blood and/or a malaria clinical score ≥6) (see Protocol Section 4.3). 
If an intolerance or contraindication to Riamet® develops since inclusion, Malarone® will be administered (see Protocol Section 5.1). 
m. Malaria clinical score for malaria signs and symptoms and the vital sign parameter body temperature (sublingual) (see Error! Reference source not found.) are assessed: 
x 
on Day 1 (pre-PfSPZ-DVI Challenge);  
x 
once daily during ambulatory visits on Day 7, 8 and 9; 
x 
twice daily from Day 10 (admission to clinical unit for confinement) onwards until Day of discharge from confinement (Day of parasite clearance AND ≥72 h after initiating antimalarial 
therapy); and 
x 
once at the EOS. 
n. Haematology and liver biochemistry laboratory tests will be performed after overnight fast for at least 8 h (see Protocol Section 4.3): 
x 
once at screening and once on Day -1; 
x 
once during ambulatory visit on Day 7;  
x 
once on Day 10 (upon admission to clinical unit for confinement); 
x 
once within 24 h after first PCR ≥250 parasites/mL; 
x 
once on Day of first PCR ≥5000 parasites/mL AND prior to initiating antimalarial therapy (non-fasted state allowed); 
x 
once at pre-discharge from clinical unit on Day of discharge from confinement (Day of parasite clearance AND ≥72 h after initiating antimalarial therapy); and 
x 
once at the EOS. 
Troponin T will be measured at screening (fasted state), at baseline prior to inoculation on Day -1 (fasted state), and on Days 1, 2 and 3 of antimalarial therapy (non-fasted state). 
FSH will be measured at screening in all women. 
o. Biochemistry laboratory tests other than liver (including urinalysis; morning void allowed) will be performed after overnight fast for at least 8 h (see Protocol Section 4.3): 
x 
once at screening and once on Day -1; 
x 
once on Day 10 (upon admission to clinical unit for confinement); 
x 
once on Day of first PCR ≥5000 parasites/mL AND prior to initiating antimalarial therapy (non-fasted state allowed); and 
x 
once at the EOS. 


Statistical Analysis Plan 
 
MMV_PfSPZ-DVI Blood 
Stage_19_01 
 
Final 1.0 of 11FEB2021 
 
Page 50 of 50 
 
p. CRP laboratory tests will be performed at the following time points: 
x 
on Day -1; 
x 
once during ambulatory visit on Day 7;  
x 
once on Day 10 (upon admission to clinical unit for confinement); 
x 
once within 24 h after first PCR ≥250 parasites/mL; 
x 
once on Day of first PCR ≥5000 parasites/mL AND prior to initiating antimalarial therapy; 
x 
on Days 2 and 3 of antimalarial therapy; 
x 
once at pre-discharge from clinical unit on Day of discharge from confinement (Day of parasite clearance AND ≥72 h after initiating antimalarial therapy); and 
x 
once at the EOS. 
q. INR, PT and aPTT laboratory tests will be performed once at screening and once on Day -1. On the other time points thereafter, only the INR test will be performed. 
r. A nasopharyngeal swab will be taken at an ambulatory visit during screening up to Day -2 (preferably as close as possible to the day of admission, based on test capacity and according to national 
laws) from participants who are still eligible to be enrolled in the study after completing all other screening tests. An rRT-PCR test will be performed on these swabs to screen for infection with 
SARS-CoV-2. 
s. A nasopharyngeal swab will be taken prior to confinement to the study site on Day 10, based on test capacity and according to national laws. 
t. Blood samples for the assessment of parasitaemia by qPCR will be drawn at the following time points: 
x 
on Day 1 (pre-PfSPZ-DVI Challenge); 
x 
once daily during ambulatory visits on Day 7, 8 and 9; 
x 
twice daily from Day 10 (admission to clinical unit for confinement) onwards until Day of first PCR ≥5000 parasites/mL AND prior to initiating antimalarial therapy; 
x 
at multiple time points (2, 6, 8, 12, 16, 24, 36, 48 and 72 h) following initiation of Riamet®;  
x 
once on Day of discharge from confinement (Day of parasite clearance AND ≥72 h after initiating antimalarial therapy); and 
x 
once at the EOS. 
All qPCR blood samples will be drawn for immediate analysis, except for the ones drawn at the multiple time points during Riamet® therapy. 
u. Blood samples for parasite transcriptomics will be drawn at the following time points: 
x 
once daily during ambulatory visits on Day 7, 8 and 9; 
x 
once daily from Day 10 (admission to clinical unit for confinement) onwards until Day of discharge from confinement (Day of parasite clearance AND ≥72 h after initiating antimalarial 
therapy); and 
x 
once at the EOS. 
v. All participants will be asked non-leading questions to determine the occurrence of any AEs at the EOS visit. 
Of note, for participants who commence antimalarial therapy on Day 24 (Error! Reference source not found.), the Day of discharge from confinement will coincide with the EOS. In this case, 
applicable assessments will not be performed in duplicate. 
 


 
 
 
 
MOCK TABLES, LISTINGS AND FIGURES 
 
A single centre, open label, pilot phase Ib study to investigate blood stage malaria infection after Direct Venous 
Inoculation of cryopreserved Plasmodium falciparum (NF54 strain) Sporozoites (PfSPZ-DVI) in malaria naïve 
healthy adult volunteers 
 
Protocol: MMV_PfSPZ-DVI Blood Stage_19_01 
SGS LS number: BE-80-1914715 
Development phase: Ib 
Sponsor: Medicines for Malaria Venture (MMV) 
Mock TLF version number: Final 1.0  
SAP version date: 11FEB2021  


MMV_PfSPZ-DVI Blood Stage_19_01 
Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 2 of 117 
Confidential document 
SIGNATURE PAGE 
Name and function 
Date (ddMMMyyyy) 
Signature 
SGS-LS author(s): 
Daniel Izquierdo 
Juncàs, Biostatistician 
11FEB2021 
 
 
 
Bastiaan Jansen, 
Biostatistical 
Coordinator 
11FEB2021 
 
 
 
Sponsor’s approval: 
The approver agrees the tables, listings and figures of the statistical analysis will be created according to this document. 
Farouk Chughlay, 
Project and Medical 
Director 
 
 
 
 
Myriam El Gaaloul 
Director, Clinical 
Sciences 
 
 
 
 


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Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 3 of 117 
Confidential document 
1. 
TABLE OF CONTENTS 
Signature page 
2 
1. 
Table of contents 
3 
1.1 
Table of contents of the Tables 
7 
1.1.1 
General Characteristics 
7 
1.1.2 
Pharmacodynamics 
7 
1.1.3 
Adverse events 
8 
1.1.4 
Laboratory data 
9 
1.1.5 
Vital signs 
9 
1.1.6 
ECG 
9 
1.1.7 
Malaria clinical score 
10 
1.2 
Table of contents of the Listings 
11 
1.2.1 
General Characteristics 
11 
1.2.2 
Pharmacodynamics 
12 
1.2.3 
Adverse events 
12 
1.2.4 
Laboratory data 
12 
1.2.5 
Vital signs 
13 
1.2.6 
ECG 
13 
1.2.7 
Malaria clinical score 
13 
1.3 
Table of contents of the Figures 
14 
1.3.1 
Pharmacodynamics 
14 


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Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 4 of 117 
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1.3.2 
Laboratory data 
14 
1.3.3 
Vital signs 
14 
1.3.4 
ECG 
14 
1.3.5 
Malaria clinical score 
14 
2. 
General layout of a TLF 
15 
2.1 
Software used 
15 
2.2 
Layout specifications in SAS 
15 
2.3 
Layout specifications in MS Word 
17 
2.4 
General table layout 
18 
2.4.1 
Standard layout for descriptive statistics on continuous parameters 
18 
2.4.2 
Standard layout for frequency tabulations 
19 
2.4.3 
Standard layout for table containing descriptive statistics and frequency tabulations 
20 
2.4.4 
Standard layout of an analysis table of contents 
21 
2.5 
General figure layout 
22 
3. 
Mock tables 
23 
3.1 
General characteristics 
23 
3.1.1 
Subject disposition 
23 
3.1.2 
Protocol deviations and eligibility 
26 
3.1.3 
Demographic and other baseline characteristics 
27 
3.1.4 
Medical history and concomitant diseases 
31 
3.1.5 
Prior and concomitant therapies 
32 


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Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
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3.2 
Pharmacodynamics 
35 
3.3 
Safety 
51 
3.3.1 
Adverse events 
51 
3.3.2 
Clinical laboratory evaluation 
58 
3.3.3 
Vital signs 
61 
3.3.4 
Electrocardiograms (ECG) 
62 
3.3.5 
Malaria clinical score 
65 
4. 
Mock listings 
68 
4.1 
General characteristics 
68 
4.1.1 
Subject disposition 
68 
4.1.2 
Protocol deviations and eligibility 
71 
4.1.3 
Demographic and other baseline characteristics 
74 
4.1.4 
Medical history and concomitant diseases 
81 
4.1.5 
Prior and concomitant therapies 
83 
4.1.6 
Comments 
85 
4.1.7 
Exposure to challenge agent 
86 
4.2 
Pharmacodynamics 
87 
4.3 
Safety 
90 
4.3.1 
Adverse events 
90 
4.3.2 
Physical examinations 
95 
4.3.3 
Clinical laboratory evaluation 
96 


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Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
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4.3.4 
Vital signs 
97 
4.3.5 
ECG 
98 
4.3.6 
Malaria clinical score 
101 
5. 
Template figures 
103 
5.1 
Pharmacodynamics 
103 
5.2 
Safety 
111 
5.2.1 
Clinical laboratory evaluation 
111 
5.2.2 
Vital signs 
113 
5.2.3 
ECG 
114 
5.2.4 
Malaria clinical score 
115 
 
 


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Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
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1.1 
TABLE OF CONTENTS OF THE TABLES 
1.1.1 
General Characteristics 
TABLE 14.1.1.1: ANALYSIS SETS ............................................................................................................................................................................... 23 
TABLE 14.1.1.2: FIRST AND LAST CONTACT IN THE STUDY ............................................................................................................................. 24 
TABLE 14.1.1.3: STUDY DISCONTINUATION.......................................................................................................................................................... 25 
TABLE 14.1.1.4: MAJOR PROTOCOL DEVIATIONS ................................................................................................................................................ 26 
TABLE 14.1.2.1: DEMOGRAPHIC DATA ................................................................................................................................................................... 27 
TABLE 14.1.2.2: ORTHOSTATIC CHANGE IN VITAL SIGNS AT SCREENING ................................................................................................... 29 
TABLE 14.1.2.3: BECK DEPRESSION INVENTORY AT SCREENING ................................................................................................................... 30 
TABLE 14.1.2.4: MEDICAL HISTORY ........................................................................................................................................................................ 31 
TABLE 14.1.2.5: CONCOMITANT DISEASES ........................................................................................................................................................... 31 
TABLE 14.1.2.6: PRIOR AND CONCOMITANT THERAPIES BY ATC CLASS (LEVEL 4) AND GENERIC TERM .......................................... 32 
TABLE 14.1.2.7: ANTIMALARIAL TREATMENT ..................................................................................................................................................... 33 
TABLE 14.1.2.8: ANTIMALARIAL TREATMENT DISCONTINUATION ............................................................................................................... 34 
 
1.1.2 
Pharmacodynamics 
TABLE 14.2.3.1.1: TIME TO FIRST PCR POSITIVITY (DAYS): DESCRIPTIVE STATISTICS ............................................................................. 36 
TABLE 14.2.3.2.1: PARASITAEMIA AT FIRST PCR POSITIVITY (PARASITES/mL): DESCRIPTIVE STATISTICS ........................................ 36 
TABLE 14.2.3.3.1: TIME TO PARASITAEMIA OF ≥5000 PARASITES PER mL BLOOD (DAYS): KAPLAN MEIER ESTIMATES ................ 37 
TABLE 14.2.3.4.1: PARASITAEMIA AT THE TIME OF ≥5000 PARASITES PER mL BLOOD (PARASITES/mL): DESCRIPTIVE 
STATISTICS ............................................................................................................................................................................................................... 38 


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TABLE 14.2.3.5.1: TIME TO FIRST DOSE OF TREATMENT WITH RIAMET (DAYS): DESCRIPTIVE STATISTICS ...................................... 38 
TABLE 14.2.3.6.1: PARASITAEMIA AT FIRST DOSE OF TREATMENT WITH RIAMET (PARASITES/mL): DESCRIPTIVE STATISTICS . 38 
TABLE 14.2.3.7.1: INCIDENCE OF PARASITAEMIA ............................................................................................................................................... 39 
TABLE 14.2.3.8.1: BLOOD-STAGE PARASITE PROFILE: LOG-LINEAR MIXED MODEL ESTIMATES .......................................................... 40 
TABLE 14.2.3.9.1: BLOOD-STAGE PARASITE PROFILE: EXTENDED LOG-LINEAR MIXED MODEL ESTIMATES ................................... 42 
TABLE 14.2.3.10.1: BLOOD-STAGE PARASITE PROFILE: MODEL DERIVED POPULATION PARAMETERS .............................................. 44 
TABLE 14.2.3.11.1: BLOOD-STAGE PARASITE PROFILE: MODEL DERIVED PARAMETERS BASED ON INDIVIDUAL PARAMETER 
ESTIMATES ............................................................................................................................................................................................................... 45 
TABLE 14.2.3.12.1: BLOOD-STAGE PARASITE PROFILE: MODEL DERIVED PARAMETERS BASED ON SIMULATED INDIVIDUAL 
PARAMETER VALUES ............................................................................................................................................................................................ 46 
TABLE 14.2.3.13.1: BLOOD-STAGE PARASITE CLEARANCE PROFILE: INDIVIDUAL LOG-LINEAR MODEL ESTIMATES .................... 47 
TABLE 14.2.3.14.1: BLOOD-STAGE PARASITE CLEARANCE PROFILE: DESCRIPTIVE STATISTICS .......................................................... 48 
TABLE 14.2.3.15.1: DESCRIPTIVE STATISTICS OF LOG10(PARASITAEMIA) ACTUAL VALUES ................................................................. 50 
 
1.1.3 
Adverse events 
TABLE 14.3.1.1: ADVERSE EVENTS OVERVIEW .................................................................................................................................................... 51 
TABLE 14.3.1.2: ADVERSE EVENTS BY MEDDRA SYSTEM ORGAN CLASS AND PREFERRED TERM ...................................................... 52 
TABLE 14.3.1.3: ADVERSE EVENTS BY MEDDRA PREFERRED TERM BY DESCENDING ORDER OF FREQUENCY .............................. 53 
TABLE 14.3.1.4: SERIOUS ADVERSE EVENTS BY MEDDRA SYSTEM ORGAN CLASS AND PREFERRED TERM .................................... 54 
TABLE 14.3.1.5: GRADE 3 OR MORE ADVERSE EVENTS BY MEDDRA SYSTEM ORGAN CLASS AND PREFERRED TERM ................. 55 
TABLE 14.3.1.6: PfSPZ INOCULUM RELATED ADVERSE EVENTS BY MEDDRA SYSTEM ORGAN CLASS AND PREFERRED TERM . 55 


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TABLE 14.3.1.7: ANTIMALARIAL TREATMENT RELATED ADVERSE EVENTS BY MEDDRA SYSTEM ORGAN CLASS AND 
PREFERRED TERM .................................................................................................................................................................................................. 56 
TABLE 14.3.1.8: SERIOUS PfSPZ INOCULUM RELATED ADVERSE EVENTS BY MEDDRA SYSTEM ORGAN CLASS AND PREFERRED 
TERM .......................................................................................................................................................................................................................... 57 
TABLE 14.3.1.9: ADVERSE EVENTS FOR WHICH THE ANTIMALARIAL TREATMENT WAS DISCONTINUED BY MEDDRA SYSTEM 
ORGAN CLASS AND PREFERRED TERM ............................................................................................................................................................ 57 
TABLE 14.3.1.10: ADVERSE EVENTS OF SPECIAL INTEREST RELATED TO PfSPZ INOCULUM BY MEDDRA SYSTEM ORGAN CLASS 
AND PREFERRED TERM ......................................................................................................................................................................................... 57 
TABLE 14.3.1.11: ADVERSE EVENTS OF SPECIAL INTEREST RELATED TO ANTIMALARIAL TREATMENT BY MEDDRA SYSTEM 
ORGAN CLASS AND PREFERRED TERM ............................................................................................................................................................ 57 
 
1.1.4 
Laboratory data 
TABLE 14.3.2.1: DESCRIPTIVE STATISTICS OF LABORATORY TEST RESULTS ............................................................................................. 58 
TABLE 14.3.2.2: CROSS-TABULATION OF LABORATORY ABNORMALITIES VERSUS BASELINE ............................................................ 59 
TABLE 14.3.2.3: LIVER ENZYME ELEVATION CATEGORIES .............................................................................................................................. 60 
 
1.1.5 
Vital signs 
TABLE 14.3.3.1: DESCRIPTIVE STATISTICS OF VITAL SIGNS ............................................................................................................................ 61 
TABLE 14.3.3.2: CROSS-TABULATION OF VITAL SIGNS ABNORMALITIES VERSUS BASELINE ............................................................... 61 
 
1.1.6 
ECG 
TABLE 14.3.4.1: DESCRIPTIVE STATISTICS OF ECG ............................................................................................................................................. 62 


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Final 1.0  of 11FEB2021 
 
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TABLE 14.3.4.2: CROSS-TABULATION OF ECG ABNORMALITIES VERSUS BASELINE ............................................................................... 63 
TABLE 14.3.4.3: TABULATION OF QTC CHANGE ABNORMALITIES ................................................................................................................ 64 
 
1.1.7 
Malaria clinical score 
TABLE 14.3.5.1: DESCRIPTIVE STATISTICS OF MALARIA CLINICAL SCORE ................................................................................................. 65 
TABLE 14.3.5.2: FREQUENCY TABLE OF THE WORST-CASE INDIVIDUAL MALARIA SIGNS AND SYMPTOMS .................................... 66 
 
 
 
 


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1.2 
TABLE OF CONTENTS OF THE LISTINGS 
1.2.1 
General Characteristics 
LISTING 16.2.1.1: ALLOCATION ................................................................................................................................................................................ 68 
LISTING 16.2.1.2: ANALYSIS PHASES ...................................................................................................................................................................... 69 
LISTING 16.2.1.3: STUDY AND ANTIMALARIAL TREATMENT DISCONTINUATION .................................................................................... 70 
LISTING 16.2.2.1: MAJOR PROTOCOL DEVIATIONS ............................................................................................................................................. 71 
LISTING 16.2.2.2: VIOLATIONS ON ELIGIBILITY CRITERIA ............................................................................................................................... 72 
LISTING 16.2.2.3: NO-INOCULATED SUBJECTS ..................................................................................................................................................... 73 
LISTING 16.2.4.1: DEMOGRAPHIC DATA ................................................................................................................................................................. 74 
LISTING 16.2.4.2: SMOKING HISTORY ..................................................................................................................................................................... 75 
LISTING 16.2.4.3: ORTHOSTATIC CHANGE IN VITAL SIGNS AT SCREENING ................................................................................................ 76 
LISTING 16.2.4.4: BECK DEPRESSION INVENTORY AT SCREENING ................................................................................................................ 77 
LISTING 16.2.4.5: SCREENING LABORATORY TESTS .......................................................................................................................................... 78 
LISTING 16.2.4.6: PREGNANCY TESTS ..................................................................................................................................................................... 79 
LISTING 16.2.4.7: rRT-PCR TESTS FOR SARS-CoV-2 INFECTION ........................................................................................................................ 80 
LISTING 16.2.4.8: MEDICAL HISTORY ..................................................................................................................................................................... 81 
LISTING 16.2.4.9: CONCOMITANT DISEASES ......................................................................................................................................................... 82 
LISTING 16.2.4.10: PRIOR AND CONCOMITANT THERAPIES.............................................................................................................................. 83 
LISTING 16.2.4.11: ANTIMALARIAL TREATMENT ................................................................................................................................................ 84 
LISTING 16.2.4.12: COMMENTS ................................................................................................................................................................................. 85 


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LISTING 16.2.5.1: EXPOSURE TO CHALLENGE AGENT ....................................................................................................................................... 86 
 
1.2.2 
Pharmacodynamics 
LISTING 16.2.6.1: PARASITAEMIA ............................................................................................................................................................................ 87 
LISTING 16.2.6.2: PARASITAEMIA ENDPOINTS ..................................................................................................................................................... 88 
LISTING 16.2.6.3: BLOOD-STAGE PARASITE CLEARANCE PROFILE: ITERATION PROCESS TO DETERMINE THE OPTIMAL LOG-
LINEAR MODEL ....................................................................................................................................................................................................... 89 
 
1.2.3 
Adverse events 
LISTING 16.2.7.1: ADVERSE EVENTS ....................................................................................................................................................................... 90 
LISTING 16.2.7.2: SERIOUS ADVERSE EVENTS ...................................................................................................................................................... 91 
LISTING 16.2.7.3: FATAL ADVERSE EVENTS ......................................................................................................................................................... 92 
LISTING 16.2.7.4: ADVERSE EVENTS FOR WHICH THE STUDY WAS DISCONTINUED ................................................................................ 92 
LISTING 16.2.7.5: ADVERSE EVENTS FOR WHICH THE ANTIMALARIAL TREATMENT WAS DISCONTINUED ...................................... 92 
LISTING 16.2.7.6: ADVERSE EVENTS AFTER ADMINISTRATION OF ANTIMALARIAL TREATMENT ....................................................... 92 
LISTING 16.2.7.7: ADVERSE EVENTS FOR WHICH ANOTHER ACTION IS TAKEN ......................................................................................... 93 
LISTING 16.2.7.8: ADVERSE EVENTS: CODING INFORMATION ......................................................................................................................... 94 
LISTING 16.2.7.9: PHYSICAL EXAMINATIONS ABNORMALITIES ..................................................................................................................... 95 
 
1.2.4 
Laboratory data 
LISTING 16.2.8.1: LABORATORY TEST RESULTS FOR SUBJECTS WITH ABNORMAL VALUES ................................................................. 96 


