Conditions: Healthy
Keywords: Healthy Participants M5717 Malaria Plasmodium falciparum
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 39
Healthy volunteers: yes

Brief summary:
The main purpose of this study was to assess the chemoprophylactic activity and dose-exposure-response relationship of single oral dose of M5717 administered after direct intravenous inoculation (DVI) of Plasmodium falciparum sporozoite (PfSPZ) challenge in healthy participants.

Detailed description:

Arms:
arm 1: Participants received single dose of placebo matched to M5717 capsule on Day 1 after 2 hours of Plasmodium falciparum Sporozoite (PfSPZ) (3200 sporozoites per injection) intravenous (IV) inoculation administration on Day 1. arm 2: Participants received single dose of M5717 30 mg capsule on Day 1 after 2 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1. arm 3: Participants received single dose of M5717 60 mg capsule on Day 1 after 2 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1. arm 4: Participants received single dose of M5717 80 mg capsule on Day 1 after 2 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1. arm 5: Participants received single dose of M5717 100 mg capsule on Day 1 after 2 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1. arm 6: Participants received single dose of M5717 200 mg capsule on Day 1 after 2 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1. arm 7: Participants received single dose of placebo matched to M5717 capsule on Day 5 after 96 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1. arm 8: Participants received single dose of M5717 60 mg capsule on Day 5 after 96 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1. arm 9: Participants received single dose of M5717 100 mg capsule on Day 5 after 96 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1. arm 10: Participants received single dose of M5717 200 mg capsule on Day 5 after 96 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1.

Interventions: intervention 1: PfSPZ Challenge intervention 2: Palcebo intervention 3: M5717 30 mg intervention 4: M5717 60 mg intervention 5: M5717 80 mg intervention 6: M5717 100 mg intervention 7: M5717 200 mg intervention 8: Placebo intervention 9: M5717 60 mg intervention 10: M5717 100 mg intervention 11: M5717 200 mg
Intervention descriptions: intervention 1: Participants received 3200 units of Plasmodium falciparum sporozoites by DVI on Day 1. intervention 2: Participants received single oral dose of placebo matched to M5717 capsule on Day 1. intervention 3: Participants received 30 mg single oral dose of M5717 capsule on Day 1. intervention 4: Participants received 60 mg single oral dose of M5717 capsule on Day 1. intervention 5: Participants received 80 mg single oral dose of M5717 capsule on Day 1. intervention 6: Participants received 100 mg single oral dose of M5717 capsule on Day 1. intervention 7: Participants received 200 mg single oral dose of M5717 capsule on Day 1. intervention 8: Participants received single oral dose of placebo matched to M5717 capsule on Day 5. intervention 9: Participants received 60 mg single oral dose of M5717 capsule on Day 5. intervention 10: Participants received 100 mg single oral dose of M5717 capsule on Day 5. intervention 11: Participants received 200 mg single oral dose of M5717 capsule on Day 5.

Protocol document:
Prot_000.pdf: 
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M5717 
 
Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model 
MS201618_0003 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
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Protocol Amendment Summary of Changes 
Protocol History 
 
Version Number 
Type 
Version Date 
1.0 
Original Protocol 
30-Sep-2019 
2.0 
Amendment 
05-Feb-2020 
3.0 
Amendment 
20-Jul-2020 
4.0 
Amendment 
03-Dec-2020 
Protocol Version 4.0 (03 December 2020) 
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The original protocol of this malaria challenge study excluded women of childbearing potential. 
Since designing the protocol, the following toxicological data have become available that allow 
inclusion of this population: 
a. 
Absence of fetal abnormalities and no adverse effects on embryo-fetal survival with M5717 
in the embryo fetal development (EFD) studies in rats (treatment from gestation day 6 to 16) 
up to the no-observed-adverse-effect level (NOAEL) of 80 mg/kg. Cmax and AUC at the 
NOAEL were respectively 12 and 21 times higher than Cmax and AUC observed in humans 
at the anticipated therapeutic dose for cure of 800 mg (blood stage).  
b. 
There was no effect on embryo-fetal survival or morphological development up to the 
NOAEL of 40 mg/kg in EFD studies in rabbits (treatment from gestation day 6 to 18). Cmax 
and AUC at the NOAEL were both 5 times higher than Cmax and AUC observed in humans 
at the anticipated therapeutic dose for cure of 800 mg.  
Although the maximum dose in this study was set at 1200 mg initially, the efficacy is expected to 
be reached at markedly lower doses. Therefore, from an (embryo) toxicological point of view, 
there is no reason to exclude women of childbearing potential in view of the results of dedicated 
EFD in animals and the doses that will be administered in the study. The inclusion of women will 
add to the value of the study as information on the compound when administered to (non pregnant) 
women will contribute to assessment of potential benefit for women from the experimental 
treatment under investigation. This will inform early on how the compound behaves in women and 
will allow inclusion of women in the next developmental clinical patient studies. 
As a preventive measure, women will need to use effective contraception in this study according 
to Merck standards. 
  