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1.2.5 
Vital signs 
LISTING 16.2.9.1: VITAL SIGNS RESULTS FOR SUBJECTS WITH ABNORMAL VALUES 
97 
1.2.6 
ECG 
LISTING 16.2.10.1: ECG RESULTS FOR SUBJECTS WITH ABNORMAL VALUES ............................................................................................. 98 
LISTING 16.2.10.2: ECG INTERPRETATION AND MORPHOLOGY FOR SUBJECTS WITH ANY ABNORMAL INTERPRETATION ....... 100 
 
1.2.7 
Malaria clinical score 
LISTING 16.2.11.1: MALARIA SIGNS AND SYMPTOMS ...................................................................................................................................... 101 
LISTING 16.2.11.2: MALARIA CLINICAL SCORES > 6 AND PARASITAEMIA ................................................................................................. 102 
 
 
 
 


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1.3 
TABLE OF CONTENTS OF THE FIGURES 
1.3.1 
Pharmacodynamics 
FIGURE 14.2.3.1.1: BLOOD-STAGE PARASITE PROFILE: MEDIAN PARASITAEMIA ACTUAL VALUES OVER TIME ........................... 104 
FIGURE 14.2.3.2.1: BLOOD-STAGE PARASITE PROFILE: INDIVIDUAL PARASITAEMIA ACTUAL VALUES OVER TIME ................... 106 
FIGURE 14.2.3.3.1: TIME TO FIRST PCR POSITIVITY: KAPLAN MEIER PLOT ................................................................................................ 108 
FIGURE 14.2.3.4.1: TIME TO PARASITAEMIA OF ≥5000 PARASITES PER mL BLOOD: KAPLAN MEIER PLOT ....................................... 110 
FIGURE 14.2.3.5.1: TIME TO FIRST DOSE OF TREATMENT WITH RIAMET: KAPLAN MEIER PLOT ......................................................... 110 
FIGURE 14.2.3.6.1: TIME TO PARASITE CLEARANCE: KAPLAN MEIER PLOT .............................................................................................. 110 
 
1.3.2 
Laboratory data 
FIGURE 14.3.2.1: INDIVIDUAL LABORATORY TEST ACTUAL VALUES OVER TIME .................................................................................. 111 
 
1.3.3 
Vital signs 
FIGURE 14.3.3.1: INDIVIDUAL VITAL SIGNS ACTUAL VALUES OVER TIME ............................................................................................... 113 
1.3.4 
ECG 
FIGURE 14.3.4.1: INDIVIDUAL ECG ACTUAL VALUES OVER TIME ................................................................................................................ 114 
1.3.5 
 Malaria clinical score 
FIGURE 14.3.5.1: INDIVIDUAL MALARIA CLINICAL SCORE ACTUAL VALUES OVER TIME.................................................................... 115 
FIGURE 14.3.5.2: INDIVIDUAL MALARIA CLINICAL SCORE AND PARASITAEMIA ACTUAL VALUES OVER TIME ........................... 117 
FIGURE 14.3.5.3: INDIVIDUAL MALARIA CLINICAL SCORE AND CRP ACTUAL VALUES OVER TIME ................................................. 117 


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2. 
GENERAL LAYOUT OF A TLF 
2.1 
SOFTWARE USED 
SAS version 9.4 or later will be used for programming. TLFs will be transferred to MS WORD. 
2.2 
LAYOUT SPECIFICATIONS IN SAS 
SAS TITLE1, left will identify the project by Sponsor protocol number. In case of a blinded testrun, the analysis version will be added, or 
a note that fake treatments were used. 
SAS TITLE1, right will show the SAS datetime stamp of the table creation (batch submit datetime). 
SAS TITLE2 will present the page numbering, right aligned, in the format “PAGE X OF Y”. 
SAS TITLE3 will contain the TLF’s identification in the form TABLE 14.x.x.x, LISTING 16.2.x.x and FIGURE 14.x.x.x followed by the 
title. The title itself and the TLF number are copied from the SAP. 
SAS TITLE4 will draw a horizontal dotted line (“-------“) over the entire width of the page. 
SAS TITLE5 will show the analysis population. 
SAS TITLE6 through 10 may be used to provide further information, when deemed useful. 
Example: 
 
1 STUDY IDENTIFIER - ANALYSIS VERSION                                                                                    SAS DATE AND TIME 
2                                                                                                                              PAGE X OF Y 
3 TABLE 14.x.x.x: <TABLE TITLE> 
4 ---------------------------------------------------------------------------------------------------------------------------------------- 
5 POPULATION: ALL SUBJECTS 
6 
7 
8 
9 
10 
 


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Footnotes will be added in SAS, as deemed appropriate by the programmer. Footnotes will be used to improve the readability of the output. 
Output will be left-aligned and all text will be in CAPITALS, except for specific test units. 
The following SAS page setup will be used: 
x LSIZE = 139 
x PSIZE = 43 
Dates are formatted using the SAS date9. format: ddMMMyyyy . E.g., 16SEP1970. 
The format of times follows a 24h clock as hh:mm, from 00:00 till 23:59. 24:00 equals 00:00 on the next day. 
Datetime fields are formatted using the SAS datetime13. or datetime15. format: ddMMMyyyy:hh:mm 
 
 


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2.3 
LAYOUT SPECIFICATIONS IN MS WORD 
All tables and listings will be generated in ASCII text files by SAS, and then converted into MS Word documents, using font COURIER 
NEW 8pt. (like in these Mock TLFs). 
Page layout: 
x landscape 
x paper size: A4 
x margins in MS Word, in cm: 
Top 
3.2 
Bottom 
3.2 
Left 
2.2 
Right 
2.2 
Gutter 
0 
Header, from edge 
0.97 
Footer, from edge 
0.94 
 
 


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2.4 
GENERAL TABLE LAYOUT 
2.4.1 
Standard layout for descriptive statistics on continuous parameters 
Use of decimal places in descriptive statistics: 
x Mean, geometric mean, median, SD, geometric SD and CI will be presented with one more decimal place than the individual values. 
x Minimum, maximum and range will be presented with the same number of decimal places than the individual values. 
x P-values will be presented with four decimal places, ratios with three decimal places and estimates and test statistics with two decimal 
places. 
PARAMETER 1 (unit) 
 
                              n  Mean      S.E.     S.D.     95% C.I. *               Min      Median    Max                           
                              -- --------- -------- -------- ------------------------ -------- --------- --------                      
 COHORT 1 (N=XX)                                                                                                                   
 ---------------                                                                                                                   
 SCREENING                    XX  XX.XXX   XX.XXX   XX.XXX   (XX.XXX ; XX.XXX)        XX.XX    XX.XXX    XX.XX                         
 BASELINE                     XX  XX.XXX   XX.XXX   XX.XXX   (XX.XXX ; XX.XXX)        XX.XX    XX.XXX    XX.XX                         
 TIME POINT 3                 XX  XX.XXX   XX.XXX   XX.XXX   (XX.XXX ; XX.XXX)        XX.XX    XX.XXX    XX.XX                         
 TIME POINT 4                 XX  XX.XXX   XX.XXX   XX.XXX   (XX.XXX ; XX.XXX)        XX.XX    XX.XXX    XX.XX                         
 FOLLOW-UP                    XX  XX.XXX   XX.XXX   XX.XXX   (XX.XXX ; XX.XXX)        XX.XX    XX.XXX    XX.XX                         
 
 COHORT 2 (N=XX)                                                                                                                   
 ---------------                                                                                                                   
 SCREENING                    XX  XX.XXX   XX.XXX   XX.XXX   (XX.XXX ; XX.XXX)        XX.XX    XX.XXX    XX.XX                         
 BASELINE                     XX  XX.XXX   XX.XXX   XX.XXX   (XX.XXX ; XX.XXX)        XX.XX    XX.XXX    XX.XX                         
 TIME POINT 3                 XX  XX.XXX   XX.XXX   XX.XXX   (XX.XXX ; XX.XXX)        XX.XX    XX.XXX    XX.XX                         
 TIME POINT 4                 XX  XX.XXX   XX.XXX   XX.XXX   (XX.XXX ; XX.XXX)        XX.XX    XX.XXX    XX.XX                         
 FOLLOW-UP                    XX  XX.XXX   XX.XXX   XX.XXX   (XX.XXX ; XX.XXX)        XX.XX    XX.XXX    XX.XX                         
Etc. 
 
* CONFIDENCE INTERVAL FOR MEAN                                                                                                         
 
 


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2.4.2 
Standard layout for frequency tabulations  
It is possible that the width of tables is too much to fit on one page (due to the number of treatments / columns). In that case, the page break will 
attempt to keep information of one treatment together. I.e., the break will not be made between “n” and “%”. 
Zero frequencies are shown, but classes that were not observed in any treatment or missing values, are not presented. 
Percentages will be shown with 1 decimal place (xx.x%). It is allowed that “100.0%” is presented as “100%” to save space. 
An example for a categorical variable: 
                             COHORT 1     COHORT 2   ALL SUBJECTS 
                              (N=XX)       (N=XX)       (N=XX)       
 PARAMETER AND CLASS           n  %         n  %         n  %        
 ------------------------- ------------ ------------ -------------   
 PARAMETER 1                   
    CLASS 1                   XX  XX.X     XX  XX.X     XX  XX.X     
    CLASS 2                   XX  XX.X     XX  XX.X     XX  XX.X     
    TOTAL                     XX   100     XX   100     XX   100      
                                                                     
 PARAMETER 2                   
    CLASS 1                   XX  XX.X     XX  XX.X     XX  XX.X     
    CLASS 2                   XX  XX.X     XX  XX.X     XX  XX.X     
    CLASS 3                   XX  XX.X     XX  XX.X     XX  XX.X     
    TOTAL                     XX   100     XX   100     XX   100      
                                                                     
 PARAMETER 3                   
    CLASS 1                   XX  XX.X     XX  XX.X     XX  XX.X     
    TOTAL                     XX   100     XX   100     XX   100      
 
 


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2.4.3 
Standard layout for table containing descriptive statistics and frequency tabulations 
In case a table contains descriptive statistics as well as tabulations (for example for demographic parameters), the following presentation will be 
used: 
                         COHORT 1         COHORT 2      ALL SUBJECTS    
                         (N=XX)           (N=XX)           (N=XX)                                         
                    ---------------- ---------------- ----------------                                   
 PARAMETER 1 (unit)                                                                                       
    n                XX               XX               XX                                                 
    Mean (S.D)       XX.X (XX.X)      XX.X (XX.X)      XX.X (XX.X)                                              
    S.E.              X.X              X.X              X.X                                               
    95% C.I. *      (XX.X; XX.X)     (XX.X; XX.X)     (XX.X; XX.X)                                        
    Median           XX.X             XX.X             XX.X                                               
    Min; Max        (XX; XX)         (XX; XX)         (XX; XX)                                            
                                                                                                          
 PARAMETER 2 (unit)                                                                                       
    n                XX               XX               XX                                                 
    Mean (S.D)       XX.X (XX.X)      XX.X (XX.X)      XX.X (XX.X)                                              
    S.E.              X.X              X.X              X.X                                               
    95% C.I. *      (XX.X; XX.X)     (XX.X; XX.X)     (XX.X; XX.X)                                        
    Median           XX.X             XX.X             XX.X                                               
    Min; Max        (XX; XX)         (XX; XX)         (XX; XX)                                            
                                                                                                          
 PARAMETER 3          
    CLASS 1          XX  XX.X         XX  XX.X         XX  XX.X                                           
    CLASS 2          XX  XX.X         XX  XX.X         XX  XX.X  
    TOTAL            XX   100         XX   100         XX   100                                               
                                                                                                          
 PARAMETER 4  
    CLASS 1          XX  XX.X         XX  XX.X         XX  XX.X                                           
    CLASS 2          XX  XX.X         XX  XX.X         XX  XX.X 
    TOTAL            XX   100         XX   100         XX   100      
                                                                                                                                                                   
* CONFIDENCE INTERVAL FOR MEAN                                                                                                             
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT IN THE SAFETY SET, EXCLUDING MISSING VALUES. 
 
 


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2.4.4 
Standard layout of an analysis table of contents 
Per section of the analysis a table of contents is created automatically. Below an example: 
STUDY IDENTIFIER - ANALYSIS VERSION                                                                                      SAS DATE AND TIME 
 
TABLE OF CONTENTS 
----------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                    
 DISPLAY / LISTING                                                                                                                  
 ---------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                    
 LISTING 16.2.1.1: SUBJECT DISPOSITION: ALLOCATION                                                                                  
 TABLE 14.1.1.1: SUBJECT DISPOSITION: TABULATION OF THE STUDY TERMINATION                                                           
 TABLE 14.1.1.2: SUBJECT DISPOSITION: TABULATION OF THE NUMBER OF SUBJECTS IN EACH ANALYSIS POPULATION                              
 LISTING 16.2.1.2: SUBJECT DISPOSITION: STUDY TERMINATION                                                                           
 LISTING 16.2.1.3: SUBJECT DISPOSITION: STUDY ANALYSIS PERIODS                                                                      
 LISTING 16.2.1.4: SUBJECT DISPOSITION: OVERALL LISTING OF VISITS AND ASSESSMENTS                                                   
 LISTING 16.2.1.5: SUBJECT DISPOSITION: ELIGIBILITY CRITERIA - VIOLATIONS                                                           
 LISTING 16.2.1.6: SUBJECT DISPOSITION: ELIGIBILITY CRITERIA - EXEMPTIONS                                                           
 LISTING 16.2.1.7: SUBJECT DISPOSITION: PROTOCOL DEVIATIONS                                                                         
 LISTING 16.2.1.8: SUBJECT DISPOSITION: NO-TREATMENT SUBJECTS                                                                       
 LISTING 16.2.1.9: SUBJECT DISPOSITION: COMMENTS                                                                                    
 LISTING 16.2.1.10: USE OF STUDY MEDICATION: ACTUAL DATA                                                                            
 TABLE 14.1.2.1: DEMOGRAPHIC DATA: DESCRIPTIVE STATISTICS                                                                           
 LISTING 16.2.2.1: DEMOGRAPHIC DATA: DEMOGRAPHIC PARAMETERS                                                                         
 LISTING 16.2.2.2: DEMOGRAPHIC DATA: SCREENING TESTS                                                                                
 LISTING 16.2.2.3: DEMOGRAPHIC DATA: MEDICAL HISTORY ABNORMALITIES                                                                  
 LISTING 16.2.2.4: DEMOGRAPHIC DATA: CONCOMITANT DISEASES                                                                           
 LISTING 16.2.2.5: PHYSICAL EXAMINATIONS                                                                                            
 
 


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2.5 
GENERAL FIGURE LAYOUT 
Please be aware that all graphs shown in this document are mock-graphs. Points, lines, axes and legends are not always study specific and are 
therefore described explicitly below each graph. 
General programmer notes: 
x Figures should be made at a high resolution and with an easily readable font size for legend and axis labels and values. 
x Markers and lines should be of sufficient size and width. 
x Labels of X- and Y-axis will be centred. 
x Colours, line types and symbols should be used in a consistent way throughout the analysis. 
x Colours, line types and symbols should be used keeping in mind figures are often printed in grey scale. 
 
 


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3. MOCK TABLES 
3.1 
GENERAL CHARACTERISTICS 
3.1.1 
Subject disposition 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.1.1.1: ANALYSIS SETS 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: ALL SCREENED SUBJECTS                                                                                                        
                                                                                                                                           
                                       COHORT 1     COHORT 2   ALL SUBJECTS                    
 ANALYSIS SET                             n  %        n  %        n  %                                                 
 ------------------------------------- ------------ ----------- ------------                                             
 ALL SCREENED SUBJECTS SET               XX          XX          XX                                                  
 SAFETY ANALYSIS SET                     XX   100    XX   100    XX   100 
 PHARMACODYNAMICS ANALYSIS SET           XX  XX.X    XX  XX.X    XX  XX.X   
 MODIFIED PHARMACODYNAMICS ANALYSIS SET  XX  XX.X    XX  XX.X    XX  XX.X   
 
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT IN THE SAFETY SET. 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.1.1.2: FIRST AND LAST CONTACT IN THE STUDY 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: ALL SCREENED SUBJECTS                                                                                                        
                                                                                                                                           
                                                                                                                                           
                                                                                                                                           
 DATE OF FIRST ICF (1):              ddMMMyyyy                                                                                             
 DATE OF LAST VISIT (2):             ddMMMyyyy                                                                                             
 DATE OF LAST CONTACT (3):           ddMMMyyyy                                                                                             
                                                                                                                                           
NOTES: (1): SIGNATURE DATE ON THE INFORMED CONSENT FORM OF THE FIRST SUBJECT.                                                              
       (2): DATE OF THE LAST VISIT IN THE STUDY (INCLUDING UNSCHEDULED VISITS).                                                            
       (3): LAST DATE OF CONTACT WITH ANY SUBJECT IN THE STUDY.                                                                            
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.1.1.3: STUDY DISCONTINUATION 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
                                                                                                                                           
                                                                                                                                           
                                 COHORT 1        COHORT 2     ALL SUBJECTS                                    
                                 (N=XX)          (N=XX)         (N=XX)                                        
 SUBJECT STATUS                   n  %            n  %           n  %                                         
----------------------------- --------------- -------------- --------------                                   
 COMPLETED                       XX  XX.X        XX  XX.X       XX  XX.X                                      
 DISCONTINUED                    XX  XX.X        XX  XX.X       XX  XX.X                                      
    ADVERSE EVENT                XX  XX.X        XX  XX.X       XX  XX.X                                      
    SUBJECT LOST TO FOLLOW-UP    XX  XX.X        XX  XX.X       XX  XX.X                                      
                                                                                                                                           
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT IN THE SAFETY SET. 
 
 


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3.1.2 
Protocol deviations and eligibility 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.1.1.4: MAJOR PROTOCOL DEVIATIONS 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY                                                                                                                       
                                                                                                                                           
                                               COHORT 1       COHORT 2     ALL SUBJECTS                      
                                               (N=XX)         (N=XX)         (N=XX)                          
 PRESENCE AND CLASS                             n  %           n  %           n  %                           
 ------------------------------------------ -------------- -------------- --------------                     
 NO MAJOR DEVIATIONS                           XX  XX.X       XX  XX.X       XX  XX.X                        
 ANY MAJOR DEVIATION                           XX  XX.X       XX  XX.X       XX  XX.X                        
    FORBIDDEN THERAPY                          XX  XX.X       XX  XX.X       XX  XX.X                        
    PROCEDURE DEVIATION                        XX  XX.X       XX  XX.X       XX  XX.X                        
                                                                                                                                           
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT IN THE SAFETY SET. 
 
 


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3.1.3 
Demographic and other baseline characteristics 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                                 SAS DATE AND TIME 
                                                                                                                                         PAGE X OF Y 
TABLE 14.1.2.1: DEMOGRAPHIC DATA 
---------------------------------------------------------------------------------------------------------------------------------------------------- 
ANALYSIS SET: SAFETY 
                                                                                                                                                     
                        COHORT 1         COHORT 2       ALL SUBJECTS                                               
                         (N=XX)           (N=XX)           (N=XX)                                                  
                    ---------------- ---------------- ----------------                                             
 AGE (years)                                                                                                       
    n                  XX               XX               XX                                                        
    Mean (S.D.)        XX.X (X.X)       XX.X (X.X)       XX.X (X.X)                                                       
    Median             XX.X             XX.X             XX.X                                                      
    Min; Max          (XX; XX)         (XX; XX)         (XX; XX)                                                   
                                                                                                                   
 HEIGHT (cm)                                                                                                       
    n                  XX               XX               XX                                                        
    Mean (S.D.)        XX.X (X.X)       XX.X (X.X)       XX.X (X.X)                                                       
    Median             XX.X             XX.X             XX.X                                                      
    Min; Max          (XX; XX)         (XX; XX)         (XX; XX)                                                   
                                                                                                                   
 WEIGHT AT SCREENING (kg)                                                                                                       
    n                  XX               XX               XX                                                        
    Mean (S.D.)        XX.X (X.X)       XX.X (X.X)       XX.X (X.X)                                                       
    Median             XX.X             XX.X             XX.X                                                      
    Min; Max          (XX; XX)         (XX; XX)         (XX; XX)                                                   
                                                                                                                   
 BMI AT SCREENING (kg/m²)                                                                                                       
    n                  XX               XX               XX                                                        
    Mean (S.D.)        XX.X (X.X)       XX.X (X.X)       XX.X (X.X)                                                       
    Median             XX.X             XX.X             XX.X                                                      
    Min; Max          (XX; XX)         (XX; XX)         (XX; XX)                                                   
                                                                                                                  
 SEX (n %) 
    FEMALE              XX  XX.X         XX  XX.X         XX  XX.X                                                  
    MALE                XX  XX.X         XX  XX.X         XX  XX.X                                                  
    TOTAL               XX   100         XX   100         XX   100          
                                                                                                                                                 
 RACE (n %) 
    BLACK               XX  XX.X         XX  XX.X         XX  XX.X                                                  
    CAUCASIAN/WHITE     XX  XX.X         XX  XX.X         XX  XX.X 
    TOTAL               XX   100         XX   100         XX   100          


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 ETHNICITY (n %) 
    HISPANIC/LATINO     XX  XX.X         XX  XX.X         XX  XX.X                                                  
    NOT HISPANIC/LATINO XX  XX.X         XX  XX.X         XX  XX.X 
    TOTAL               XX   100         XX   100         XX   100          
                                                  
                                                                                                                   
 SMOKING STATUS (n %) 
    EX-SMOKER           XX  XX.X         XX  XX.X         XX  XX.X                                                  
    NON-SMOKER          XX  XX.X         XX  XX.X         XX  XX.X                                                  
    SMOKER              XX  XX.X         XX  XX.X         XX  XX.X 
    TOTAL               XX   100         XX   100         XX   100          
                                                  
                                                                                                                                                     
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT IN THE SAFETY SET, EXCLUDING MISSING VALUES.  
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                                 SAS DATE AND TIME 
                                                                                                                                         PAGE X OF Y 
TABLE 14.1.2.2: ORTHOSTATIC CHANGE IN VITAL SIGNS AT SCREENING 
---------------------------------------------------------------------------------------------------------------------------------------------------- 
ANALYSIS SET: SAFETY 
 
SYSTOLIC BLOOD PRESSURE (mmHg) 
 
                            COHORT 1        COHORT 2        ALL SUBJECTS 
                            (N=XX)           (N=XX)           (N=XX)                                                                                               
                       ---------------- ---------------- ----------------                                                                                          
 SUPINE RESULT                                                                                                                                   
    n                    XX               XX               XX                                                                                                      
    Mean (S.D.)          XX.X (X.X)       XX.X (X.X)       XX.X (X.X)                                                       
    Median               XX.X             XX.X             XX.X                                                                                                    
    Min; Max            (XX; XX)         (XX; XX)         (XX; XX)                                                                                                 
                                                                                                                                                                   
 STANDING RESULT                                                                                                                                   
    n                    XX               XX               XX                                                                                                      
    Mean (S.D.)          XX.X (X.X)       XX.X (X.X)       XX.X (X.X)                                                       
    Median               XX.X             XX.X             XX.X                                                                                                    
    Min; Max            (XX; XX)         (XX; XX)         (XX; XX)                                                                                                 
                                                                                                                                                                   
 ORTHOSTATIC CHANGE 
    n                    XX               XX               XX                                                                                                      
    Mean (S.D.)          XX.X (X.X)       XX.X (X.X)       XX.X (X.X)                                                       
    Median               XX.X             XX.X             XX.X                                                                                                    
    Min; Max            (XX; XX)         (XX; XX)         (XX; XX)                                                                                                 
                                                                                                                                                     
ORTHOSTATIC CHANGE = VALUE IN SUPINE POSITION - VALUE IN STANDING POSITION. 
Programmer notes: repeat the table by parameter: systolic blood pressure, diastolic blood pressure and heart rate. 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                                 SAS DATE AND TIME 
                                                                                                                                         PAGE X OF Y 
TABLE 14.1.2.3: BECK DEPRESSION INVENTORY AT SCREENING 
---------------------------------------------------------------------------------------------------------------------------------------------------- 
ANALYSIS SET: SAFETY 
 
                                                  COHORT 1         COHORT 2       ALL SUBJECTS                                                                     
                                                  (N=XX)           (N=XX)          (N=XX)                                                                          
                                                ---------------- --------------- ---------------                                                                   
 BECK DEPRESSION INVENTORY TOTAL SCORE                                                                                                                             
    n                                             XX               XX              XX                                                                              
    Mean (S.D.)                                   XX.X (X.X)       XX.X (X.X)      XX.X (X.X)                                                       
    Median                                        XX.X             XX.X            XX.X                                                                            
    Min; Max                                     (XX; XX)         (XX; XX)        (XX; XX)                                                                         
                                                                                                                                                                   
 BECK DEPRESSION INVENTORY INTERPRETATION 
    NORMAL                                        XX  XX.X         XX  XX.X        XX  XX.X                                                                        
    MILD MOOD DISTURBANCE                         XX  XX.X         XX  XX.X        XX  XX.X                                                                        
    BORDERLINE CLINICAL DEPRESSION                XX  XX.X         XX  XX.X        XX  XX.X     
    TOTAL                                         XX   100         XX   100        XX   100          
                                                                                
                                                                                                                                                     
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT IN THE SAFETY SET, EXCLUDING MISSING VALUES.  
 
 
 


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3.1.4 
Medical history and concomitant diseases 
 
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TABLE 14.1.2.4: MEDICAL HISTORY 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY                                                                                                                       
                                                                                                                                           
                                                    COHORT 1       COHORT 2     ALL SUBJECTS                 
                                                    (N=XX)         (N=XX)         (N=XX)                     
 SYSTEM ORGAN CLASS AND PREFERRED TERM               n  %           n  %           n  %                      
 ----------------------------------------------- -------------- -------------- --------------                
 NO MEDICAL HISTORY FINDINGS                        XX  XX.X       XX  XX.X       XX  XX.X                   
 WITH ANY MEDICAL HISTORY FINDING                   XX  XX.X       XX  XX.X       XX  XX.X                   
 EYE DISORDERS                                      XX  XX.X       XX  XX.X       XX  XX.X                   
    CATARACT                                        XX  XX.X       XX  XX.X       XX  XX.X                   
 GASTROINTESTINAL DISORDERS                         XX  XX.X       XX  XX.X       XX  XX.X                   
    DUODENAL ULCER                                  XX  XX.X       XX  XX.X       XX  XX.X                   
    UMBILICAL HERNIA                                XX  XX.X       XX  XX.X       XX  XX.X                   
 INFECTIONS AND INFESTATIONS                        XX  XX.X       XX  XX.X       XX  XX.X                   
    APPENDICITIS                                    XX  XX.X       XX  XX.X       XX  XX.X                   
    TUBERCULOSIS                                    XX  XX.X       XX  XX.X       XX  XX.X                   
                                                                                                                                           
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT IN THE SAFETY SET. 
Programmer notes: repeat similar table for concomitant diseases: 
 
TABLE 14.1.2.5: CONCOMITANT DISEASES 
 
 


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3.1.5 
Prior and concomitant therapies 
 
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TABLE 14.1.2.6: PRIOR AND CONCOMITANT THERAPIES BY ATC CLASS (LEVEL 4) AND GENERIC TERM 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
ANALYSIS PHASE = OVERALL 
                                                                                                                                           
                                   COHORT 1       COHORT 2     ALL SUBJECTS                                  
 ATC CLASS (LEVEL 4)               (N=XX)         (N=XX)         (N=XX)                                      
 AND GENERIC TERM                   n  %           n  %           n  %                                       
 ------------------------------ -------------- -------------- --------------                                 
 NO THERAPIES TAKEN                XX  XX.X       XX  XX.X       XX  XX.X                                    
 WITH THERAPIES TAKEN              XX  XX.X       XX  XX.X       XX  XX.X                                    
 ANALGESICS                        XX  XX.X       XX  XX.X       XX  XX.X                                    
    PARACETAMOL                    XX  XX.X       XX  XX.X       XX  XX.X                                    
    ULTRACET                       XX  XX.X       XX  XX.X       XX  XX.X                                    
    ZOLMITRIPTAN                   XX  XX.X       XX  XX.X       XX  XX.X                                    
 CARDIAC THERAPY                   XX  XX.X       XX  XX.X       XX  XX.X                                    
    CAFFEINE                       XX  XX.X       XX  XX.X       XX  XX.X                                    
    IBUFROFEN                      XX  XX.X       XX  XX.X       XX  XX.X                                    
Etc.                                                                                                                                           
                                                                                                                                           
 
ANALYSIS PHASE = SCREENING 
 
Etc.                                                                                                                                       
                                                                                                                                           
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT AND PER ANALYSIS PHASE IN THE SAFETY SET. 


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TABLE 14.1.2.7: ANTIMALARIAL TREATMENT 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
                                      COHORT 1       COHORT 2     ALL SUBJECTS    
                                      (N=XX)         (N=XX)         (N=XX)                                                                          
                                       n  %           n  %           n  %                                                                           
                                   -------------- -------------- --------------                                                                     
 START OF ANTIMALARIAL TREATMENT 
    PRIOR TO DAY 24                   XX  XX.X       XX  XX.X       XX  XX.X                                                                        
    ON DAY 24                         XX  XX.X       XX  XX.X       XX  XX.X  
    TOTAL                             XX   100       XX   100       XX   100        
                                                                     
 ANTIMALARIAL TREATMENT ADMINISTERED       
    MALARONE 250/100 mg               XX  XX.X       XX  XX.X       XX  XX.X                                                                        
    RIAMET 20/120 mg                  XX  XX.X       XX  XX.X       XX  XX.X   
    TOTAL                             XX   100       XX   100       XX   100        
                                                                   
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT IN THE SAFETY SET. 
                                                                        
 


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TABLE 14.1.2.8: ANTIMALARIAL TREATMENT DISCONTINUATION 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
                                                                                                                                           
                                                                                                                                           
                                 COHORT 1        COHORT 2     ALL SUBJECTS                                    
                                 (N=XX)          (N=XX)         (N=XX)                                        
 SUBJECT STATUS                   n  %            n  %           n  %                                         
----------------------------- --------------- -------------- --------------                                   
 COMPLETED                       XX  XX.X        XX  XX.X       XX  XX.X                                      
 DISCONTINUED                    XX  XX.X        XX  XX.X       XX  XX.X                                      
    ADVERSE EVENT                XX  XX.X        XX  XX.X       XX  XX.X                                      
    SUBJECT LOST TO FOLLOW-UP    XX  XX.X        XX  XX.X       XX  XX.X                                      
                                                                                                                                           
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT IN THE SAFETY SET. 
 
 


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3.2 
PHARMACODYNAMICS 
 
Programmer note: all PD tables shown in this section will be repeated for the m-PD analysis set with adjusted numbering (e.g. 14.2.3.1.2). 


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TABLE 14.2.3.1.1: TIME TO FIRST PCR POSITIVITY (DAYS): DESCRIPTIVE STATISTICS  
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 
                              n  Geom. Mean  95% C.I. <a>    Geom S.D. Min; Max        
                              -- ----------- --------------- --------- --------   
  
 COHORT 1 (N=XX)              XX  XX.XXX     XX.XXX; XX.XXX   XX.XXX    XX.XX     
 COHORT 2 (N=XX)              XX  XX.XXX     XX.XXX; XX.XXX   XX.XXX    XX.XX     
 ALL SUBJECTS (N=XX)          XX  XX.XXX     XX.XXX; XX.XXX   XX.XXX    XX.XX     
 
<a> TWO-SIDED 95% CONFIDENCE INTERVAL ON THE GEOMETRIC MEAN.                                                                    
POSITIVE PARASITAEMIA IS DEFINED AS qPCR OUTCOME ≥ 250 PARASITES PER mL BLOOD. 
ONLY SUBJECTS THAT REACHED POSITIVE PARASITAEMIA ARE INCLUDED. 
 
Programmer note: repeat Table 14.2.3.1.1 excluding the last footnote for: 
 
TABLE 14.2.3.2.1: PARASITAEMIA AT FIRST PCR POSITIVITY (PARASITES/mL): DESCRIPTIVE STATISTICS 
 
 
 


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TABLE 14.2.3.3.1: TIME TO PARASITAEMIA OF ≥5000 PARASITES PER mL BLOOD (DAYS): KAPLAN MEIER ESTIMATES 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 
                                       COHORT 1              COHORT 2         ALL SUBJECTS    
                                       (N=XX)                (N=XX)             (N=XX)                      
                                --------------------- ------------------- -------------------                 
 25th QUANTILE (95% CI)            XX.X (XX.X; XX.X)   XX.X (XX.X; XX.X)   XX.X (XX.X; XX.X)                      
 MEDIAN (95% CI)                   XX.X (XX.X; XX.X)   XX.X (XX.X; XX.X)   XX.X (XX.X; XX.X)                      
 75th QUANTILE (95% CI)            XX.X (XX.X; XX.X)   XX.X (XX.X; XX.X)   XX.X (XX.X; XX.X)                      
                                                                     
 NUMBER ASSESSED                   XX                  XX                  XX 
 NUMBER CENSORED                   XX                  XX                  XX 
 NUMBER OF EVENTS <a>              XX                  XX                  XX 
 
<a> SUBJECTS WITH PARASITAEMIA OF ≥5000 PARASITES PER mL BLOOD. 
 


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Programmer note: repeat Table 14.2.3.1.1 for: 
 
TABLE 14.2.3.4.1: PARASITAEMIA AT THE TIME OF ≥5000 PARASITES PER mL BLOOD (PARASITES/mL): DESCRIPTIVE STATISTICS 
 
TABLE 14.2.3.5.1: TIME TO FIRST DOSE OF TREATMENT WITH RIAMET (DAYS): DESCRIPTIVE STATISTICS 
 
TABLE 14.2.3.6.1: PARASITAEMIA AT FIRST DOSE OF TREATMENT WITH RIAMET (PARASITES/mL): DESCRIPTIVE STATISTICS 
 
In the previous tables the footnotes will be adapted accordingly. 
 
 


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TABLE 14.2.3.7.1: INCIDENCE OF PARASITAEMIA 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 
                                                       PARASITAEMIA OF ≥5000           
                           POSITIVE PARASITAEMIA <a> 
 PARASITES PER mL BLOOD <b>       
                           -------------------------  -------------------------  
                              n  %     90% C.I. <c>      n  %     90% C.I. <c>   
 ------------------------- -------------------------  -------------------------  
 COHORT 1 (N=XX)              XX  XX.X  XX.X; XX.X       XX  XX.X  XX.X; XX.X    
 COHORT 2 (N=XX)              XX  XX.X  XX.X; XX.X       XX  XX.X  XX.X; XX.X    
 ALL SUBJECTS (N=XX)          XX  XX.X  XX.X; XX.X       XX  XX.X  XX.X; XX.X    
 
 
<a> INCIDENCE OF POSITIVE PARASITAEMIA BETWEEN INOCULATION WITH PfSPZ AND DAY 28. 
<b> INCIDENCE OF PARASITAEMIA OF ≥5000 PARASITES PER mL BLOOD BETWEEN INOCULATION WITH PfSPZ AND DAY 28. 
<c> TWO-SIDED 90% EXACT CLOPPER-PEARSON CONFIDENCE INTERVAL. 
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
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TABLE 14.2.3.8.1: BLOOD-STAGE PARASITE PROFILE: LOG-LINEAR MIXED MODEL ESTIMATES 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 
  PARAMETER                               VALUE   RSE   SHRINKAGE   COMMENT                                       
 --------------------------------------- ------- ----- ----------- ---------------------------------------------  
  **Typical parameters**                                                                                          
  GR                                                    -           Parasite growth rate (1/hour)                 
  Finoc                                                 -           Inoculum viability (-)                        
  Pinoc                                                 -           Inoculum size (-)                             
                                                                                                                  
  **Inter-individual variability**                                                                                
  omega(GR)                                                         LogNormal                                     
  omega(Finoc)                                                      LogNormal                                     
  omega(Pinoc)                                                      LogNormal                                     
                                                                                                                  
  **Correlation of random effects**                                                                               
  corr(GR,Finoc)                                        -           Correlation coefficient                       
  corr(GR,Pinoc)                                        -           Correlation coefficient                       
  corr(Finoc,Pinoc)                                     -           Correlation coefficient                       
  ...                                                   -           ...                                           
                                                                                                                  
  **Parameter-Covariate relationships**                                                                           
  beta_GR(AGE)                                          -           AGE in Years on GR                            
  beta_GR(WT0)                                          -           Weight in kg on GR                            
  beta_GR(SEX_0)                                        -           Gender female on GR                           
  ...                                                   -           ...                                           
                                                                                                                  
  **Residual variability**                                                                                        
  error_PROP1                                                       Proportional Error (fraction) - Parasitemia   
  error_ADD1                                                        Absolute Error - Parasitemia                  
                                                                                                                  
  Objective function                              -                 -                                             
  AIC                                             -                 -                                             
  BIC                                             -                 -                                             
 
------------------------------------------------------------------------------------------------------------------------------------------ 
Model: ../PATH/TO/MODEL/DIRECTORY, Significant digits: 3 (Objective function rounded to closest integer value), omega values reported in standard 
deviation. 


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Programmer note 1: In the previous table, rows for correlation of random effects and rows for Parameter-Covariate relationships can be added or 
removed, depending on the final selected model. 
Programmer note 2: In the previous table, the path to the model directory in the footnote should be adapted accordingly. 
 
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
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TABLE 14.2.3.9.1: BLOOD-STAGE PARASITE PROFILE: EXTENDED LOG-LINEAR MIXED MODEL ESTIMATES 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 
  PARAMETER                               VALUE   RSE   SHRINKAGE   COMMENT                                       
 --------------------------------------- ------- ----- ----------- ---------------------------------------------  
  **Typical parameters**                                                                                          
  GR                                                    -           Parasite growth rate (1/hour)                 
  Finoc                                                 -           Inoculum viability (-)                        
  Pinoc                                                 -           Inoculum size (-)                             
  Fmax                                                  -           Maximum fraction of hidden parasites (-)      
  Phi                                                   -           Oscillation phase (-)                         
  Plen                                                  -           Period length of the oscillation (h)          
                                                                                                                  
  **Inter-individual variability**                                                                                
  omega(GR)                                                         LogNormal                                     
  omega(Finoc)                                                      LogNormal                                     
  omega(Pinoc)                                                      LogNormal                                     
  omega(Fmax)                                                       LogNormal                                     
  omega(Phi)                                                        LogNormal                                     
  omega(Plen)                                                       LogNormal                                     
                                                                                                                  
  **Correlation of random effects**                                                                               
  corr(GR,Finoc)                                        -           Correlation coefficient                       
  corr(GR,Pinoc)                                        -           Correlation coefficient                       
  corr(Finoc,Pinoc)                                     -           Correlation coefficient                       
  ...                                                   -           ...                                           
                                                                                                                  
  **Parameter-Covariate relationships**                                                                           
  beta_GR(AGE)                                          -           AGE in Years on GR                            
  beta_GR(WT0)                                          -           Weight in kg on GR                            
  beta_GR(SEX_0)                                        -           Gender female on GR                           
  ...                                                   -           ...                                           
                                                                                                                  
  **Residual variability**                                                                                        
  error_PROP1                                                       Proportional Error (fraction) - Parasitemia   
  error_ADD1                                                        Absolute Error - Parasitemia                  
                                                                                                                  
  Objective function                              -                 -                                             
  AIC                                             -                 -                                             
  BIC                                             -                 -                                             
 
------------------------------------------------------------------------------------------------------------------------------------------ 


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Model: ../PATH/TO/MODEL/DIRECTORY, Significant digits: 3 (Objective function rounded to closest integer value), omega values reported in standard 
deviation. 
 
Programmer note 1: The table should be included only if such an extended log-linear model had been estimated (refer to SAP section 2.1.3.1).  
Programmer note 2: In the previous table, rows for correlation of random effects and rows for Parameter-Covariate relationships can be added or 
removed, depending on the final selected model. 
Programmer note 3: In the previous table, the path to the model directory in the footnote should be adapted accordingly. 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
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TABLE 14.2.3.10.1: BLOOD-STAGE PARASITE PROFILE: MODEL DERIVED POPULATION PARAMETERS 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 
  PARAMETER                                                 MEAN    95%-CI         
 --------------------------------------------------------- ------- --------------  
                                                                                   
  **Parasitaemia multiplication rate (log10)**                                     
  PMR_48h <a>                                               X.XX    X.XX; X.XX<c>     
                                                                                   
  PMR_Plen <b>                                              X.XX    X.XX; X.XX<c>     
                                                                                   
  **Predicted time to reach parasitaemia thresholds (h)**                          
  TIME_PCRPOS <a>                                           XXX.X   XXX.X; XXX.X<d>   
  TIME_PCR5000 <a>                                          XXX.X   XXX.X; XXX.X<d>   
                                                                                   
  TIME_PCRPOS <b>                                           XXX.X   XXX.X; XXX.X<d>   
  TIME_PCR5000 <b>                                          XXX.X   XXX.X; XXX.X<d>   
 
------------------------------------------------------------------------------------------------------------------------------------------ 
POPULATION PARAMETER ESTIMATES OBTAINED UPON SAMPLING OF 1'000 SETS OF MODEL POPULATION PARAMETERS FROM THE UNCERTAINTY DISTRIBUTION: 
MEAN: SAMPLE ARITHMETIC MEAN FOR PARASITAEMIA MULTIPLICATION RATE; SAMPLE GEOMETRIC MEAN FOR PREDICTED TIME TO REACH PARASITAEMIA THRESHOLDS, I.E. 
EXP(MEAN(LOG-TRANSFORMED TIMES)); 
95%-CI: 95% CONFIDENCE INTERVAL FOR THE MEAN (SEE FOOTNOTES <c> and <d>).  
 
<a> derivation based on the log-linear mixed model; 
<b> derivation based on the extended log-linear mixed model. 
<c> calculated as -1.96*S.E.+MEAN; 1.96*S.E.+MEAN, where S.E. denotes the standard error of MEAN, i.e. S.E.=S.D./SQRT(1'000) with S.D. denoting the 
sample standard deviation.  
<d> calculated as EXP(-1.96*S.E. + LOG(MEAN)); EXP(1.96*S.E. + LOG(MEAN)), where S.E=S.D./SQRT(1'000) with S.D. denoting the sample standard 
deviation of the log-transformed times. 
 
Programmer note 1: Rows corresponding to the extended log-linear model <b> to be omitted if such model had not been inferred (refer to SAP 
section 2.1.3.1).  
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
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TABLE 14.2.3.11.1: BLOOD-STAGE PARASITE PROFILE: MODEL DERIVED PARAMETERS BASED ON INDIVIDUAL PARAMETER ESTIMATES 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 
  PARAMETER                                                 N    MEAN (RSE)  ___ S.D. __  _95%-PI        RANGE        
 --------------------------------------------------------- ---- --------------- --------- -------------- -------------  
                                                                                                                           
  **Parasitaemia multiplication rate (log10)**                                                                             
  PMR_48h <a>                                               XX   X.XX (XX%<c>)   X.XX      X.XX; X.XX__ _X.XX; X.XX   
                                                                                                                           
  PMR_Plen <b>                                              XX   X.XX (XX%<c>)   X.XX      X.XX; X.XX___ X.XX; X.XX   
                                                                                                                           
  **Predicted time to reach parasitaemia thresholds (h)**                                                                  
  TIME_PCRPOS <a>                                           XX   XXX.X (XX%<d>)  XXX.X     XXX.X; XXX.X  XXX.X; XXX.X        
  TIME_PCR5000 <a>                                          XX   XXX.X (XX%<d>)  XXX.X     XXX.X; XXX.X  XXX.X; XXX.X 
                                                                                                                           
  TIME_PCRPOS <b>                                           XX   XXX.X (XX%<d>)  XXX.X     XXX.X; XXX.X  XXX.X; XXX.X 
  TIME_PCR5000 <b>                                          XX   XXX.X (XX%<d>)  XXX.X     XXX.X; XXX.X  XXX.X; XXX.X 
 
------------------------------------------------------------------------------------------------------------------------------------------ 
SUMMARY STATISTICS OF INDIVIDUAL PARAMETER ESTIMATES: 
N: NUMBER OF INDIVIDUALS; 
MEAN: ARITHMETIC MEAN FOR PARASITAEMIA MULTIPLICATION RATE; GEOMETRIC MEAN FOR PREDICTED TIME TO REACH PARASITAEMIA THRESHOLDS; 
S.D.: STANDARD DEVIATION; 
RSE: RELATIVE STANDARD ERROR FOR MEAN (IN PERCENTILES; see footnotes <c> and <d>); 
95%-PI: 95% PREDICTION INTERVAL (see footnote <e>); 
RANGE: OBSERVED MINIMUM AND MAXIMUM. 
 