M5717 
 
Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model 
MS201618_0003 
 
 
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I N F O R M A T I O N 
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In this context it is important to note that there is no untoward drug-drug interaction anticipated 
between M5717 and the oral contraceptive pill to diminish the efficacy of the oral contraceptive 
or increase the exposure of the oral contraceptive (see below). Likewise, oral hormonal 
contraceptives (i.e. combined estrogen- and progestogen-containing hormonal contraceptives to 
inhibit ovulation) do not act as perpetrators, hence no effect by oral contraceptive pill on M5717 
pharmacokinetics (PK) and pharmacodynamics (PD) is anticipated. 
So far in human hepatocytes, M5717 did not induce any CYP enzymes (1A2, 2B6, 2C9, 2C19, 
and 3A4) at the maximum concentration (margin of above 600 of in vitro versus Cmax at 800 mg) 
refer to Investigator’s Brochure [IB]). For contraceptives, PXR-mediated induction of 
drug-metabolizing enzymes (e.g., 3A4) leading to increased metabolism of ethinylestradiol and 
progesterones is the main concern for decreased efficacy (Lee, 2009). As M5717 did not induce 
3A4 in vitro, drug-drug interactions via induction of the metabolism of contraceptive steroids by 
M5717 are not expected.  
In contrast, M5717 is a weak 2D6 and 3A4 inhibitor, but preliminary physiological based 
pharmacokinetic modeling suggested that this level of inhibition was insufficient to increase 
midazolam concentrations. An interaction of decreased metabolism by 3A4 (leading to increased 
exposure of contraceptives) and possible safety concerns related to contraceptive use is therefore 
not likely.  
In summary, from a toxicological point of view, as well as interaction regarding efficacy of 
contraception and safety considerations, there seems to be no objection to include women of 
childbearing potential on adequate contraceptives in the study. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis (Study Intervention Groups 
and Duration) 
Corrected Study Intervention 
Day 4 to Day 5 for ‘Late liver 
stage’. 
Incorrect translation of ‘after 4 
days’ in the Schedule of Activities. 
1.3 Schedule of Activities (Tables 1 and 3) 
 
 
Added clarification that BP 
and PR can be measured 
within 24 hours before 
malaria inoculum.   
Clarification purposes 
1.3 Schedule of Activities (Tables 1 and 3) 
Clarified pregnancy and 
FSH testing. 
All women can now be included; 
requirement for negative serum 
pregnancy test at the Screening 
Visit, Day -1, Day 4, and End of 
Study visits applies to all female 
participants. FSH testing is 
applicable to women of non-
childbearing potential only.  
1.3 Schedule of Activities (Tables 2 and 4) 
Added urine pregnancy test 
at End of Study Visit. 
Omitted in original protocol. 
1.3 Schedule of Activities (Tables 3 and 4) 
Corrected Study Intervention 
Day 4 to Day 5 in table titles 
for ‘Late liver stage’ 
participants and cross 
checked mark in Table 3. 
Incorrect translation of ‘after 4 
days’ in the Schedule of Activities. 


M5717 
 
Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities (Tables 3 and 4) 
Study Day 32 added. 
Omitted in original protocol due to 
incorrect translation of ‘after 4 
days’ in the Schedule of Activities. 
1.3 Schedule of Activities (Table 1 through 
Table 4) 
Removed vital signs and 
clinical laboratory 
assessments at 168, 264 
and 408 hours after Study 
Intervention Administration. 
 
 
Blinded data from the first cohort 
(200 mg M5717 or placebo) in the 
current study indicate a lower dose 
range (probably below 200 mg) to 
be tested in subsequent cohorts to 
characterize the exposure-
response relationship.  
No safety concerns at these low 
doses that would necessitate the 
initially implemented frequent 
scheduled assessments are 
anticipated on the basis of safety 
data from the first-in-human (FIH) 
study and accumulated safety data 
from the current study.   
Deleting 3 safety assessments will 
decrease the burden, as well as 
the number of ambulatory visits 
and blood samples for the 
participants in the study. The 
proposed change will not affect the 
unscheduled safety laboratory 
assessments when parasitemia 
develops, since when qPCR level 
reaches ≥ 100 aPf/mL, an 
additional clinical laboratory 
sample should be taken within 24 
hours (unless already scheduled). 
1.3 Schedule of Activities (Table 1 through 
Table 4) 
Updates and/or corrections 
were made to several 
timepoints in the tables as 
follows: 
 
Ambulatory visit was 
removed and added as a 
phone call visit at study Day 
18 in Table 2. 
 