<a> derivation based on log-linear mixed model; 
<b> derivation based on extended log-linear mixed model. 
<c> relative standard error of ARITHMETIC MEAN in percentile calculated as S.D./SQRT(N)/MEAN*100; 
<d> relative standard error of GEOMETRIC MEAN in percentile calculated as S.D.(LOG-TRANSFORMED TIMES)/SQRT(N - 1)*100; 
<e> 95% prediction interval calculated as -t(N-1,0.025,0.975)*S.D.+ ARITHMETIC MEAN; t(N-1,0.025,0.975)*S.D.+ ARITHMETIC MEAN, where t(N-
1,0.025,0.975) denotes the Student t-value for N-1 degrees of freedom. Note that these procedure assumes normal distribution of the variable.   
 
Programmer note 1: Derived parameters for the extended log-linear model <b> should be omitted if such model had not been inferred (refer to SAP 
section 2.1.3.1).  
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
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TABLE 14.2.3.12.1: BLOOD-STAGE PARASITE PROFILE: MODEL DERIVED PARAMETERS BASED ON SIMULATED INDIVIDUAL PARAMETER VALUES 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 
  PARAMETER                                                 MEAN    95%-PI         
 --------------------------------------------------------- ------- --------------  
                                                                                   
  **Parasitaemia multiplication rate (log10)**                                     
  PMR_48h <a>                                               X.XX    X.XX; X.XX     
                                                                                   
  PMR_Plen <b>                                              X.XX    X.XX; X.XX     
                                                                                   
  **Predicted time to reach parasitaemia thresholds (h)**                          
  TIME_PCRPOS <a>                                           XXX.X   XXX.X; XXX.X   
  TIME_PCR5000 <a>                                          XXX.X   XXX.X; XXX.X   
                                                                                   
  TIME_PCRPOS <b>                                           XXX.X   XXX.X; XXX.X   
  TIME_PCR5000 <b>                                          XXX.X   XXX.X; XXX.X   
 
------------------------------------------------------------------------------------------------------------------------------------------ 
SUMMARY STATISTICS UPON SIMULATING 1'000 SETS OF POPULATION PARAMETERS (SAMPLING FROM UNCERTAINTY DISTRIBUTION) AND 1'000 SETS OF INDIVIDUAL 
PARAMETER VALUES (SAMPLING FROM IIV DISTRIBUTION) FOR EACH POPULATION (IN TOTAL 1'000'000 SETS OF INDIVIDUAL PARAMETER VALUES): 
MEAN: SAMPLE ARITHMETIC MEAN FOR PARASITAEMIA MULTIPLICATION RATE; SAMPLE GEOMETRIC MEAN FOR PREDICTED TIME TO REACH PARASITAEMIA THRESHOLDS; 
95%-PI: 95% PREDICTION INTERVAL CALCULATED FROM THE 0.025TH AND 0.975TH SAMPLE QUANTILES. 
 
<a> derivation based on log-linear mixed model; 
<b> derivation based on extended log-linear mixed model. 
 
Programmer note 1: The table should be included only if the model parameter IIV distribution could be estimated for all model parameters (refer to 
SAP section 2.1.3.1).  
Programmer note 2: Derived parameters for the extended log-linear model <b> should be omitted if such model had not been inferred (refer to SAP 
section 2.1.4).  
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
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TABLE 14.2.3.13.1: BLOOD-STAGE PARASITE CLEARANCE PROFILE: INDIVIDUAL LOG-LINEAR MODEL ESTIMATES 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 
COHORT = COHORT 1  
SUBJECT = XXX 
 
 
                                     ESTIMATE  S.E.   95% C.I.    P-VALUE  
-----------------------------------  --------  -----  ----------- ---------     
MODEL ESTIMATES:                                                                                
 INTERCEPT                           XX.X      XX.X   XX.X; XX.X                      
 TIME                                XX.X      XX.X   XX.X; XX.X  X.XX <a>                      
 
DERIVED PARAMETERS: 
 LOG10PRR48                          XX.X             XX.X; XX.X                      
 PC50                                XX.X             XX.X; XX.X                      
 PC99                                XX.X             XX.X; XX.X                      
 
TYPE 3 TESTS OF FIXED EFFECTS: 
 TIME                                                             X.XX <b> 
 
 
 
<a> P-VALUE BASED ON T-TEST. 
<b> P-VALUE BASED ON F-TEST. 
LOG10PRR48 = LOG10 PARASITE REDUCTION RATIO PER 48h; PC50 = PARASITE CLEARANCE HALF-LIFE (HOURS); PC99 = TIME TO REACH PARASITE CLEARANCE OF 99% 
(HOURS). 
ESTIMATES RESULTING FROM THE OPTIMAL LOG-LINEAR REGRESSION MODEL WITH TIME AS INDEPENDENT VARIABLE. 
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.2.3.14.1: BLOOD-STAGE PARASITE CLEARANCE PROFILE: DESCRIPTIVE STATISTICS 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 
TIME TO PARASITE CLEARANCE (DAYS) 
 
                              n  Geom. Mean  95% C.I. <a>    Geom. S.D. Min; Max      
                              -- ----------- --------------- ---------- ---------   
  
 COHORT 1 (N=XX)              XX  XX.XXX     XX.XXX; XX.XXX   XX.XXX    XX;XX     
 COHORT 2 (N=XX)              XX  XX.XXX     XX.XXX; XX.XXX   XX.XXX    XX;XX     
 ALL SUBJECTS (N=XX)          XX  XX.XXX     XX.XXX; XX.XXX   XX.XXX    XX;XX     
 
<a> TWO-SIDED 95% CONFIDENCE INTERVAL ON THE GEOMETRIC MEAN.                                                                    
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.2.3.14.1: BLOOD-STAGE PARASITE CLEARANCE PROFILE: DESCRIPTIVE STATISTICS 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 
LOG10 PARASITE REDUCTION RATIO PER 48h (LOG10PRR48) 
 
                              n  Mean        95% C.I.        Min; Max      
                              -- ----------- --------------- ---------   
  
 COHORT 1 (N=XX)              XX  XX.XXX     XX.XXX; XX.XXX  XX;XX     
 COHORT 2 (N=XX)              XX  XX.XXX     XX.XXX; XX.XXX  XX;XX     
 ALL SUBJECTS (N=XX)          XX  XX.XXX     XX.XXX; XX.XXX  XX;XX     
 
SUMMARY STATISTICS ESTIMATED BY USING THE INVERSE-VARIANCE METHOD TO CALCULATE THE WEIGHTED AVERAGE LINEAR REGRESSION SLOPE AND              
CORRESPONDING STANDARD ERROR.    
ONLY SUBJECTS WHOSE OPTIMAL LOG-LINEAR REGRESSION MODEL OVERALL P-VALUE < 0.001 ARE INCLUDED. 
 
Programmer notes: 
x Show the table for all parameters starting in a new page in the following order: time to parasite clearance, log10PRR48, PC50, PC99. 
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.2.3.15.1: DESCRIPTIVE STATISTICS OF LOG10(PARASITAEMIA) ACTUAL VALUES 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 
 
 ANALYSIS PHASE           COHORT 1         COHORT 2       ALL SUBJECTS    
   ANALYSIS VISIT         (N=XX)           (N=XX)           (N=XX)       
---------------------- ---------------- ---------------- ----------------  
SCREENING 
 DAY 1, PREDOSE 
    n                     XX               XX               XX             
    Mean (S.D)            XX.X (X.X)       XX.X (X.X)       XX.X (X.X)     
    Median                XX.X             XX.X             XX.X           
    Min; Max             (XX; XX)         (XX; XX)         (XX; XX)        
    95% C.I. <a>         (XX; XX)         (XX; XX)         (XX; XX)        
 
CHALLENGE 
 DAY 7                                                                     
    n                     XX               XX               XX             
    Mean (S.D)            XX.X (X.X)       XX.X (X.X)       XX.X (X.X)     
    Median                XX.X             XX.X             XX.X           
    Min; Max             (XX; XX)         (XX; XX)         (XX; XX)        
    95% C.I. <a>         (XX; XX)         (XX; XX)         (XX; XX)        
 DAY 8                                                                     
    n                     XX               XX               XX             
    Mean (S.D)            XX.X (X.X)       XX.X (X.X)       XX.X (X.X)     
    Median                XX.X             XX.X             XX.X           
    Min; Max             (XX; XX)         (XX; XX)         (XX; XX)    
    95% C.I. <a>         (XX; XX)         (XX; XX)         (XX; XX)        
ETC. 
 
RESCUE 
 RIAMET DAY 1, 2H                                                                     
    n                     XX               XX               XX             
    Mean (S.D)            XX.X (X.X)       XX.X (X.X)       XX.X (X.X)     
    Median                XX.X             XX.X             XX.X           
    Min; Max             (XX; XX)         (XX; XX)         (XX; XX)        
    95% C.I. <a>         (XX; XX)         (XX; XX)         (XX; XX)   
 
 
<a> TWO-SIDED 95% CONFIDENCE INTERVAL ON THE ARITHMETIC MEAN.  
 


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3.3 
SAFETY  
3.3.1 
Adverse events 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.3.1.1: ADVERSE EVENTS OVERVIEW 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
                                                                           COHORT 1        COHORT 2        ALL SUBJECTS             
                                                                            (N=XX)          (N=XX)           (N=XX)                
 TOTAL NUMBER OF SUBJECTS WITH:                                          n  %      m      n  %      m      n  %      m             
 ---------------------------------------------------------------------- ---------------- ---------------- ----------------          
 AT LEAST ONE AE                                                        XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX            
 AT LEAST ONE SERIOUS AE                                                XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX           
 AT LEAST ONE GRADE ≥ 3 AE                                              XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX            
 AT LEAST ONE FATAL AE                                                  XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX            
 AT LEAST ONE AE RELATED TO PfSPZ INOCULUM                              XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX            
 AT LEAST ONE AE RELATED TO ANTIMALARIAL TREATMENT                      XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX        
 AT LEAST ONE AE RELATED TO RIAMET                                      XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX            
 AT LEAST ONE AE RELATED TO MALARONE                                    XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX            
 AT LEAST ONE SERIOUS AE RELATED TO PfSPZ INOCULUM                      XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX  
 AT LEAST ONE AE FOR WHICH THE STUDY WAS DISCONTINUED                   XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX                                            
 AT LEAST ONE AE FOR WHICH THE ANTIMALARIAL TREATMENT WAS DISCONTINUED  XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX                                            
 AT LEAST ONE AE FOR WHICH RIAMET WAS DISCONTINUED                      XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX                                            
 AT LEAST ONE AE FOR WHICH MALARONE WAS DISCONTINUED                    XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX                                            
 AT LEAST ONE AE OF SPECIAL INTEREST                                    XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX  
 AT LEAST ONE AE OF SPECIAL INTEREST RELATED TO PfSPZ INOCULUM          XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX                                            
 AT LEAST ONE AE OF SPECIAL INTEREST RELATED TO ANTIMALARIAL TREATMENT  XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX                                            
 
                                                                                                                                         
n= NUMBER OF SUBJECTS WITH EVENT, m = NUMBER OF EVENTS, AE = ADVERSE EVENT.                                           
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT IN THE SAFETY SET. 
ONLY ADVERSE EVENTS THAT STARTED AFTER PfSPZ INOCULATION ARE SHOWN. 
RELATED IS DEFINED AS RELATED/SUSPECTED TO CHALLENGE AGENT/ANTIMALARIAL TREATMENT ACCORDING TO THE INVESTIGATOR, OR A MISSING RELATEDNESS. 
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
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TABLE 14.3.1.2: ADVERSE EVENTS BY MEDDRA SYSTEM ORGAN CLASS AND PREFERRED TERM 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
                                                              COHORT 1        COHORT 2        ALL SUBJECTS     
                                                               (N=XX)          (N=XX)           (N=XX)         
SYSTEM ORGAN CLASS AND PREFERRED TERM                       n  %      m      n  %      m      n  %      m      
 -------------------------------------------------------   ---------------- ---------------- ----------------  
 ANY AE                                                    XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX     
 GASTROINTESTINAL DISORDERS                                XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX     
    DIARRHOEA                                              XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX     
 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS      XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX     
    FATIGUE                                                XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX     
    FEELING HOT                                            XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX     
    INJECTION SITE ERYTHEMA                                XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX     
 INFECTIONS AND INFESTATIONS                               XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX     
    RHINITIS                                               XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX     
    PNEUMONIA                                              XX  XX.X   XX    XX  XX.X   XX    XX  XX.X   XX     
 
 
Etc. 
 
 
n= NUMBER OF SUBJECTS WITH EVENT, m = NUMBER OF EVENTS, AE = ADVERSE EVENT. 
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT IN THE SAFETY SET. 
ONLY ADVERSE EVENTS THAT STARTED AFTER PfSPZ INOCULATION ARE SHOWN. 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.3.1.3: ADVERSE EVENTS BY MEDDRA PREFERRED TERM BY DESCENDING ORDER OF FREQUENCY 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
                                                           COHORT 1   COHORT 2   ALL SUBJECTS     
                                                            (N=XX)     (N=XX)      (N=XX)         
 PREFERRED TERM                                             n  %       n  %       n  %     
 -------------------------------------------------------   ---------- ---------- ------------ 
 DIARRHOEA                                                 XX  XX.X   XX  XX.X   XX  XX.X  
 FATIGUE                                                   XX  XX.X   XX  XX.X   XX  XX.X  
 FEELING HOT                                               XX  XX.X   XX  XX.X   XX  XX.X  
 INJECTION SITE ERYTHEMA                                   XX  XX.X   XX  XX.X   XX  XX.X  
 RHINITIS                                                  XX  XX.X   XX  XX.X   XX  XX.X  
 PNEUMONIA                                                 XX  XX.X   XX  XX.X   XX  XX.X  
 
 
Etc. 
 
 
n= NUMBER OF SUBJECTS WITH EVENT, AE = ADVERSE EVENT. 
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT IN THE SAFETY SET. 
ONLY ADVERSE EVENTS THAT STARTED AFTER PfSPZ INOCULATION ARE SHOWN. 
 
Programmer note: the adverse events will be sorted by descending order of frequency in the all subjects group. 
  
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.3.1.4: SERIOUS ADVERSE EVENTS BY MEDDRA SYSTEM ORGAN CLASS AND PREFERRED TERM 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
 
                                                           COHORT 1    COHORT 2   ALL SUBJECTS     
                                                           (N=XX)      (N=XX)       (N=XX)         
SYSTEM ORGAN CLASS AND PREFERRED TERM                      n  %        n  %        n  %       
 -------------------------------------------------------  ----------- ----------- ------------- 
 ANY AE                                                   XX  XX.X    XX  XX.X    XX  XX.X    
 GASTROINTESTINAL DISORDERS                               XX  XX.X    XX  XX.X    XX  XX.X    
    DIARRHOEA                                             XX  XX.X    XX  XX.X    XX  XX.X    
 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS     XX  XX.X    XX  XX.X    XX  XX.X    
    FATIGUE                                               XX  XX.X    XX  XX.X    XX  XX.X    
    FEELING HOT                                           XX  XX.X    XX  XX.X    XX  XX.X    
    INJECTION SITE ERYTHEMA                               XX  XX.X    XX  XX.X    XX  XX.X    
 INFECTIONS AND INFESTATIONS                              XX  XX.X    XX  XX.X    XX  XX.X    
    RHINITIS                                              XX  XX.X    XX  XX.X    XX  XX.X    
    PNEUMONIA                                             XX  XX.X    XX  XX.X    XX  XX.X    
Etc. 
 
n= NUMBER OF SUBJECTS WITH EVENT, AE = ADVERSE EVENT. 
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT IN THE SAFETY SET. 
ONLY ADVERSE EVENTS THAT STARTED AFTER PfSPZ INOCULATION ARE SHOWN. 
 
 
 


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Programmer note: repeat Table 14.2.1.4 for: 
 
TABLE 14.3.1.5: GRADE 3 OR MORE ADVERSE EVENTS BY MEDDRA SYSTEM ORGAN CLASS AND PREFERRED TERM 
 
TABLE 14.3.1.6: PfSPZ INOCULUM RELATED ADVERSE EVENTS BY MEDDRA SYSTEM ORGAN CLASS AND PREFERRED TERM 
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.3.1.7: ANTIMALARIAL TREATMENT RELATED ADVERSE EVENTS BY MEDDRA SYSTEM ORGAN CLASS AND PREFERRED TERM 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
ANTIMALARIAL TREATMENT = RIAMET OR MALARONE 
 
                                                           COHORT 1    COHORT 2   ALL SUBJECTS     
                                                           (N=XX)      (N=XX)       (N=XX)         
SYSTEM ORGAN CLASS AND PREFERRED TERM                      n  %        n  %        n  %       
 -------------------------------------------------------  ----------- ----------- ------------- 
 ANY AE                                                   XX  XX.X    XX  XX.X    XX  XX.X    
 GASTROINTESTINAL DISORDERS                               XX  XX.X    XX  XX.X    XX  XX.X    
    DIARRHOEA                                             XX  XX.X    XX  XX.X    XX  XX.X    
 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS     XX  XX.X    XX  XX.X    XX  XX.X    
    FATIGUE                                               XX  XX.X    XX  XX.X    XX  XX.X    
    FEELING HOT                                           XX  XX.X    XX  XX.X    XX  XX.X    
    INJECTION SITE ERYTHEMA                               XX  XX.X    XX  XX.X    XX  XX.X    
 INFECTIONS AND INFESTATIONS                              XX  XX.X    XX  XX.X    XX  XX.X    
    RHINITIS                                              XX  XX.X    XX  XX.X    XX  XX.X    
    PNEUMONIA                                             XX  XX.X    XX  XX.X    XX  XX.X    
 
 
ANTIMALARIAL TREATMENT = RIAMET 
Etc. 
 
 
n= NUMBER OF SUBJECTS WITH EVENT, AE = ADVERSE EVENT. 
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT IN THE SAFETY SET. 
ONLY ADVERSE EVENTS THAT STARTED AFTER PfSPZ INOCULATION ARE SHOWN. 
 
 
 


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Programmer note: repeat Table 14.2.1.4 for: 
 
TABLE 14.3.1.8: SERIOUS PfSPZ INOCULUM RELATED ADVERSE EVENTS BY MEDDRA SYSTEM ORGAN CLASS AND PREFERRED TERM 
 
Programmer note: repeat Table 14.2.1.8 for: 
 
TABLE 14.3.1.9: ADVERSE EVENTS FOR WHICH THE ANTIMALARIAL TREATMENT WAS DISCONTINUED BY MEDDRA SYSTEM ORGAN CLASS AND PREFERRED TERM 
 
Programmer note: repeat Table 14.2.1.4 for: 
 
TABLE 14.3.1.10: ADVERSE EVENTS OF SPECIAL INTEREST RELATED TO PfSPZ INOCULUM BY MEDDRA SYSTEM ORGAN CLASS AND PREFERRED TERM 
 
Programmer note: repeat Table 14.2.1.8 for: 
 
TABLE 14.3.1.11: ADVERSE EVENTS OF SPECIAL INTEREST RELATED TO ANTIMALARIAL TREATMENT BY MEDDRA SYSTEM ORGAN CLASS AND PREFERRED TERM 
 
 
 
 
 


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3.3.2 
Clinical laboratory evaluation 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.3.2.1: DESCRIPTIVE STATISTICS OF LABORATORY TEST RESULTS 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
LABORATORY CATEGORY: LABORATORY PARAMETER 1 (unit) 
 
 
                                         ACTUAL VALUES                                  CHANGES FROM BASELINE                
                       -------------------------------------------------- -------------------------------------------------- 
                           COHORT 1         COHORT 2       ALL SUBJECTS       COHORT 1         COHORT 2       ALL SUBJECTS        
                            (N=XX)           (N=XX)           (N=XX)           (N=XX)           (N=XX)           (N=XX)      
                       ---------------- ---------------- ---------------- ---------------- ---------------- ---------------- 
 BASELINE                                                                                                                    
    n                     XX               XX               XX                                                               
    Mean (S.D)            XX.X (X.X)       XX.X (X.X)       XX.X (X.X)                                                       
    Median                XX.X             XX.X             XX.X                                                             
    Min; Max             (XX; XX)         (XX; XX)         (XX; XX)                                                          
 DAY X                                                                                                                       
    n                     XX               XX               XX               XX               XX               XX            
    Mean (S.D)            XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)    
    Median                XX.X             XX.X             XX.X             XX.X             XX.X             XX.X          
    Min; Max             (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)       
 DAY X                                                                                                                       
    n                     XX               XX               XX               XX               XX               XX            
    Mean (S.D)            XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)    
    Median                XX.X             XX.X             XX.X             XX.X             XX.X             XX.X          
    Min; Max             (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)    
 DAY X                                                                                                                       
    n                     XX               XX               XX               XX               XX               XX            
    Mean (S.D)            XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)    
    Median                XX.X             XX.X             XX.X             XX.X             XX.X             XX.X          
    Min; Max             (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)       
    
Etc. 
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.3.2.2: CROSS-TABULATION OF LABORATORY ABNORMALITIES VERSUS BASELINE 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
LABORATORY CATEGORY: LABORATORY PARAMETER 1 (unit) 
                                                                       ABNORMALITY AT BASELINE                                                     
                                                                ---------------------------------------                                          
 COHORT/                                                          LOW       NORMAL    HIGH     MISSING                                           
 ANALYSIS VISIT             ABNORMALITY       N  %      N’ %      n  %      n  %      n  %      n  %                                             
 ------------------------- --------------- --------- --------- --------- --------- --------- ---------                                          
 COHORT 1 (N=XX)                                                                                                                       
 -------------------------                                                                                                                       
 DAY 7                      LOW              XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            NORMAL           XX  XX.X            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            HIGH             XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            TOTAL            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
 WORST-CASE POST-BASELINE   LOW              XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            NORMAL           XX  XX.X            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            HIGH             XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            LOW + HIGH       XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            TOTAL            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
 WORST-CASE CHALLENGE       LOW              XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            NORMAL           XX  XX.X            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            LOW + HIGH       XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            TOTAL            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
 WORST-CASE RESCUE          LOW              XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            NORMAL           XX  XX.X            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            TOTAL            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                                                                                                                                           
 COHORT 2 (N=XX)                                                                                                                       
 -------------------------                                                                                                                       
 DAY 7                      NORMAL           XX  XX.X            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            HIGH             XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            TOTAL            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                                                                                                                                           
Etc. 
 
N = TOTAL NUMBER OF SUBJECTS PER ABNORMALITY WITHIN EACH COHORT AND ANALYSIS VISIT 
N’ = TOTAL NUMBER OF SUBJECTS WITH A POST-BASELINE EMERGENT ABNORMALITY WITHIN EACH COHORT AND ANALYSIS VISIT 
THE WORST-CASE ANALYSIS VISIT CONSIDERS ALL POST-BASELINE ASSESSMENTS, INCLUDING UNSCHEDULED ASSESSMENTS, AND IS SHOWN OVERALL                
AND BY ANALYSIS PHASE. 
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT AND PER ANALYSIS VISIT IN THE SAFETY SET, EXCLUDING 
SUBJECTS WITH MISSING VALUES PER COHORT AND PER ANALYSIS VISIT. 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.3.2.3: LIVER ENZYME ELEVATION CATEGORIES 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
                                           COHORT 1   COHORT 2   ALL SUBJECTS 
                                            (N=XX)     (N=XX)      (N=XX)    
 CRITERION                                 n    %       n   %       n   %    
 --------------------------------------- ----------- ----------- ------------- 
 ALT  
    > 8XULN                               XX  XX.X    XX  XX.X    XX  XX.X   
    > 5XULN                               XX  XX.X    XX  XX.X    XX  XX.X   
    > 3XULN                               XX  XX.X    XX  XX.X    XX  XX.X   
 AST  
    > 8XULN                               XX  XX.X    XX  XX.X    XX  XX.X   
    > 5XULN                               XX  XX.X    XX  XX.X    XX  XX.X   
    > 3XULN                               XX  XX.X    XX  XX.X    XX  XX.X   
 ALT OR AST  
    > 8XULN                               XX  XX.X    XX  XX.X    XX  XX.X   
    > 5XULN                               XX  XX.X    XX  XX.X    XX  XX.X   
    > 3XULN                               XX  XX.X    XX  XX.X    XX  XX.X   
 TOTAL BILIRUBIN > 2XULN                  XX  XX.X    XX  XX.X    XX  XX.X  
 CONJUGATED BILIRUBIN FRACTION >35%       XX  XX.X    XX  XX.X    XX  XX.X 
 POTENTIAL HY’S LAW CASE                  XX  XX.X    XX  XX.X    XX  XX.X   
 
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT IN THE SAFETY SET, EXCLUDING SUBJECTS WITH MISSING VALUES. 
FOR EACH OF THE CRITERIA, THE HIGHEST POST-BASELINE VALUE IS CONSIDERED. 
POTENTIAL HY’S LAW CASE: ALT OR AST > 3XULN AND TOTAL BILIRUBIN > 2XULN AT THE SAME SAMPLE, TOGETHER WITH A CONJUGATED BILIRUBIN FRACTION >35%. 
 
 


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3.3.3 
Vital signs 
The analysis tables for vital signs parameters are largely identical to the laboratory tables. 
 
TABLE 14.3.3.1: DESCRIPTIVE STATISTICS OF VITAL SIGNS 
 
TABLE 14.3.3.2: CROSS-TABULATION OF VITAL SIGNS ABNORMALITIES VERSUS BASELINE 
 
 
 


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3.3.4 
Electrocardiograms (ECG) 
The analysis tables for ECG parameters are largely identical to the laboratory tables. 
 
TABLE 14.3.4.1: DESCRIPTIVE STATISTICS OF ECG 
 
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.3.4.2: CROSS-TABULATION OF ECG ABNORMALITIES VERSUS BASELINE 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
ECG PARAMETER 1 (unit) 
 
                                                                         ABNORMALITY AT BASELINE 
                                                                ---------------------------------------                                          
 COHORT /                                                         LOW       NORMAL    HIGH     MISSING                                           
 ANALYSIS VISIT             ABNORMALITY       N  %      N’ %      n  %      n  %      n  %      n  %                                             
 -------------------------- --------------- --------- --------- --------- --------- --------- ---------                                          
 COHORT 1  (N=XX)                                                                                                                       
 --------------------------                                                                                                                       
 RIAMET DAY 2               LOW              XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            NORMAL           XX  XX.X            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            HIGH             XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            TOTAL            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
 RIAMET DAY 3               LOW              XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            NORMAL           XX  XX.X            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            HIGH             XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            TOTAL            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
 WORST-CASE POST-BASELINE   LOW              XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            NORMAL           XX  XX.X            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            HIGH             XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            LOW + HIGH       XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            TOTAL            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                                                                                                                                           
 COHORT 2  (N=XX)                                                                                                                       
 --------------------------                                                                                                                       
 RIAMET DAY 2               LOW              XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            NORMAL           XX  XX.X            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            HIGH             XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                            TOTAL            XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X                                          
                                                                                                                                           
Etc. 
 
N = TOTAL NUMBER OF SUBJECTS PER ABNORMALITY WITHIN EACH COHORT AND ANALYSIS VISIT 
N’ = TOTAL NUMBER OF SUBJECTS WITH A POST-BASELINE EMERGENT ABNORMALITY WITHIN EACH COHORT AND ANALYSIS VISIT 
THE WORST-CASE ANALYSIS VISIT CONSIDERS ALL POST-BASELINE ASSESSMENTS, INCLUDING UNSCHEDULED ASSESSMENTS. 
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT AND PER ANALYSIS VISIT IN THE SAFETY SET, EXCLUDING 
SUBJECTS WITH MISSING VALUES PER COHORT AND PER ANALYSIS VISIT. 
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.3.4.3: TABULATION OF QTC CHANGE ABNORMALITIES 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
QTcB INTERVAL (ms) 
 
                                COHORT 1            COHORT 2          ALL SUBJECTS      
                                 (N=XX)              (N=XX)              (N=XX)         
                             n  %     cN’ %      n  %     cN’ %      n  %     cN’ %     
 ------------------------- ------------------- ------------------- -------------------  
 RIAMET DAY 2          
   > 60                     XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  
   ]30,60]                  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  
   <= 30 (NORMAL)           XX  XX.X            XX  XX.X            XX  XX.X            
   TOTAL                    XX   100            XX   100            XX   100            
                                                                                        
 RIAMET DAY 3          
   > 60                     XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  
   ]30,60]                  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  
   <= 30 (NORMAL)           XX  XX.X            XX  XX.X            XX  XX.X            
   TOTAL                    XX   100            XX   100            XX   100            
                                                                                        
 WORST-CASE POST-BASELINE                                                                           
   > 60                     XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  
   ]30,60]                  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  XX  XX.X  
   <= 30 (NORMAL)           XX  XX.X            XX  XX.X            XX  XX.X            
   TOTAL                    XX   100            XX   100            XX   100            
                                                                                                             
cN’ = CUMULATIVE NUMBER OF SUBJECTS WITH A QTC CHANGE ABNORMALITY WITHIN EACH COHORT AND ANALYSIS VISIT 
THE WORST-CASE ANALYSIS VISIT CONSIDERS ALL POST-BASELINE ASSESSMENTS, INCLUDING UNSCHEDULED ASSESSMENTS. 
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT AND PER ANALYSIS VISIT IN THE SAFETY SET, EXCLUDING 
SUBJECTS WITH MISSING VALUES PER COHORT AND PER ANALYSIS VISIT. 


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3.3.5 
Malaria clinical score 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.3.5.1: DESCRIPTIVE STATISTICS OF MALARIA CLINICAL SCORE 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
                                         ACTUAL VALUES                                  CHANGES FROM BASELINE                
                       -------------------------------------------------- -------------------------------------------------- 
                           COHORT 1         COHORT 2       ALL SUBJECTS       COHORT 1         COHORT 2       ALL SUBJECTS        
                            (N=XX)           (N=XX)           (N=XX)           (N=XX)           (N=XX)           (N=XX)      
                       ---------------- ---------------- ---------------- ---------------- ---------------- ---------------- 
 BASELINE                                                                                                                    
    n                     XX               XX               XX                                                               
    Mean (S.D)            XX.X (X.X)       XX.X (X.X)       XX.X (X.X)                                                       
    Median                XX.X             XX.X             XX.X                                                             
    Min; Max             (XX; XX)         (XX; XX)         (XX; XX)                                                          
 DAY 7                                                                                                                       
    n                     XX               XX               XX               XX               XX               XX            
    Mean (S.D)            XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)    
    Median                XX.X             XX.X             XX.X             XX.X             XX.X             XX.X          
    Min; Max             (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)       
 DAY 8                                                                                                                       
    n                     XX               XX               XX               XX               XX               XX            
    Mean (S.D)            XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)    
    Median                XX.X             XX.X             XX.X             XX.X             XX.X             XX.X          
    Min; Max             (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)    
 WORST-CASE POST-BASELINE                                                                                                                       
    n                     XX               XX               XX               XX               XX               XX            
    Mean (S.D)            XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)       XX.X (X.X)    
    Median                XX.X             XX.X             XX.X             XX.X             XX.X             XX.X          
    Min; Max             (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)         (XX; XX)       
    
Etc. 
 
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
TABLE 14.3.5.2: FREQUENCY TABLE OF THE WORST-CASE INDIVIDUAL MALARIA SIGNS AND SYMPTOMS 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
ANALYSIS PHASE = CHALLENGE + RESCUE 
 
                       COHORT 1     COHORT 2  ALL SUBJECTS 
                        (N=XX)      (N=XX)      (N=XX)    
 MALARIA SIGN/SYMPTOM    n  %        n  %        n  %     
 -------------------- ----------- ----------- ------------ 
 ANY SYMPTOM                                              
    0                   XX  XX.X    XX  XX.X    XX  XX.X  
    1                   XX  XX.X    XX  XX.X    XX  XX.X  
    2                   XX  XX.X    XX  XX.X    XX  XX.X  
    3                   XX  XX.X    XX  XX.X    XX  XX.X  
    TOTAL               XX   100    XX   100    XX   100  
                                                          
 HEADACHE                                                 
    0                   XX  XX.X    XX  XX.X    XX  XX.X  
    1                   XX  XX.X    XX  XX.X    XX  XX.X  
    2                   XX  XX.X    XX  XX.X    XX  XX.X  
    3                   XX  XX.X    XX  XX.X    XX  XX.X  
    TOTAL               XX   100    XX   100    XX   100  
                                                          
 MYALGIA                                                  
    0                   XX  XX.X    XX  XX.X    XX  XX.X  
    1                   XX  XX.X    XX  XX.X    XX  XX.X  
    2                   XX  XX.X    XX  XX.X    XX  XX.X  
    3                   XX  XX.X    XX  XX.X    XX  XX.X  
    TOTAL               XX   100    XX   100    XX   100  
                                                          
 ARTHRALGIA                                               
    0                   XX  XX.X    XX  XX.X    XX  XX.X  
    1                   XX  XX.X    XX  XX.X    XX  XX.X  
    2                   XX  XX.X    XX  XX.X    XX  XX.X  
    3                   XX  XX.X    XX  XX.X    XX  XX.X  
    TOTAL               XX   100    XX   100    XX   100  
Etc. 
 
 
ANALYSIS PHASE = CHALLENGE 
 
Etc. 


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0=ABSENT; 1=MILD; 2=MODERATE; 3=SEVERE 
THE DENOMINATOR FOR THE PERCENTAGE CALCULATIONS IS THE TOTAL NUMBER OF SUBJECTS PER COHORT IN THE SAFETY SET, EXCLUDING SUBJECTS WITH MISSING VALUES. 
THE WORST-CASE IS THE HIGHEST POST-BASELINE SCORE WITHIN THE ANALYSIS PHASE AND IS DERIVED PER SIGN/SYMPTOM. 
ANY SYMPTOM SHOWS THE WORST-CASE SEVERITY OF THE SIGN/SYMPTOM WITH THE HIGHEST SEVERITY. 
 
Programmer notes:  
x All malaria signs and symptoms will be shown (headache, myalgia, arthralgia, fatigue/lethargy, malaise, chills/shivering/rigors, 
sweating/hot spells, anorexia, nausea, vomiting, abdominal discomfort, fever, tachycardia and hypotension) 
 


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4. 
MOCK LISTINGS 
4.1 
GENERAL CHARACTERISTICS 
4.1.1 
Subject disposition 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
LISTING 16.2.1.1: ALLOCATION 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: ALL SCREENED SUBJECTS 
 
                                                                                                  
 SUBJECT DATETIME OF SIGNING     
 NUMBER  INFORMED CONSENT [1] COHORT     SAF PD  m-PD   
 ------- -------------------- ---------- --- --- ----  
                                                        
 XXXX    ddMMMyyyy:hh:mm      COHORT 1   YES NO  NO   
 XXXX    ddMMMyyyy:hh:mm      COHORT 1   YES YES YES   
 XXXX    ddMMMyyyy:hh:mm      COHORT 2   YES YES YES   
 XXXX    ddMMMyyyy:hh:mm      COHORT 1   YES YES YES   
 XXXX    ddMMMyyyy:hh:mm      COHORT 2   YES NO  NO   
 XXXX    ddMMMyyyy:hh:mm      COHORT 1   YES YES YES   
 XXXX    ddMMMyyyy:hh:mm      COHORT 1   YES NO  NO   
 XXXX    ddMMMyyyy:hh:mm      COHORT 2   YES YES YES   
 XXXX    ddMMMyyyy:hh:mm      COHORT 2   YES YES NO   
 XXXX    ddMMMyyyy:hh:mm      COHORT 1   YES YES YES   
 XXXX    ddMMMyyyy:hh:mm      COHORT 2   NO  NO  NO    
 XXXX    ddMMMyyyy:hh:mm      COHORT 1   YES YES NO   
ETC… 
 
[1] DATETIME OF THE EARLIEST AVAILABLE INFORMED CONSENT FORM SIGNATURE.  
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                          SAS DATE AND TIME 
                                                                                                                                  PAGE X OF Y 
LISTING 16.2.1.2: ANALYSIS PHASES 
--------------------------------------------------------------------------------------------------------------------------------------------- 
ANALYSIS SET: SAFETY 
 
                                    FIRST USE OF      LAST USE OF                                                                       
          SUBJECT DATETIME OF       ANTIMALARIAL      ANTIMALARIAL      DISCONTINUATION ANALYSIS                                     DURATION 
 COHORT   NUMBER  INOCULATION       TREATMENT         TREATMENT         DATE            PHASE        START           STOP            (DAYS)   
 -------- ------- ----------------- ----------------- ----------------- --------------- ------------ --------------- --------------- -------- 
                                                                                                                                     
 COHORT 1  XXXXXX  ddMMMyyyy:hh:mm   ddMMMyyyy:hh:mm   ddMMMyyyy:hh:mm   ddMMMyyyy      SCREENING    ddMMMyyyy:hh:mm ddMMMyyyy:hh:mm  XX       
                                                                                        CHALLENGE    ddMMMyyyy:hh:mm ddMMMyyyy:hh:mm  XX       
                                                                                        RESCUE       ddMMMyyyy:hh:mm ddMMMyyyy:hh:mm  XX       
           XXXXXX  ddMMMyyyy:hh:mm   ddMMMyyyy:hh:mm   ddMMMyyyy:hh:mm   ddMMMyyyy      SCREENING    ddMMMyyyy:hh:mm ddMMMyyyy:hh:mm  XX       
                                                                                        CHALLENGE    ddMMMyyyy:hh:mm ddMMMyyyy:hh:mm  XX       
                                                                                        RESCUE       ddMMMyyyy:hh:mm ddMMMyyyy:hh:mm  XX       
           XXXXXX  ddMMMyyyy:hh:mm   ddMMMyyyy:hh:mm   ddMMMyyyy:hh:mm   ddMMMyyyy      SCREENING    ddMMMyyyy:hh:mm ddMMMyyyy:hh:mm  XX       
                                                                                        CHALLENGE    ddMMMyyyy:hh:mm ddMMMyyyy:hh:mm  XX       
                                                                                        RESCUE       ddMMMyyyy:hh:mm ddMMMyyyy:hh:mm  XX       
 COHORT 2  XXXXXX  ddMMMyyyy:hh:mm   ddMMMyyyy:hh:mm   ddMMMyyyy:hh:mm   ddMMMyyyy      SCREENING    ddMMMyyyy:hh:mm ddMMMyyyy:hh:mm  XX       
                                                                                        CHALLENGE    ddMMMyyyy:hh:mm ddMMMyyyy:hh:mm  XX       
                                                                                        RESCUE       ddMMMyyyy:hh:mm ddMMMyyyy:hh:mm  XX       
 
 ETC… 
 
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
LISTING 16.2.1.3: STUDY AND ANTIMALARIAL TREATMENT DISCONTINUATION 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
 
                    DATE OF DISCONTINUATION                      STUDY DISCONTINUATION           ANTIMALARIAL TREATMENT DISCONTINUATION      
          SUBJECT --------------------------------- DAYS  -------------------------------------- -------------------------------------- 
COHORT    NUMBER  STUDY      ANTIMALARIAL TREATMENT [1]    TYPE          REASON                   TYPE          REASON                
--------  ------- ---------- ---------------------- ----- -------------- ----------------------- -------------- ----------------------- 
                                                                                                                                
COHORT 1  XXXXXX  ddMMMyyyy  ddMMMyyyy               XX    COMPLETED                              COMPLETED                           
          XXXXXX  ddMMMyyyy  ddMMMyyyy               XX    COMPLETED                              COMPLETED                           
          XXXXXX  ddMMMyyyy  ddMMMyyyy               XX    DISCONTINUED  ADVERSE EVENT (SEQ XX):  DISCONTINUED  ADVERSE EVENT (SEQ XX): 
                                                                         PREFERRED TERM                         PREFERRED TERM         
COHORT 2  XXXXXX  ddMMMyyyy  ddMMMyyyy               XX    ONGOING                                ONGOING                              
          
ETC… 
 
[1] NUMBER OF DAYS IN STUDY AT DATE OF DISCONTINUATION, CALCULATED WITH REFERENCE TO THE DATE OF INOCULATION. 
          
 


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4.1.2 
Protocol deviations and eligibility 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
LISTING 16.2.2.1: MAJOR PROTOCOL DEVIATIONS 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
          SUBJECT                                                                                                           
 COHORT   NUMBER   TYPE   DEVIATION CLASS           DEVIATION                      DEVIATION (SPECIFICATION)                
 -------- -------- ------ ------------------------- ------------------------------ ---------------------------------------- 
                                                                                                                            
 COHORT 1 XXXX     MAJOR  PROCEDURE DEVIATION       NO COMPLIANCE WITH ASSESSMENT  PK URINE COLLECTION X-XH POSTDOSE,       
                                                    WINDOW                         STARTED XH XXMIN. EARLIER                
                                                    NO COMPLIANCE WITH VISIT       VISIT X DONE X DAY LATER                 
                                                    SCHEDULES                                                               
          XXXX     MAJOR  PROCEDURE DEVIATION       NO COMPLIANCE WITH ASSESSMENT  ECG PXDX XX MIN.POSTDOSE,  DONE XX MIN.  
                                                    WINDOW                         EARLIER                                  
                                                                                   ECG PXDX XH. POSTDOSE, DONE X MIN.       
                                                                                   EARLIER                                  
                                                                                   PK URINE COLLECTION X-XH POSTDOSE,       
                                                                                   STARTED XXMIN. EARLIER                   
                                                    NO COMPLIANCE WITH VISIT       VISIT X DONE X DAY LATER                 
                                                    SCHEDULES                                                               
          XXXX     MAJOR  TREATMENT DEVIATION       NO COMPLIANCE WITH STUDY MED.  MEDICATION XX MIN. INFUSION, DOSE NOT    
                                                    INTAKE                         GIVEN COMPLETELY                         
                   MAJOR  PROCEDURE DEVIATION       NO COMPLIANCE WITH ASSESSMENT  PK BLOOD SAMPLING XH POSTDOSE, DONE X    
                                                    WINDOW                         MIN. EARLIER                             
                                                                                   ECG XXMIN. POSTDOSE, DONE XX MIN.        
                                                                                   EARLIER                                  
                                                                                   ECG XH. POSTDOSE, DONE XX MIN. EARLIER   
                                                    NO COMPLIANCE WITH VISIT       VISIT X DONE X DAY LATER                 
                                                    SCHEDULES                                                               
          XXXX     MAJOR  SELECTION CRITERIA        SELECTION CRITERIA NOT MET     SELECTION CRITERIA ARE NOT MET (EX03,    
                                                                                   EX10)                                    
ETC…         
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
LISTING 16.2.2.2: VIOLATIONS ON ELIGIBILITY CRITERIA 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
               SUBJECT                                                                         
 COHORT        NUMBER  TYPE       CRITERION                                                            ANSWER    
 ------------- ------- ---------- -------------------------------------------------------------------  -------- 
                                                                                               
 COHORT 1      XXXX    INCLUSION  9.BODY WEIGHT OF AT LEAST 50 KG AND A BODY MASS INDEX (BMI) OF 19.0  NO 
    TO 30.0 KG/M2  
 COHORT 2      XXXX    INCLUSION  9.BODY WEIGHT OF AT LEAST 50 KG AND A BODY MASS INDEX (BMI) OF 19.0  NO 
    TO 30.0 KG/M2                                        
                       EXCLUSION  17.PERSONAL HISTORY OF MALARIA                                       YES       
 
NOTE: ONLY VIOLATIONS ARE SHOWN. 
 