Hospitalization, ambulatory 
visits, and ambulatory phone 
call visits in Table 3 and 4 
timepoints were updated. 
 
Timepoints of physical 
examination, urine drugs of 
abuse, alcohol breath test, 
diary cards, and PK 
sampling timepoints were 
also updated in Table 3. 
Updates and/or corrections to 
tables. 
4.3.2 Selection of Further Doses 
Corrected Study Intervention 
Day 4 to Day 5 for ‘Late liver 
stage’ participants. 
Incorrect translation of after 4 days 
in the Schedule of Activities. 


M5717 
 
Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model 
MS201618_0003 
 
 
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I N F O R M A T I O N 
5/119 
 
 
Section # and Name 
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria 
Added that women of 
childbearing potential can be 
included. 
In order to expand the study to the 
female study population which 
allows to gain more representative 
data.  
8.2.2 Vital Signs 
Added that oral temperature 
may be used if in opinion of 
Investigator the reading is 
more reliable than the 
tympanic measurement. 
Increase reliability of 
measurement. 
8.2.4 Clinical Safety Laboratory 
Assessments 
Added further clarification on 
fasting times. 
Clarify fasting times for all cohorts. 
8.2.4 Clinical Safety Laboratory 
Assessments 
Added mandatory text for 
additional serum or highly 
sensitive urine pregnancy 
tests that may be needed. 
Mandatory text. 
10 References 
Reference added. 
To add a reference used in this 
amendment. 
Appendix 1 Abbreviations 
Abbreviations added. 
To define abbreviations used in 
this amendment. 
Appendix 3 Contraception 
Removed text that female 
participants must not be 
women of childbearing 
potential. 
Not relevant anymore. 
 
 
- Confidential - 
This document is the property of Merck Healthcare KGaA, Darmstadt, Germany, or one of its subsidiaries. It is 
intended for restricted use only and may not – in full or part – be passed on, reproduced, published or used without 
express permission of Merck Healthcare KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2020 by Merck 
Healthcare KGaA, Darmstadt, Germany, or its subsidiary. All rights reserved. 
 


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M5717 
 
Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model 
MS201618_0003 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
7/119 
 
 
6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability .....................................................................................50 
6.3 
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................51 
6.3.1 
Study Intervention Assignment ..........................................................51 
6.3.2 
Blinding ..............................................................................................52 
6.3.3 
Emergency Unblinding .......................................................................53 
6.4 
Study Intervention Compliance ..........................................................53 
6.5 
Concomitant Therapy .........................................................................53 
6.5.1 
Rescue Medicine .................................................................................54 
6.5.2 
Permitted Medicines ...........................................................................55 
6.5.3 
Prohibited Medicines ..........................................................................55 
6.5.4 
Other Interventions .............................................................................55 
6.6 
Dose Selection and Modification ........................................................56 
6.7 
Study Intervention after the End of the Study ....................................56 
6.8 
Special Precautions .............................................................................56 
6.9 
Management of Adverse Events of Interest ........................................56 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ...............................................................57 
7.1 
Discontinuation of Study Intervention................................................57 
7.1.1 
Temporary Discontinuation ................................................................57 
7.1.2 
Rechallenge .........................................................................................57 
7.2 
Participant Discontinuation/Withdrawal from the Study ...................57 
7.3 
Lost to Follow-Up...............................................................................58 
8 
Study Assessments and Procedures ....................................................58 
8.1 
Efficacy Assessments and Procedures ................................................59 
8.2 
Safety Assessments and Procedures ...................................................59 
8.2.1 
Physical Examinations ........................................................................59 
8.2.2 
Vital Signs ..........................................................................................60 
8.2.3 
Electrocardiograms .............................................................................60 
8.2.4 
Clinical Safety Laboratory Assessments ............................................61 
8.2.5 
Suicidal Risk Monitoring ....................................................................61 
8.3 
Adverse Events and Serious Adverse Events .....................................61 


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M5717 
 
Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model 
MS201618_0003 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
10/119 
 