 
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
LISTING 16.2.2.3: NO-INOCULATED SUBJECTS 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: ALL SCREENED SUBJECTS MINUS SAFETY 
 
 SUBJECT  
 NUMBER  STUDY TERMINATION REASON                                 
 ------- -------------------------------------------------------- 
                                                             
 XXXX     OTHER: PERSONAL REASON                                   
 XXXX     SUBJECT DID NOT FULFILL ALL INCLUSION/EXCLUSION CRITERIA 
 XXXX     OTHER: PERSONAL REASON                                   
 XXXX     SUBJECT DID NOT FULFILL ALL INCLUSION/EXCLUSION CRITERIA 
 XXXX     SUBJECT DID NOT FULFILL ALL INCLUSION/EXCLUSION CRITERIA 
 XXXX     OTHER: BLOOD SAFETY RESULTS                              
 XXXX     OTHER: BLOOD SAFETY RESULTS                              
 XXXX     SUBJECT WITHDREW CONSENT 
 
ETC… 
                                 
 


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4.1.3 
Demographic and other baseline characteristics 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
LISTING 16.2.4.1: DEMOGRAPHIC DATA 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
                     DATE OF                                                                                            
                     SIGNING                                                                                  
         SUBJECT     INFORMED  AGE      HEIGHT  WEIGHT  BMI                                                   
COHORT   NUMBER  PD  CONSENT   (years)  (cm)    (kg)    (kg/m²)  SEX     COUNTRY RACE  ETHNICITY              
-------- ------- --- --------- -------  ------  ------  -------  ------  ------- ----  ---------------------  
                                                                                                     
COHORT 1 XXX     YES ddMMMyyyy XX       XXX     XX.X    XX.X     MALE    BELGIUM WHITE HISPANIC OR LATINO     
         XXX     YES ddMMMyyyy XX       XXX     XX.X    XX.X     MALE    BELGIUM WHITE NOT HISPANIC OR LATINO 
         XXX     YES ddMMMyyyy XX       XXX     XX.X    XX.X     MALE    FRANCE  WHITE HISPANIC OR LATINO     
         XXX     YES ddMMMyyyy XX       XXX     XX.X    XX.X     MALE    BELGIUM WHITE HISPANIC OR LATINO     
         XXX     NO  ddMMMyyyy XX       XXX     XX.X    XX.X     MALE    BELGIUM WHITE HISPANIC OR LATINO     
COHORT 2 XXX     YES ddMMMyyyy XX       XXX     XX.X    XX.X     MALE    FRANCE  WHITE NOT HISPANIC OR LATINO 
         XXX     YES ddMMMyyyy XX       XXX     XX.X    XX.X     FEMALE  FRANCE  WHITE HISPANIC OR LATINO     
         XXX     YES ddMMMyyyy XX       XXX     XX.X    XX.X     MALE    FRANCE  WHITE NOT HISPANIC OR LATINO 
ETC… 
 
SCREENING HEIGHT, WEIGHT AND BMI ARE LISTED. 
 
 


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Final 1.0  of 11FEB2021 
 
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                                                                                                                               PAGE X OF Y 
LISTING 16.2.4.2: SMOKING HISTORY 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
                                              SMOKING HABITS            
                               --------------------------------------------  
            SUBJECT                                   
COHORT      NUMBER  STATUS     QUANTITY    FREQUENCY  START DATE STOP DATE         
----------- ------- ---------- ----------- ---------- ---------- ----------  
                                                                
COHORT 1    XXX     SMOKER     4 CIGARETTE QD         ddMMMyyyy                 
            XXX     EX-SMOKER  1 CIGARETTE QD         ddMMMyyyy  ddMMMyyyy      
            XXX     NON-SMOKER 
 
COHORT 2    XXX     SMOKER     3 CIGARETTE QD         ddMMMyyyy                 
            XXX     SMOKER     2 CIGARETTE QD         ddMMMyyyy                 
            XXX     EX-SMOKER  7 CIGARETTE QD         ddMMMyyyy  ddMMMyyyy      
ETC… 
 
 


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                                                                                                                               PAGE X OF Y 
LISTING 16.2.4.3: ORTHOSTATIC CHANGE IN VITAL SIGNS AT SCREENING  
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
                                            HEART RATE (beats/min)  SYSTOLIC BLOOD PRESSURE (mmHg) DIASTOLIC BLOOD PRESSURE (mmHg) 
               SUBJECT ASSESSMENT      USE ------------------------ ------------------------------ ------------------------------- 
COHORT         NUMBER  DATE            [1] SUPINE  STANDING CHANGE  SUPINE  STANDING CHANGE        SUPINE  STANDING CHANGE  
-------------- ------- --------------- --- ------- -------- ------- ------- -------- ------        ------- -------- ------- 
                                                                                                                       
COHORT 1       XXX     ddMMMyyyy            XXX     XXX      XXX     XXX     XXX      XXX           XXX     XXX      XXX     
               XXX     ddMMMyyyy            XXX     XXX      XXX     XXX     XXX      XXX           XXX     XXX      XXX     
                                                                                                                       
COHORT 2       XXX     ddMMMyyyy            XXX     XXX      XXX     XXX     XXX      XXX           XXX     XXX      XXX     
               XXX     ddMMMyyyy            XXX     XXX      XXX     XXX     XXX      XXX           XXX     XXX      XXX     
               XXX     ddMMMyyyy            XXX     XXX      XXX     XXX     XXX      XXX           XXX     XXX      XXX     
               XXX     ddMMMyyyy            XXX     XXX      XXX     XXX     XXX      XXX           XXX     XXX      XXX     
                       ddMMMyyyy       NO   XXX     XXX      XXX     XXX     XXX      XXX           XXX     XXX      XXX     
ETC…      
     
[1] NO = SAMPLE NOT USED IN ANALYSIS TABLES AND FIGURES.  
ORTHOSTATIC CHANGE = VALUE IN SUPINE POSITION - VALUE IN STANDING POSITION.


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Final 1.0  of 11FEB2021 
 
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                                                                                                                               PAGE X OF Y 
LISTING 16.2.4.4: BECK DEPRESSION INVENTORY AT SCREENING 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
               SUBJECT ASSESSMENT      SUICIDAL       TOTAL                                  
COHORT         NUMBER  DATETIME        THOUGHTS? (Q9) SCORE   INTERPRETATION                 
-------------- ------- --------------- -------------- ------- ------------------------------ 
                                                                                             
COHORT 1       XXX     ddMMMyyyy:hh:mm XXX            XXX     NORMAL                         
               XXX     ddMMMyyyy:hh:mm XXX            XXX     MILD MOOD DISTURBANCE          
                                                                                             
COHORT 2       XXX     ddMMMyyyy:hh:mm XXX            XXX     NORMAL                         
               XXX     ddMMMyyyy:hh:mm XXX            XXX     BORDERLINE CLINICAL DEPRESSION 
               XXX     ddMMMyyyy:hh:mm XXX            XXX     NORMAL                         
               XXX     ddMMMyyyy:hh:mm XXX            XXX     NORMAL                         
 
ETC…  
 
 


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Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                           SAS DATE AND TIME 
                                                                                                                                   PAGE X OF Y 
LISTING 16.2.4.5: SCREENING LABORATORY TESTS 
---------------------------------------------------------------------------------------------------------------------------------------------- 
ANALYSIS SET: SAFETY 
 
A) URINE DRUG SCREEN AND ETHANOL 
 
                                      DRUG SCREENING                       ETHANOL    
                                ------------------------------- ------------------------------ 
             SUBJECT ANALYSIS   ASSESSMENT                      ASSESSMENT                                                                                 
 COHORT      NUMBER  VISIT      DATETIME         RESULT         DATETIME         RESULT    
 ----------- ------- ---------- ---------------- -------------- ---------------  ------------   
                                                                                                 
 COHORT 1    XXX     SCREENING  ddMMMyyyy:hh:mm  NEGATIVE       ddMMMyyyy:hh:mm   NEGATIVE       
                     DAY -1     ddMMMyyyy:hh:mm  NEGATIVE       ddMMMyyyy:hh:mm   NEGATIVE       
             XXX     SCREENING  ddMMMyyyy:hh:mm  NEGATIVE       ddMMMyyyy:hh:mm   NEGATIVE       
                     DAY -1     ddMMMyyyy:hh:mm  NEGATIVE       ddMMMyyyy:hh:mm   NEGATIVE       
             XXX     SCREENING  ddMMMyyyy:hh:mm  NEGATIVE       ddMMMyyyy:hh:mm   NEGATIVE       
             XXX     SCREENING  ddMMMyyyy:hh:mm  NEGATIVE       ddMMMyyyy:hh:mm   NEGATIVE       
                                                                                                 
 COHORT 2    XXX     SCREENING  ddMMMyyyy:hh:mm  NEGATIVE       ddMMMyyyy:hh:mm   NEGATIVE       
                     DAY -1     ddMMMyyyy:hh:mm  NEGATIVE       ddMMMyyyy:hh:mm   NEGATIVE       
 
ETC… 
 
B) VIRAL SEROLOGY AT SCREENING 
 
                                       HEPATITIS A  HEPATITIS B  HEPATITIS C  HEPATITIS E                   EPSTEIN BARR 
              SUBJECT ASSESSMENT       VIRUS        SURFACE      VIRUS        VIRUS        CYTOMEGALOVIRUS  VIRUS         
 COHORT       NUMBER  DATETIME         ANTIBODY     ANTIGEN      ANTIBODY     ANTIBODY     ANTIBODY         ANTIBODY      HIV SEROLOGY 
 ------------ ------- ---------------- ------------ ------------ ------------ ------------ ---------------- ------------- ------------   
                                                                                                                      
 COHORT 1     XXX     ddMMMyyyy:hh:mm  POSITIVE     NEGATIVE     NEGATIVE     NEGATIVE     NEGATIVE         NEGATIVE      NEGATIVE    
              XXX     ddMMMyyyy:hh:mm  NEGATIVE     NEGATIVE     NEGATIVE     NEGATIVE     NEGATIVE         NEGATIVE      NEGATIVE 
              XXX     ddMMMyyyy:hh:mm  NEGATIVE     NEGATIVE     NEGATIVE     NEGATIVE     NEGATIVE         NEGATIVE      NEGATIVE 
              XXX     ddMMMyyyy:hh:mm  NEGATIVE     NEGATIVE     NEGATIVE     NEGATIVE     NEGATIVE         NEGATIVE      NEGATIVE 
              XXX     ddMMMyyyy:hh:mm  NEGATIVE     NEGATIVE     NEGATIVE     NEGATIVE     NEGATIVE         NEGATIVE      NEGATIVE 
              XXX     ddMMMyyyy:hh:mm  NEGATIVE     NEGATIVE     NEGATIVE     NEGATIVE     NEGATIVE         NEGATIVE      NEGATIVE 
                                                                                                                             
 COHORT 2     XXX     ddMMMyyyy:hh:mm  NEGATIVE     NEGATIVE     NEGATIVE     NEGATIVE     NEGATIVE         NEGATIVE      NEGATIVE 
              XXX     ddMMMyyyy:hh:mm  NEGATIVE     NEGATIVE     NEGATIVE     NEGATIVE     NEGATIVE         NEGATIVE      NEGATIVE 
              
 ETC… 
 


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Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
LISTING 16.2.4.6: PREGNANCY TESTS 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
                     SUBJECT                           ASSESSMENT                                                          
COHORT               NUMBER  ANALYSIS VISIT            DATETIME         SPECIMEN TYPE        HCG RESULT          
-------------------- ------- ------------------------- ---------------- -------------------- ------------------- 
                                                                                                                 
COHORT 1             XXX     SCREENING                 ddMMMyyyy:hh:mm  SERUM                XX            
                             DAY -1                    ddMMMyyyy:hh:mm  URINE                NEGATIVE            
                             END OF STUDY              ddMMMyyyy:hh:mm  SERUM                XX            
                     XXX     SCREENING                 ddMMMyyyy:hh:mm  SERUM                XX            
                             DAY -1                    ddMMMyyyy:hh:mm  URINE                NEGATIVE            
ETC… 
  
 


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Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
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                                                                                                                               PAGE X OF Y 
LISTING 16.2.4.7: rRT-PCR TESTS FOR SARS-CoV-2 INFECTION 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
                     SUBJECT                           ASSESSMENT                                                          
COHORT               NUMBER  ANALYSIS VISIT            DATETIME         RESULT            
-------------------- ------- ------------------------- ---------------- ------------ 
                                                                                          
COHORT 1             XXX     SCREENING                 ddMMMyyyy:hh:mm  NEGATIVE          
                             DAY 9                     ddMMMyyyy:hh:mm  NEGATIVE          
                     XXX     SCREENING                 ddMMMyyyy:hh:mm  NEGATIVE          
                             DAY 9                     ddMMMyyyy:hh:mm  NEGATIVE          
ETC… 
 
 


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Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
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4.1.4 
Medical history and concomitant diseases 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
LISTING 16.2.4.8: MEDICAL HISTORY 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
                  SUBJECT                                                                                                                  
 COHORT           NUMBER     SYSTEM ORGAN CLASS          PREFERRED TERM     VERBATIM             START DATE  END DATE    COMMENTS          
 ---------------- ---------- --------------------------- ------------------ -------------------  ----------  ----------  ----------------- 
                                                                                                                                           
 COHORT 1         XXX        GASTROONTESTINAL DISORDERS  DIARRHOEA          DIARRHOEA            ddMMMyyyy   ddMMMyyyy                     
                                                         ABDOMINAL HERNIA   ABDOMINAL HERNIA     ddMMMyyyy   ddMMMyyyy   XXXXXXXXXXXXXXXXX 
                             INFECTIONS AND INFESTATIONS ABSCESS            ABSCESES             ddMMMyyyy   ddMMMyyyy                     
                                                                                                                                           
                  XXX        PSYCHIATRIC DISORDERS       DEPRESSION         DEPRESSION           ddMMMyyyy   ddMMMyyyy                     
                                                                                                                                           
                  XXX        PSYCHIATRIC DISORDERS       INSOMNIA           INSOMNIA             ddMMMyyyy   ddMMMyyyy                     
                                                                                                                                           
ETC… 
 
 


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Final 1.0  of 11FEB2021 
 
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                                                                                                                               PAGE X OF Y 
LISTING 16.2.4.9: CONCOMITANT DISEASES 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
                         SUBJECT                                                                                                           
 COHORT                  NUMBER  SYSTEM ORGAN CLASS          PREFERRED TERM     VERBATIM           START DATE   COMMENTS                   
 ----------------------- ------- --------------------------- ------------------ ------------------ ------------ -------------------------- 
                                                                                                                                           
 COHORT 1                XXX     GASTROINTESTINAL DISORDERS  DIARRHOEA          DIARRHOEA          ddMMMyyyy                               
                                                             ABDOMINAL HERNIA   ABDOMINAL HERNIA   ddMMMyyyy                               
                                 INFECTIONS AND INFESTATIONS ABSCESS            ABSCESES           ddMMMyyyy                               
                                                                                                                                           
                         XXX     PSYCHIATRIC DISORDERS       DEPRESSION         DEPRESSION         ddMMMyyyy    XXXXXXXXXXXXXXXXXXXXXXX    
                                                                                                                                           
                         XXX     PSYCHIATRIC DISORDERS       INSOMNIA           INSOMNIA           ddMMMyyyy                               
                                                                                                                                           
ETC… 
 
 


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Final 1.0  of 11FEB2021 
 
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4.1.5 
Prior and concomitant therapies 
 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
LISTING 16.2.4.10: PRIOR AND CONCOMITANT THERAPIES 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
COHORT 1 
 
 SUBJECT ANALYSIS  ATC CLASS (LEVEL 4)         --------THERAPY-----                                                                        
 NUMBER  PHASE     GENERIC TERM                START DATE END DATE  DOSE, FREQ, ROUTE  INDICATION                            COMMENTS                 
 ------- --------- --------------------------- ---------- --------- ------------------ ------------------------------------- ------------- 
 XXXX    SCREENING DIHYDROPYRIDINE DERIVATIVES ddMMMyyyy  ddMMMyyyy 10 mg QD PO        HIGH BLOOD PRESSURE (MEDICAL HISTORY)               
                   AMLODIPINE                                                                                                              
         CHALLENGE PROGESTOGENS                ddMMMyyyy  ddMMMyyyy 150 mg 1X IM       CONTRACEPTIVE                                       
                   MEDROXYPROGESTERONE ACETATE                                                                                             
         RESCUE    PROGESTOGENS                ddMMMyyyy  ONGOING   150 mg 1X IM       CONTRACEPTIVE                                       
                   MEDROXYPROGESTERONE ACETATE                                                                                             
 XXXX    SCREENING PROGESTOGENS                ddMMMyyyy  ddMMMyyyy 150 mg 1X IM       CONTRACEPTIVE                                       
                   MEDROXYPROGESTERONE ACETATE                                                                                             
         CHALLENGE ANILIDES                    ddMMMyyyy  ddMMMyyyy 1000 mg T.I.D. PO  AE (SEQ X): PREFERRED TERM                          
                   PARACETAMOL                                                                                                             
         RESCUE    PENICILLINS WITH EXTENDED   ddMMMyyyy  ddMMMyyyy 250 mg T.I.D. PO   AE (SEQ X): PREFERRED TERM                          
                   SPECTRUM                                                                                                                
                   AMOXICILLIN                                                                                                             
                   AMASE INHIBITORS            ddMMMyyyy  ddMMMyyyy 375 mg T.I.D. PO   AE (SEQ X): PREFERRED TERM                          
                   AUGMENTIN /00756801/                                                                                                    
 ETC… 
 
COHORT 2 
 
ETC… 
 
 


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Final 1.0  of 11FEB2021 
 
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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
LISTING 16.2.4.11: ANTIMALARIAL TREATMENT 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
                SUBJECT DAY IN                                                                                
 COHORT         NUMBER  STUDY[1] GENERIC TERM          DOSING DATETIME   NUMBER OF TABLETS  DOSE/TABLET        
 -------------- ------- -------- --------------------- ----------------- ------------------ ------------------  
 COHORT 1       XXXX    12       RIAMET                ddMMMyyyy:hh:mm   XX                 20/120 MG/TABLET 
                        13       RIAMET                ddMMMyyyy:hh:mm   XX                 20/120 MG/TABLET 
                        14       RIAMET                ddMMMyyyy:hh:mm   XX                 20/120 MG/TABLET 
                XXXX    13       RIAMET                ddMMMyyyy:hh:mm   XX                 20/120 MG/TABLET  
                        14       RIAMET                ddMMMyyyy:hh:mm   XX                 20/120 MG/TABLET  
                        15       RIAMET                ddMMMyyyy:hh:mm   XX                 20/120 MG/TABLET  
                XXXX    18       RIAMET                ddMMMyyyy:hh:mm   XX                 20/120 MG/TABLET      
                        18       MALARONE              ddMMMyyyy:hh:mm   XX                 250/100 MG/TABLET 
 
ETC… 
 
[1] NUMBER OF DAYS IN STUDY AT DATE OF ANTIMALARIAL TREATMENT, CALCULATED WITH REFERENCE TO THE DATE OF INOCULATION. 
                
 
 


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Final 1.0  of 11FEB2021 
 
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4.1.6 
Comments 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
LISTING 16.2.4.12: COMMENTS 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
                  SUBJECT                                                                                                  
COHORT            NUMBER  REFERENCE       COMMENT                                                                          
----------------- ------- --------------- -------------------------------------------------------------------------------  
                                                                                                                           
COHORT 1          XXXX    LBSEQ: XX       XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX             
                          VSSEQ: XX       XXXXXXXXXXXXXXXXXXXXXXXXXXXX                                                     
                  XXXX    EGSEQ: XX       XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX             
                          LBSEQ: XX       XXXXXXXXXXXXXXXXXXXXXXXXXXXX                                                     
COHORT 2          XXXX    EGSEQ: XX       XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX             
                          PESEQ: XX       XXXXXXXXXXXXXXXXXXXXXXXXXXXX                                                     
 
ETC… 
 
 


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Final 1.0  of 11FEB2021 
 
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4.1.7 
Exposure to challenge agent 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
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LISTING 16.2.5.1: EXPOSURE TO CHALLENGE AGENT 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
                                                                                           
               SUBJECT PfSPZ CHALLENGE          ADMINISTRATION                                       
 COHORT        NUMBER  DATETIME         DOSE    ROUTE          FORMULATION                            
 ------------- ------- ---------------- ------- -------------- ------------ 
                                                                                                 
 COHORT 1      XXXX    ddMMMyyyy:hh:mm  X.XXX   XXXXXXXX       XXXXXXXXX                                 
               XXXX    ddMMMyyyy:hh:mm  X.XXX   XXXXXXXX       XXXXXXXXX 
               XXXX    ddMMMyyyy:hh:mm  X.XXX   XXXXXXXX       XXXXXXXXX                                  
               XXXX    ddMMMyyyy:hh:mm  X.XXX   XXXXXXXX       XXXXXXXXX                                  
               XXXX    ddMMMyyyy:hh:mm  X.XXX   XXXXXXXX       XXXXXXXXX                                  
   
ETC… 
 
 


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Final 1.0  of 11FEB2021 
 
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4.2 
PHARMACODYNAMICS 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
LISTING 16.2.6.1: PARASITAEMIA 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 
COHORT 1 
                                                                              qPCR 
                                                                              RESULT           
SUBJECT       FIRST ANTIMALARIAL     ANALYSIS       DAY  SAMPLE           USE  (p/mL)  
NUMBER  m-PD  TREATMENT DATETIME     VISIT          [1]  DATETIME         [2]  [3]      
------- ----- ---------------------- -------------- ---- ---------------- ---  ------   
                                                                                
XXXX    YES    ddMMMyyyy:hh:mm       BASELINE       1    ddMMMyyyy:hh:mm        XX      
                                     DAY 7          7    ddMMMyyyy:hh:mm        XX      
                                     DAY 8          8    ddMMMyyyy:hh:mm        XX      
                                     DAY 9          9    ddMMMyyyy:hh:mm        XX      
                                     DAY 10         10   ddMMMyyyy:hh:mm        XX      
                                     DAY 11         11   ddMMMyyyy:hh:mm        XX      
                                     DAY 12         12   ddMMMyyyy:hh:mm        XX $     
                                     DAY 13         13   ddMMMyyyy:hh:mm        XX $     
                                     DAY 14 *       14   ddMMMyyyy:hh:mm        XX $    
                                     UNSCHEDULED *  15   ddMMMyyyy:hh:mm   NO   XX      
                                     UNSCHEDULED *  16   ddMMMyyyy:hh:mm   NO   XX      
                                     DAY 21         21   ddMMMyyyy:hh:mm        XX      
ETC…  
                                                                                                                  
[1] DAY VS. INOCULATION, DAYS ON WHICH ANTIMALARIAL TREATMENT IS TAKEN ARE FLAGGED (*). 
[2] NO = NOT USED IN ANALYSIS TABLES AND FIGURES. 
[3] POSITIVE qPCR RESULTS (≥250 PARASITES PER ML BLOOD) ARE FLAGGED ($). 
 


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Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
LISTING 16.2.6.2: PARASITAEMIA ENDPOINTS 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 
COHORT 1 
 
               TIME TO       PARASITAEMIA  TIME TO    PARASITAEMIA  TIME TO     PARASITAEMIA                  
               POSITIVE      AT FIRST      ≥5000      AT ≥5000      FIRST DOSE  AT FIRST DOSE                   
SUBJECT        PARASITAEMIA  POSITIVE PCR  PARASITES  PARASITES     OF RIAMET   OF RIAMET       TIME TO PARASITE   
NUMBER   m-PD  (DAYS)        (PARASITES/mL)(DAYS)[1]  (PARASITES/mL)(DAYS)      (PARASITES/mL)  CLEARENCE (DAYS)   
-------  ----- ------------- ------------- ---------- ------------- ----------- -------------- ---------------- 
                                                                     
XXXX     YES   XX            XXXX           XX°       -             XX          XXXX            XX                
XXXX     YES   XX            XXXX           XX        XXXX          XX          XXXX            XX                
XXXX     NO    XX            XXXX           XX        XXXX          XX          XXXX            XX                
XXXX     YES   XX            XXXX           XX        XXXX          XX          XXXX            XX                
        
ETC…           
                                                                                                                         
[1] ABSENCE OF EVENT IS FLAGGED (°). 
POSITIVE PARASITAEMIA IS DEFINED AS qPCR OUTCOME ≥250 PARASITES PER mL BLOOD. 
PARASITE CLEARANCE IS DEFINED AS qPCR OUTCOME BELOW THE LIMIT OF QUANTIFICATION (<50 PARASITES PER mL BLOOD). 
  
 


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Final 1.0  of 11FEB2021 
 
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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
LISTING 16.2.6.3: BLOOD-STAGE PARASITE CLEARANCE PROFILE: ITERATION PROCESS TO DETERMINE THE OPTIMAL LOG-LINEAR MODEL 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 
COHORT 1 
  
                              TIME                              OPTIMAL 
SUBJECT       USE             ESTIMATE    LOG10PRR48   P-VALUE  FLAG 
NUMBER  m-PD  [1]  ITERATION  (95% CI)    (95% CI)     [2]      [3] 
------- ----- ---- ---------- ----------- ------------ -------- -------- 
                                                                   
XXXX    YES   YES   1         XX (XX;XX)   XX (XX;XX)   XXX                        
                    2         XX (XX;XX)   XX (XX;XX)   XXX             
                    3         XX (XX;XX)   XX (XX;XX)   XXX      YES       
                    4         XX (XX;XX)   XX (XX;XX)   XXX             
 
XXXX    YES  YES   1         XX (XX;XX)   XX (XX;XX)   XXX                        
                   2         XX (XX;XX)   XX (XX;XX)   XXX             
                   3         XX (XX;XX)   XX (XX;XX)   XXX       
                   4         XX (XX;XX)   XX (XX;XX)   XXX             
                   5         XX (XX;XX)   XX (XX;XX)   XXX      YES      
                   6         XX (XX;XX)   XX (XX;XX)   XXX             
 
ETC…    
                                                                                                                  
[1] YES = SUBJECT INCLUDED IN THE DESCRIPTIVE STATISTICS OF DERIVED PARAMETERS OF THE LOG-LINEAR MODEL FOR PARASITE CLEARANCE. A SUBJECT IS INCLUDED 
WHEN THE OPTIMAL LOG-LINEAR REGRESSION MODEL P-VALUE < 0.001. 
[2] OVERALL MODEL P-VALUE BASED ON F-TEST. 
[3] OPTIMAL MODEL IS DEFINED BY THE MINIMUM OVERALL MODEL P-VALUE. 
 


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Final 1.0  of 11FEB2021 
 
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4.3 
SAFETY 
4.3.1 
Adverse events 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                                  SAS DATE AND TIME 
                                                                                                                                          PAGE X OF Y 
LISTING 16.2.7.1: ADVERSE EVENTS 
----------------------------------------------------------------------------------------------------------------------------------------------------- 
ANALYSIS SET: SAFETY 
 
COHORT 1 
 
 SUBJECT ANALYSIS                                        -------- ADVERSE EVENT --------  OUT TOX SI  REL REL REL ACT ACT ACT  RX   ONSET ONSET DUR   
 NUMBER  PHASE     PREFERRED TERM (VERBATIM) [1]         START DATETIME   STOP DATETIME   [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]  [13]  [14]   
 ------- --------- ------------------------------------- ---------------  --------------- --- --- --- --- --- --- --- --- ---- ---- ----- ----- ----- 
                                                                                                                                                    
 XXXX    SCREENING NONE                                                                                                                             
         CHALLENGE PAIN NOS (XXXXXXXXX)                  ddMMMyyyy:hh:mm  ddMMMyyyy:hh:mm REC GR1 NO  NO  NO  NO  NO  NO  NO   NO   XXX   XXX   XXX  
                   PULMONARY EMBOLISM (XXXXXXXXX) *      ddMMMyyyy:hh:mm  ONGOING         REC GR1 NO  NO  NO  NO  NO  NO  NO   YES  XXX   XXX   >XXX 
                   TINEA PEDIS (XXXXXXXXX)               ddMMMyyyy:hh:mm  ddMMMyyyy:hh:mm REC GR2 YES NO  NO  NO  NO  NO  NO   NO   XXX   XXX   XXX  
                   VEIN WALL HYPERTROPHY (XXXXXXXXX)     ddMMMyyyy:hh:mm  ddMMMyyyy:hh:mm REC GR1 NO  NO  NO  NO  NO  NO  NO   NO   XXX   XXX   XXX  
                                                                                                                                                    
 XXXX    SCREENING NONE                                                                                                                             
         CHALLENGE NONE                                                                                                                             
         RESCUE    DIARRHOEA NOS (XXXXXXXXX)             ddMMMyyyy:hh:mm    MMMyyyy       REC GR3 YES YES YES YES NO  NO  NO   NO   XXX   XXX   XXX  
                   DIZZINESS (XXXXXXXXX)                 ddMMMyyyy:hh:mm  ddMMMyyyy:hh:mm REC GR1 NO  YES YES YES NO  NO  NO   NO   XXX   XXX   XXX  
                   PAIN IN FOOT (XXXXXXXXX) !            UNKNOWN          ddMMMyyyy:hh:mm REC GR1 NO  NO  NO  NO  NO  NO  NO   YES                  
                   VOMITING NOS (XXXXXXXXX)              ddMMMyyyy:hh:mm  ddMMMyyyy:hh:mm REC GR1 NO  NO  NO  NO  PER PER PER  YES  XXX   XXX   XXX  
ETC… 
       
                                                                                                           
[1] SAES ARE FLAGGED WITH *. AES FOR WHICH ANOTHER ACTION IS TAKEN ARE FLAGGED WITH (!). 
[2] OUTCOME: REC = RECOVERED/RESOLVED; RECI = RECOVERING/RESOLVING; NREC = NOT RECOVERED/NOT RESOLVED; RECS = RECOVERED WITH SEQUELAE;  
FAT = FATAL; UNK = UNKNOWN. 
[3] AE TOXICITY: GR1 = GRADE 1-MILD; GR2 = GRADE 2-MODERATE; GR3 = GRADE 3-SEVERE; GR4 = GRADE 4-LIFE-THREATENING; GR5 = GRADE 5-DEATH.   
[4] SI: ADVERSE EVENT OF SPECIAL INTEREST. 
[5,6,7] RELATIONSHIP TO PfSPZ INOCULUM, RIAMET, MALARONE: NO=NOT RELATED/NOT SUSPECTED; YES=RELATED/SUSPECTED; NAP=NOT APPLICABLE.   
[8,9,10] ACTION TAKEN TOWARDS PfSPZ INOCULUM, RIAMET, MALARONE: PER=PERMANENTLY DISCONTINUED; NO=NO ACTION TAKEN; UNK=UNKNOWN; NAP=NOT APPLICABLE. 
[11] RX: CONCOMITANT THERAPY STARTED BECAUSE OF THE AE. 
[12] ONSET: DAY OF ONSET VERSUS FIRST PfSPZ INOCULATION, OR TIME OF ONSET IF ON DAY 1. 
[13] ONSET: DAY OF ONSET VERSUS START OF THE ANALYSIS PHASE, OR TIME OF ONSET IF ON DAY OF START OF THE ANALYSIS PHASE. 
[14] DURATION: DURATION (DAYS) OF THE INDIVIDUAL EVENT. 
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                                 SAS DATE AND TIME 
                                                                                                                                         PAGE X OF Y 
LISTING 16.2.7.2: SERIOUS ADVERSE EVENTS 
---------------------------------------------------------------------------------------------------------------------------------------------------- 
ANALYSIS SET: SAFETY 
 
COHORT 1 
 
 SUBJECT ANALYSIS                             -------- ADVERSE EVENT -------- SAE        OUT TOX SI  REL REL REL ACT ACT ACT  RX   ONSET ONSET DUR     
 NUMBER  PHASE     PREFERRED TERM (VERBATIM)  START DATETIME  STOP DATETIME   REASON [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]  [13]  [14]   
 ------- --------- -------------------------- --------------- --------------- ---------- --- --- --- --- --- --- --- --- ---- ---- ----- ----- ----- 
 XXXX    CHALLENGE PAIN NOS (XXXXXXXXX)       ddMMMyyyy:hh:mm ddMMMyyyy:hh:mm OMI        REC GR1 NO  NO  NO  NO  NO  NO  NO   NO   XXX   XXX   XXX   
                   PULMONARY EMBOLISM (XXXXX) ddMMMyyyy:hh:mm ONGOING         HOS        REC GR1 NO  NO  NO  NO  NO  NO  NO   YES  XXX   XXX   >XXX  
                   VEIN WALL HYPERTROPHY (XX) ddMMMyyyy:hh:mm ddMMMyyyy:hh:mm OMI        REC GR2 YES NO  NO  NO  NO  NO  NO   NO   XXX   XXX   XXX   
                                                                                                   
 XXXX    RESCUE    VOMITING NOS (XXXXXXXXX)   ddMMMyyyy:hh:mm ddMMMyyyy:hh:mm OMI        REC GR1 NO  YES YES YES NO  NO  NO   NO   XXX   XXX   XXX  
   
ETC… 
                                                                                                                     
[1] DTH = RESULTS IN DEATH; LIF = LIFE-THREATENING; HOS = REQUIRES OR PROLONGS HOSPITALISATION; DIS = RESULTS IN DISABILITY; CON = CONGENITAL 
ANOMALY; OMI = OTHER MEDICAL IMPORTANT AE. 
[2] OUTCOME: REC = RECOVERED/RESOLVED; RECI = RECOVERING/RESOLVING; NREC = NOT RECOVERED/NOT RESOLVED; RECS = RECOVERED WITH SEQUELAE;  
FAT = FATAL; UNK = UNKNOWN. 
[3] AE TOXICITY: GR1 = GRADE 1-MILD; GR2 = GRADE 2-MODERATE; GR3 = GRADE 3-SEVERE; GR4 = GRADE 4-LIFE-THREATENING; GR5 = GRADE 5-DEATH.   
[4] SI: ADVERSE EVENT OF SPECIAL INTEREST. 
[5,6,7] RELATIONSHIP TO PfSPZ INOCULUM, RIAMET, MALARONE: NO=NOT RELATED/NOT SUSPECTED; YES=RELATED/SUSPECTED; NAP=NOT APPLICABLE.   
[8,9,10] ACTION TAKEN TOWARDS PfSPZ INOCULUM, RIAMET, MALARONE: PER=PERMANENTLY DISCONTINUED; NO=NO ACTION TAKEN; UNK=UNKNOWN; NAP=NOT APPLICABLE. 
[11] RX: CONCOMITANT THERAPY STARTED BECAUSE OF THE AE. 
[12] ONSET: DAY OF ONSET VERSUS FIRST PfSPZ INOCULATION, OR TIME OF ONSET IF ON DAY 1. 
[13] ONSET: DAY OF ONSET VERSUS START OF THE ANALYSIS PHASE, OR TIME OF ONSET IF ON DAY OF START OF THE ANALYSIS PHASE. 
[14] DURATION: DURATION (DAYS) OF THE INDIVIDUAL EVENT. 
 
 


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Programmer note: repeat listing 16.2.7.1 for: 
 
LISTING 16.2.7.3: FATAL ADVERSE EVENTS 
 
LISTING 16.2.7.4: ADVERSE EVENTS FOR WHICH THE STUDY WAS DISCONTINUED 
 
LISTING 16.2.7.5: ADVERSE EVENTS FOR WHICH THE ANTIMALARIAL TREATMENT WAS DISCONTINUED 
 
LISTING 16.2.7.6: ADVERSE EVENTS AFTER ADMINISTRATION OF ANTIMALARIAL TREATMENT 
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                                  SAS DATE AND TIME 
                                                                                                                                          PAGE X OF Y 
LISTING 16.2.7.7: ADVERSE EVENTS FOR WHICH ANOTHER ACTION IS TAKEN 
----------------------------------------------------------------------------------------------------------------------------------------------------- 
ANALYSIS SET: SAFETY 
 
COHORT 1 
 
 SUBJECT ANALYSIS                                         
 NUMBER  PHASE     PREFERRED TERM (VERBATIM)             OTHER ACTION TAKEN   
 ------- --------- ------------------------------------- ------------------------------------------------------ 
                                                              
 XXXX    CHALLENGE PAIN NOS (XXXXXXXXX)                   XXXXXXXXXXXXXXXXXXXXXXXXXXX 
                   PULMONARY EMBOLISM (XXXXXXXXX)         XXXXXXXXXXXXXXXXXXXXXXXXXXX 
                                                              
 XXXX    RESCUE    DIARRHOEA NOS (XXXXXXXXX)              XXXXXXXXXXXXXXXXXXXXXXXXXXX 
                   DIZZINESS (XXXXXXXXX)                  XXXXXXXXXXXXXXXXXXXXXXXXXXX 
                   VOMITING NOS (XXXXXXXXX)               XXXXXXXXXXXXXXXXXXXXXXXXXXX 
ETC… 
       
                                                                                                           
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
LISTING 16.2.7.8: ADVERSE EVENTS: CODING INFORMATION 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
COHORT 1 
 
                                                                                                                                  SUBJECT  
 SYSTEM ORGAN CLASS           HIGH LEVEL GROUP TERM    HIGH LEVEL TERM          PREFERRED TERM   LOWER LEVEL TERM VERBATIM        NUMBER   
 ---------------------------- ------------------------ ------------------------ ---------------- ---------------- --------------- ------   
                                                                                                                                           
 GASTROINTESTINAL DISORDERS   DENTAL AND GINGIVAL      DENTAL AND PERIODONTAL   DENTAL CARIES    CARIES DENTAL    CARIES DENTAL   XXX      
                              CONDITIONS               INFECTIONS AND                                                                      
                                                       INFLAMMATIONS                                                                       
                                                                                                                                           
                                                       DENTAL DISORDERS NEC     TOOTH DISORDER   TOOTH DISORDER   TOOTH DISORDER  XXX      
                                                                                                                                           
                              GASTROINTESTINAL         DIARRHOEA (EXCL          DIARRHOEA        DIARRHOEA        DIARRHEA        XXX      
                              MOTILITY AND DEFAECATION INFECTIVE)                                                                          
                              CONDITIONS                                                                                                   
                                                                                                 LOOSE STOOLS     LOOSE STOOLS    XXX      
                                                                                                                                  XXX      
                                                                                                                                  XXX      
                                                                                                                                  XXX      
                                                                                                                                           
 INFECTIONS AND INFESTATIONS  INFESTATIONS - PATHOGEN  UPPER RESPIRATORY TRACT  NASOPHARYNGITIS  COMMON COLD      COMMON COLD     XXX      
                              UNSPECIFIED              INFECTIONS                                                                          
                                                                                                                                  XXX      
                                                                                                                                  XXX      
                                                                                                                                  XXX      
                                                                                                                                           
                              VIRAL INFECTIOUS         VIRAL INFECTIONS NEC     GASTROENTERITIS  GASTROENTERITIS  GASTROENTERITIS XXX      
                              DISORDERS                                         VIRAL            VIRAL            VIRAL                    
                                                                                                                                           
                                                                                VIRAL UPPER      UPPER            UPPER           XXX      
                                                                                RESPIRATORY      RESPIRATORY      RESPIRATORY              
                                                                                TRACT INFECTION  TRACT INFECTION  TRACT                    
                                                                                                 VIRAL NOS        INFECTION VIRAL          
ETC… 
 
 


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4.3.2 
Physical examinations 
 
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LISTING 16.2.7.9: PHYSICAL EXAMINATIONS ABNORMALITIES 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
               SUBJECT ANALYSIS      ASSESSMENT                                                                                CLINICAL      
 COHORT        NUMBER  VISIT         DATETIME         CRF BODY SYSTEM           DESCRIPTION (VERBATIM)                         SIGNIFICANT           
 ------------- ------- ------------- ---------------- ------------------------- ---------------------------------------------- ----------- 
                                                                                                                                    
 COHORT 1      XXXXXX  DAY -1        ddMMMyyyy:hh:mm  EARS, NOSE & THROAT       ANGINA (NOT TREATED)                           NO           
               XXXXXX  DAY -1        ddMMMyyyy:hh:mm  MUSCULOSKELETAL           BACK PAIN                                      NO           
               XXXXXX  DAY 10        ddMMMyyyy:hh:mm  SKIN                      SCARS (UPPER THORAX) CNS                       NO           
               XXXXXX  END OF STUDY  ddMMMyyyy:hh:mm  MUSCULOSKELETAL           MOVEMENT-PAIN + CREPITATIO IN BOTH KNEES CNS   YES           
               XXXXXX  DAY 10        ddMMMyyyy:hh:mm  MUSCULOSKELETAL           HIGH MUSCULAR TENSION (NECK)                   NO           
               XXXXXX  DAY 10        ddMMMyyyy:hh:mm  MUSCULOSKELETAL           MUSC. TENSION SHOULDER-NECK-MUSC. (NCS)        NO           
ETC… 
 
 
ONLY ABNORMALITIES ARE SHOWN. 
 
 
 


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4.3.3 
Clinical laboratory evaluation 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
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LISTING 16.2.8.1: LABORATORY TEST RESULTS FOR SUBJECTS WITH ABNORMAL VALUES 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
COHORT 1 
SUBJECT NUMBER (SEX) = XXXXXXXXX (MALE) 
 
                           ANALYSIS     ANALYSIS    SAMPLE           USE         CHG                ABN FAS CSA                      
 LABORATORY TEST (UNIT)    PHASE        VISIT       DATETIME         [1] RESULT  [2]   NORMAL RANGE [3] TED [4]  COMMENT             
 ------------------------- ------------ ----------- ---------------- --- ------- ----- ------------ --- --- ---  ------------------- 
                                                                                                                                     
 TEST 1 (UNIT)             SCREENING    SCREENING   ddMMMyyyy:hh:mm      XX            XX-XX            YES NO   XXXXXXXXXXXXXX      
                                        DAY -1      ddMMMyyyy:hh:mm      XX            XX-XX            YES NO   XXXXXXXXXXX         
                           CHALLENGE    DAY X       ddMMMyyyy:hh:mm      XX      XX    XX-XX        H   YES NO                       
                                        DAY X       ddMMMyyyy:hh:mm      XX      XX    XX-XX        H   YES NO                       
                                        DAY X       ddMMMyyyy:hh:mm      XX      XX    XX-XX        H   YES NO                       
                           RESCUE       DAY X       ddMMMyyyy:hh:mm      XX      XX    XX-XX            YES NO                       
                                        DAY X       ddMMMyyyy:hh:mm      XX      XX    XX-XX            YES NO                       
                                        DAY X       ddMMMyyyy:hh:mm      XX      XX    XX-XX            YES NO                       
                                        DAY X       ddMMMyyyy:hh:mm      XX      XX    XX-XX            NO  NO                       
                                                                                                                                     
 TEST 2 (UNIT)             SCREENING    SCREENING   ddMMMyyyy:hh:mm      XX            XX-XX            YES NO                       
                                        DAY -1      ddMMMyyyy:hh:mm      XX            XX-XX            YES NO                       
                           CHALLENGE    DAY X       ddMMMyyyy:hh:mm      XX      XX    XX-XX            YES NO                       
                                        DAY X       ddMMMyyyy:hh:mm  NO  XX      XX    XX-XX            YES NO                       
                                        DAY X       ddMMMyyyy:hh:mm      XX      XX    XX-XX            YES NO                       
ETC… 
  
 
[1] NO =  SAMPLE NOT USED IN ANALYSIS TABLES AND FIGURES. 
[2] CHANGE FROM BASELINE VALUE. 
[3] ABNORMALITY: H = ABNORMALLY HIGH VALUE / L = ABNORMALLY LOW VALUE COMPARED TO THE NORMAL RANGE. 
[4] SAMPLE WITH CLINICALLY SIGNIFICANT ABNORMALITIES (CRF DATA). 
 
 


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4.3.4 
Vital signs 
 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                           SAS DATE AND TIME 
                                                                                                                                   PAGE X OF Y 
LISTING 16.2.9.1: VITAL SIGNS RESULTS FOR SUBJECTS WITH ABNORMAL VALUES 
---------------------------------------------------------------------------------------------------------------------------------------------- 
ANALYSIS SET: SAFETY 
 
COHORT 1 
 
                                                                SUPINE         SUPINE 
                                                                SBP (mmHg)     DBP (mmHg)    HEART RATE (bpm)  TEMPERATURE (°C)  WEIGHT (kg)       
                                                             -------------- -------------- ------------------ ---------------- ---------------  
SUBJECT ANALYSIS     ANALYSIS      VITAL SIGN       USE  CSA TEST   CHG ABN TEST   CHG ABN TEST   CHG ABN     TEST   CHG ABN   TEST    CHG ABN  
NUMBER  PHASE        VISIT         DATETIME         [1]  [2] RESULT [3] [4] RESULT [3] [4] RESULT [3] [4]     RESULT [3] [4]   RESULT  [3] [4]  
------- ------------ ------------- ---------------- ---  --- ------ --- --- ------ --- --- ------ --- ------- ------ --- ----- ------- --- ---  
                                                                                                                                                
XXXX    SCREENING    SCREENING     ddMMMyyyy:hh:mm           XX             XX             XX                 XX.X             XX               
                     DAY -1        ddMMMyyyy:hh:mm           XX             XX             XX                 XX.X             XX               
        CHALLENGE    BASELINE      ddMMMyyyy:hh:mm       NO  XX     XX      XX     XX      XX     XX  L       XX.X   X.X       XX      XX       
                     TIME POINT 4  ddMMMyyyy:hh:mm           XX     XX      XX     XX      XX     XX          XX.X   X.X       XX      XX       
                     TIME POINT 5  ddMMMyyyy:hh:mm  NO       XX     XX      XX     XX      XX     XX          XX.X   X.X H     XX      XX       
XXXX    SCREENING    SCREENING     ddMMMyyyy:hh:mm           XX     XX      XX     XX      XX     XX          XX.X   X.X H     XX      XX       
                     DAY -1        ddMMMyyyy:hh:mm           XX     XX      XX     XX      XX     XX          XX.X   X.X H     XX      XX       
        CHALLENGE    BASELINE      ddMMMyyyy:hh:mm           XX     XX      XX     XX      XX     XX          XX.X   X.X       XX      XX       
                     TIME POINT 4  ddMMMyyyy:hh:mm           XX     XX      XX     XX      XX     XX          XX.X   X.X       XX      XX       
                     TIME POINT 5  ddMMMyyyy:hh:mm           XX     XX      XX     XX      XX     XX          XX.X   X.X       XX      XX       
ETC…    
              
[1] NO = NOT USED IN ANALYSIS TABLES AND FIGURES. 
[2] CLINICALLY SIGNIFICANT ABNORMALITY (CRF DATA). 
[3] CHANGE FROM BASELINE VALUE. 
[4] ABNORMALITY: H = ABNORMALLY HIGH VALUE / L = ABNORMALLY LOW VALUE COMPARED TO THE NORMAL RANGE. 
 
 


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4.3.5 
ECG 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
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LISTING 16.2.10.1: ECG RESULTS FOR SUBJECTS WITH ABNORMAL VALUES 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
COHORT 1 
SUBJECT NUMBER (SEX) =XXXXXXXX (MALE) 
 
                                                            HEART RATE (bpm)     PR (ms)         QRS (ms)                       
                                                            ---------------- --------------- ---------------                    
 ANALYSIS     ANALYSIS     ECG                      USE CSA TEST   CHG   ABN TEST   CHG  ABN TEST   CHG ABN                     
 PHASE        VISIT        TRIPLET ECG DATETIME     [1] [2] RESULT [3]   [4] RESULT [3]  [4] RESULT [3] [4]  COMMENT/MORPHOLOGY 
 ------------ ------------ ------- ---------------- --- --- ------ ----- --- ------ ---- --- ------ --- ---- ------------------ 
                                                                                                                                
 SCREENING    SCREENING    ECG 1   ddMMMyyyy:hh:mm  NO  NO  XXX          L   XXX             XXX                                
                           ECG 2   ddMMMyyyy:hh:mm  NO  NO  XXX          L   XXX             XXX                                
                           ECG 3   ddMMMyyyy:hh:mm  NO  NO  XXX          L   XXX             XXX             XXXXXXXXX          
                           MEAN    ddMMMyyyy:hh:mm      NO  XXX          L   XXX             XXX                                
 CHALLENGE    BASELINE     ECG 1   ddMMMyyyy:hh:mm  NO      XXX              XXX             XXX                                
                           ECG 2   ddMMMyyyy:hh:mm  NO      XXX              XXX             XXX                                
                           ECG 3   ddMMMyyyy:hh:mm  NO      XXX              XXX             XXX                                
                           MEAN    ddMMMyyyy:hh:mm          XXX              XXX             XXX                                
              TIME POINT 3 ECG 1   ddMMMyyyy:hh:mm  NO  NO  XXX    XXX   L   XXX    XX   H   XXX    XX  H                       
                           ECG 2   ddMMMyyyy:hh:mm  NO  NO  XXX    XXX   L   XXX    XX   H   XXX    XX  H    XXXXXXXXXXXXXX     
                           ECG 3   ddMMMyyyy:hh:mm  NO  NO  XXX    XXX   L   XXX    XX   H   XXX    XX  H                       
                           MEAN    ddMMMyyyy:hh:mm      NO  XXX    XXX   L   XXX    XX   H   XXX    XX  H                       
 
 ETC… 
 
[1] NO = NOT USED IN ANALYSIS TABLES AND FIGURES. 
[2] CLINICALLY SIGNIFICANT ABNORMALITY (CRF DATA). 
[3] CHANGE FROM BASELINE VALUE. 
[4] ABNORMALITY: H = ABNORMALLY HIGH VALUE / L = ABNORMALLY LOW VALUE COMPARED TO THE NORMAL RANGE. 
 
 
 


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                                                                                                                               PAGE X OF Y 
LISTING 16.2.10.1: ECG RESULTS FOR SUBJECTS WITH ABNORMAL VALUES 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
COHORT 1 
SUBJECT NUMBER (SEX) = XXXXXXXX (MALE) 
                                                                    QT (ms)                     QTcB (ms)               QTcF (ms)         
                                                          -------------------------- -------------------------- -----------------------  
 ANALYSIS  ANALYSIS     ECG                      USE  CSA TEST         CHG           TEST         CHG           TEST         CHG      
 PHASE     VISIT        TRIPLET ECG DATETIME     [1]  [2] RESULT ABN   [3]   ABN     RESULT ABN   [3]   ABN     RESULT ABN   [3]   ABN     
 --------- ------------ ------- ---------------- ---  --- ------ ----- ----- ------- ------ ----- ----- ------- ------ ----- ----- ---- 
                                                                                                                                        
 SCREENING SCREENING    ECG 1   ddMMMyyyy:hh:mm  NO   NO  XXX     H                  XXX     H                  XXX     H      
                        ECG 2   ddMMMyyyy:hh:mm  NO   NO  XXX     H                  XXX     H                  XXX     H      
                        ECG 3   ddMMMyyyy:hh:mm  NO   NO  XXX     H                  XXX     H                  XXX     H      
                        MEAN    ddMMMyyyy:hh:mm       NO  XXX     H                  XXX     H                  XXX     H      
 CHALLENGE BASELINE     ECG 1   ddMMMyyyy:hh:mm  NO       XXX                        XXX                        XXX                     
                        ECG 2   ddMMMyyyy:hh:mm  NO       XXX                        XXX                        XXX                     
                        ECG 3   ddMMMyyyy:hh:mm  NO       XXX                        XXX                        XXX                     
                        MEAN    ddMMMyyyy:hh:mm           XXX                        XXX                        XXX                     
           TIME POINT 3 ECG 1   ddMMMyyyy:hh:mm  NO   NO  XXX          XXX   [30,60] XXX          XXX   [30,60] XXX          XXX        
                        ECG 2   ddMMMyyyy:hh:mm  NO   NO  XXX          XXX   [30,60] XXX          XXX   [30,60] XXX          XXX        
                        ECG 3   ddMMMyyyy:hh:mm  NO   NO  XXX          XXX   [30,60] XXX          XXX   [30,60] XXX          XXX        
                        MEAN    ddMMMyyyy:hh:mm       NO  XXX          XXX   [30,60] XXX          XXX   [30,60] XXX          XXX        
 
 ETC… 
 
[1] NO = NOT USED IN ANALYSIS TABLES AND FIGURES. 
[2] CLINICALLY SIGNIFICANT ABNORMALITY (CRF DATA). 
[3] CHANGE FROM BASELINE VALUE. 
[4] ABNORMALITY: H = ABNORMALLY HIGH VALUE / L = ABNORMALLY LOW VALUE COMPARED TO THE NORMAL RANGE. 
 
 


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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
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LISTING 16.2.10.2: ECG INTERPRETATION AND MORPHOLOGY FOR SUBJECTS WITH ANY ABNORMAL INTERPRETATION 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
                                                                                                                                           
COHORT 1 
SUBJECT NUMBER (SEX) = XXXXXXXX (MALE)                                                                                                     
 
ANALYSIS     ECG              USE                CSA                                                                                       
VISIT        DATETIME         [1] INTERPRETATION [2] FINDING                        COMMENT                                             
------------ ---------------- --- -------------- --- ------------------------------ ----------------------------------------------------   
                                                                                                                                           
SCREENING    ddMMMyyyy:hh:mm  NO   ABNORMAL      YES                                XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX    
BASELINE     ddMMMyyyy:hh:mm  NO   ABNORMAL      NO   XXXXXXXXXX                                                                           
TIMEPOINT 3  ddMMMyyyy:hh:mm  NO   ABNORMAL      NO                                 XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX    
                                                                                                                                           
ETC… 
 
[1] NO = NOT USED IN ANALYSIS TABLES AND FIGURES. 
[2] CLINICALLY SIGNIFICANT ABNORMALITY (CRF DATA). 
 


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4.3.6 
Malaria clinical score 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                                SAS DATE AND TIME 
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LISTING 16.2.11.1: MALARIA SIGNS AND SYMPTOMS 
--------------------------------------------------------------------------------------------------------------------------------------------------- 
ANALYSIS SET: SAFETY 
 
COHORT 1                    
                                                                                                                        
        FIRST ANTIMALARIAL                                        MCS 
SUBJECT TREATMENT          ANALYSIS   DAY  ASSESSMENT      USE ---------                                                         
NUMBER  DATETIME           VISIT      [1]  DATETIME        [2] ACT  CHG  HEA MYA ART FAT MAL CHI SWE ANO NAU VOM ABD FEV TAC HYP 
------- ----------------   --------- ---- ---------------- --- ---- ---- --- --- --- --- --- --- --- --- --- --- --- --- --- --- 
                                                                                                                           
XXXX    ddMMMyyyy:hh:mm     BASELINE  1    ddMMMyyyy:hh:mm      XX.X XX.X XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  
                            DAY 7     7    ddMMMyyyy:hh:mm      XX.X XX.X XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  
                            DAY 8     8    ddMMMyyyy:hh:mm      XX.X XX.X XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  
                            DAY 9     9    ddMMMyyyy:hh:mm      XX.X XX.X XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  
                            DAY 10    10   ddMMMyyyy:hh:mm      XX.X XX.X XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  
                            DAY 11    11   ddMMMyyyy:hh:mm      XX.X XX.X XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  
                            DAY 12    12   ddMMMyyyy:hh:mm      XX.X XX.X XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  
                            DAY 13    13   ddMMMyyyy:hh:mm      XX.X XX.X XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  
                            DAY 14    14 * ddMMMyyyy:hh:mm      XX.X XX.X XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  
                            UNSCHED   15 * ddMMMyyyy:hh:mm   NO XX.X XX.X XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  
                            UNSCHED   16 * ddMMMyyyy:hh:mm   NO XX.X XX.X XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  
                            DAY 21    21   ddMMMyyyy:hh:mm      XX.X XX.X XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  XX  
ETC…   
 
[1] DAY VS. INOCULATION, DAYS ON WHICH ANTIMALARIAL TREATMENT IS TAKEN ARE FLAGGED (*). 
[2] NO = NOT USED IN ANALYSIS TABLES AND FIGURES. 
MCS=MALARIA CLINICAL SCORE (/42); ACT=ACTUAL VALUE; CHG=CHANGE FROM BASELINE. 
MALARIA SIGNS AND SYMPTOMS: HEADACHE, MYALGIA, ARTHRALGIA, FATIGUE/LETHARGY, MALAISE, CHILLS/SHIVERING/RIGORS, SWEATING/HOT SPELLS, ANOREXIA, NAUSEA, 
VOMITING, ABDOMINAL DISCOMFORT, FEVER, TACHYCARDIA, HYPOTENSION. 
 
 


MMV_PfSPZ-DVI Blood Stage_19_01 
Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 102 of 117 
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MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                                SAS DATE AND TIME 
                                                                                                                                        PAGE X OF Y 
LISTING 16.2.11.2: MALARIA CLINICAL SCORES > 6 AND PARASITAEMIA 
--------------------------------------------------------------------------------------------------------------------------------------------------- 
ANALYSIS SET: SAFETY 
 
COHORT 1                    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
          PARASITAEMIA 
                                                                           ----------------------------------- 
        FIRST ANTIMALARIAL                                         MCS                                 RESULT 
SUBJECT TREATMENT          ANALYSIS   DAY  ASSESSMENT       USE ---------- ANALYSIS   ASSESSMENT       (p/mL) 
NUMBER  DATETIME           VISIT      [1]  DATETIME         [2] ACT  CHG   VISIT      DATETIME         [3]  
------- ----------------   ---------- ---- ---------------- --- ---- ----- ---------- ---------------- -------  
                                                                                                         
XXXX    ddMMMyyyy:hh:mm     BASELINE  1    ddMMMyyyy:hh:mm      XX.X XX.X   BASELINE  ddMMMyyyy:hh:mm  XX.X 
                            DAY 11    11   ddMMMyyyy:hh:mm      XX.X XX.X   DAY 11    ddMMMyyyy:hh:mm  XX.X $ 
                            DAY 12    12   ddMMMyyyy:hh:mm      XX.X XX.X   DAY 12    ddMMMyyyy:hh:mm  XX.X $ 
                            DAY 13    13   ddMMMyyyy:hh:mm      XX.X XX.X   DAY 13    ddMMMyyyy:hh:mm  XX.X $ 
                            DAY 14    14 * ddMMMyyyy:hh:mm      XX.X XX.X   DAY 14    ddMMMyyyy:hh:mm  XX.X $ 
                            UNSCHED   15 * ddMMMyyyy:hh:mm   NO XX.X XX.X   DAY 14    ddMMMyyyy:hh:mm  XX.X $ 
ETC…   
 
[1] DAY VS. INOCULATION, DAYS ON WHICH ANTIMALARIAL TREATMENT IS TAKEN ARE FLAGGED (*). 
[2] NO = NOT USED IN ANALYSIS TABLES AND FIGURES. 
[3] POSITIVE qPCR RESULTS (≥ 250 PARASITES PER ML BLOOD) ARE FLAGGED ($). 
MCS=MALARIA CLINICAL SCORE (/42); ACT=ACTUAL VALUE; CHG=CHANGE FROM BASELINE. 


MMV_PfSPZ-DVI Blood Stage_19_01 
Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 103 of 117 
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5. 
TEMPLATE FIGURES 
5.1 
PHARMACODYNAMICS 
 
Programmer note: all PD figures shown in this section will be repeated for the m-PD set with adjusted numbering (e.g. 14.2.3.1.2). 
 


MMV_PfSPZ-DVI Blood Stage_19_01 
Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 104 of 117 
Confidential document 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
FIGURE 14.2.3.1.1: BLOOD-STAGE PARASITE PROFILE: MEDIAN PARASITAEMIA ACTUAL VALUES OVER TIME 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 


MMV_PfSPZ-DVI Blood Stage_19_01 
Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 105 of 117 
Confidential document 
Programmer notes: 
x One line per cohort and for all subjects. 
x Legend: Cohort 1, Cohort 2, All subjects. 
x X-axis ‘Analysis Time Point’ will show scheduled time points from Day 7 to Riamet Day 4, 72h. 
x Y-axis label: 'log10(Parasitaemia)'. 
x No CI interval will be shown. 
x Jittering should be allowed to distinguish overlapping symbols. 
 
 


MMV_PfSPZ-DVI Blood Stage_19_01 
Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 106 of 117 
Confidential document 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
FIGURE 14.2.3.2.1: BLOOD-STAGE PARASITE PROFILE: INDIVIDUAL PARASITAEMIA ACTUAL VALUES OVER TIME 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 


MMV_PfSPZ-DVI Blood Stage_19_01 
Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 107 of 117 
Confidential document 
Programmer notes: 
x A separate plot per cohort and all subjects starting in a new page. 
x One line per subject. 
x Legend: Subject numbers. 
x X-axis label: ‘Time from first PCR positivity (days)’. 
x Y-axis label: 'log10(Parasitaemia)'.  
x For each subject, show the assessments from the subject's first PCR positivity to parasite clearance. 
x Different plotting symbols will be used on the first assessment when antimalarial treatment was given and will be denoted by a footnote. 
 
 
 


MMV_PfSPZ-DVI Blood Stage_19_01 
Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 108 of 117 
Confidential document 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
FIGURE 14.2.3.3.1: TIME TO FIRST PCR POSITIVITY: KAPLAN MEIER PLOT 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: PD 
 
 
 
POSITIVE PARASITAEMIA IS DEFINED AS qPCR OUTCOME ≥ 250 PARASITES PER mL BLOOD. 
 


MMV_PfSPZ-DVI Blood Stage_19_01 
Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 109 of 117 
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Programmer notes: 
x One line per cohort and all subjects. 
x X-axis label: ‘Time from PfSPZ inoculation (days)’. 
x Y-axis label: ‘Probability (%)’. 
 


MMV_PfSPZ-DVI Blood Stage_19_01 
Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 110 of 117 
Confidential document 
Programmer note: repeat Figure 14.2.3.3.1 for: 
 
FIGURE 14.2.3.4.1: TIME TO PARASITAEMIA OF ≥5000 PARASITES PER mL BLOOD: KAPLAN MEIER PLOT 
 
FIGURE 14.2.3.5.1: TIME TO FIRST DOSE OF TREATMENT WITH RIAMET: KAPLAN MEIER PLOT 
 
FIGURE 14.2.3.6.1: TIME TO PARASITE CLEARANCE: KAPLAN MEIER PLOT 
 
The footnotes and axes will be adapted accordingly. 
 
 
 
 


MMV_PfSPZ-DVI Blood Stage_19_01 
Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 111 of 117 
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5.2 
SAFETY 
5.2.1 
Clinical laboratory evaluation 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
FIGURE 14.3.2.1: INDIVIDUAL LABORATORY TEST ACTUAL VALUES OVER TIME 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
 


MMV_PfSPZ-DVI Blood Stage_19_01 
Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 112 of 117 
Confidential document 
Programmer notes: 
x A separate plot per cohort and all subjects starting in a new page. 
x One line per subject and one line for the median. 
x X-axis ‘Analysis Time Point’ will show scheduled time points. 
x Label Y-axis will be the laboratory test result. 
x The following laboratory parameters will be shown in separate plots: liver biochemistry parameters (albumin, AST, ALT, ALP, GGT, 
total and direct bilirubin and total serum proteins), CRP and haemoglobin. 
 
 


MMV_PfSPZ-DVI Blood Stage_19_01 
Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 113 of 117 
Confidential document 
5.2.2 
Vital signs 
The analysis figures for vital signs parameters are largely identical to the laboratory figures. 
 
 
FIGURE 14.3.3.1: INDIVIDUAL VITAL SIGNS ACTUAL VALUES OVER TIME 
Programmer notes: 
x The following vital signs parameters will be shown in separate plots: heart rate and body temperature. 
x The median time to first antimalarial treatment administration will be shown with a reference line. 
  
 


MMV_PfSPZ-DVI Blood Stage_19_01 
Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 114 of 117 
Confidential document 
5.2.3 
ECG 
The analysis figures for ECG parameters are largely identical to the laboratory figures. 
 
FIGURE 14.3.4.1: INDIVIDUAL ECG ACTUAL VALUES OVER TIME 
 
Programmer note: the following ECG parameters will be shown in separate plots: QTcF and QTcB. 
  
 


MMV_PfSPZ-DVI Blood Stage_19_01 
Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 115 of 117 
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5.2.4 
Malaria clinical score 
 
MMV_PFSPZ-DVI BLOOD STAGE_19_01 - ANALYSIS VERSION                                                                       SAS DATE AND TIME 
                                                                                                                               PAGE X OF Y 
FIGURE 14.3.5.1: INDIVIDUAL MALARIA CLINICAL SCORE ACTUAL VALUES OVER TIME 
------------------------------------------------------------------------------------------------------------------------------------------ 
ANALYSIS SET: SAFETY 
 
 


MMV_PfSPZ-DVI Blood Stage_19_01 
Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 116 of 117 
Confidential document 
Programmer notes: 
x A separate plot per cohort and all subjects starting in a new page. 
x One line per subject and one line for the median. 
x X-axis ‘Analysis Time Point’ will show scheduled time points. 
x Label Y-axis will be ‘Malaria clinical score’. 
x Different symbols will be used for the time points where antimalarial treatment was taken for the first time and for the time point of peak 
parasitaemia. They will be specified in a footnote. 
x The median time to first antimalarial treatment administration will be shown with a reference line. 
 
 
 


MMV_PfSPZ-DVI Blood Stage_19_01 
Mock Tables, Listings and Figures 
Final 1.0  of 11FEB2021 
 
Page 117 of 117 
Confidential document 
Programmer note: repeat Figure 14.3.5.1 for: 
 
FIGURE 14.3.5.2: INDIVIDUAL MALARIA CLINICAL SCORE AND PARASITAEMIA ACTUAL VALUES OVER TIME 
 
FIGURE 14.3.5.3: INDIVIDUAL MALARIA CLINICAL SCORE AND CRP ACTUAL VALUES OVER TIME 
 
x Each figure will show a separate plot per cohort starting in a new page followed by a separate plot per individual subject starting in a 
new page. 
x One line per subject and parameter. I.e. individual subjects plots will have 2 lines; cohort plots will have 2*8 = 16 lines (if no missing 
data). 
x X-axis ‘Time from PfSPZ inoculation (days)’ will show the relative time in days of the individual subject assessments. 
x Label Y-axis will be ‘Malaria clinical score’ on the left Y-axis and 'log10(Parasitaemia)' / 'CRP (unit)' on the right Y-axis. 
x The first antimalarial treatment administration will be shown with a reference line. 


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