 
Table of In-Text Tables 
Table 1 
Schedule of Activities (for DVI and Study Intervention 
Administration on Day 1; Part I, Screening to Week 2) .....................17 
Table 2 
Schedule of Activities (for DVI and Study Intervention on Day 1; 
Part II, Week 3 to End of Study) ........................................................21 
Table 3 
Schedule of Activities (for DVI on Day 1 and Study Intervention 
on Day 5; Part I, Screening to Week 2) ..............................................24 
Table 4 
Schedule of Activities (for DVI on Day 1 and Study Intervention 
on Day 5; Part II, Week 3 to End of Study) ........................................29 
Table 5 
Allowed Time Windows for Scheduled Time Points .........................32 
Table 6 
Objectives and Endpoints (Outcome Measures) .................................38 
Table 7 
Definition of Individual PK Parameters .............................................65 
Table 8 
Posterior Probability for True Protection Rate > 50%........................68 
Table 9 
Analysis Populations ..........................................................................69 
Table 10 
Statistical Analysis Methods Used for Efficacy Analyses .................70 
Table 11 
Statistical Analysis Methods Used for Safety Analyses .....................71 
Table 12 
Protocol-Required Clinical Laboratory Assessments .........................94 
 


M5717 
 
Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model 
MS201618_0003 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
11/119 
 
 
Table of In-Text Figures 
Figure 1 
Overall Study Design per Cohort for Dose Finding ...........................16 
Figure 2 
Plasmodium Life Cycle: Sporogony in Mosquito (Sexual Cycle) 
and Human Stages (Asexual Cycle) ...................................................33 
Figure 3 
Overall Study Design Assuming 5 Cohorts for Dose-Finding ...........39 
Figure 4 
Summary of Adaptive Design Steps after Evaluation of First and 
Second Cohort ....................................................................................43 
 
 
 
 


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M5717 
 
Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model 
MS201618_0003 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
13/119 
 
 
Objectives and Endpoints: 
Primary Objectives 
Endpoints 
To assess chemoprophylactic activity of single oral 
doses of M5717 administered after DVI of Plasmodium 
falciparum sporozoites (PfSPZ) challenge in healthy 
participants.  
Response endpoints: 
• Number of participants over time with positive 
parasitemia defined as first positive qPCR outcome 
equal or greater than 100 asexual parasites per mL 
of blood within 28 days of PfSPZ challenge  
• Time to parasitemia, defined as time from PfSPZ 
DVI to the first qPCR outcome equal or greater 
than 100 asexual parasites per mL of blood (time 
frame: number of days from PfSPZ DVI challenge 
to positive parasitemia, or 28 days)  
• Number of participants with documented blood 
stage parasite growth, defined as an increase of 
qPCR measured asexual parasites per mL 
compared to the first parasitemia measurement, 
within 28 days of PfSPZ DVI  
• Clinical symptoms of malaria using the Malaria 
Clinical Score.  
To explore the dose-exposure-response relationship of a 
single oral dose of M5717 administered after DVI of 
PfSPZ challenge in healthy participants.  
Dose-exposure-response relationship: 
• Selected pharmacokinetic (PK) endpoints/ 
concentrations (e.g. AUC0-24, AUC0-168, C24, C168) 
and pharmacodynamic (PD) endpoints (cured/not-
cured) will be used for PK/PD modeling 
approaches. 
Secondary Objectives 
Endpoints  
To evaluate the safety and tolerability of single, oral 
doses of M5717 in healthy participants following infection 
with PfSPZ challenge 
• Nature, incidence, frequency, severity of (treatment 
emergent) adverse events (AEs)/ serious adverse 
events (SAEs), and relationship to the study 
intervention 
• Incidence of clinically significant changes and 
abnormalities in safety laboratory parameters 
(hematology, coagulation, biochemistry [specifically 
alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST), alkaline phosphatase 
(ALP), bilirubin (total)], and urinalysis) 
• Incidence of clinically significant changes and 
abnormalities in vital signs and 12-lead 
electrocardiogram (ECG). 
To investigate the PK of M5717 after administration of 
single, oral doses in healthy participants following 
infection with PfSPZ 
Exposure endpoints: 
• 
Concentration-time curve for M5717 after single-
dose administration 
• 
Pharmacokinetic parameters of M5717 such as 
AUC0-∞, AUC0-t, AUC0-24, AUC0-168, Cmax, C24, C168, 
tmax, t1/2, λZ, CL/f and Vz/f to be specified in the 
Integrated Analysis Plan. 
DVI=direct 
venous 
inoculation, 
PD=pharmacodynamics, 
PfSPZ=Plasmodium 
Falciparum 
Sporozoites, 
PK=pharmacokinetics, qPCR=quantitative polymerase chain reaction. 
 
 


M5717 
 
Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model 
MS201618_0003 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
14/119 
 
 
Overall Design:  
This is a Phase Ib, single center, sequential, double-blind, randomized, placebo-controlled study 
to investigate the chemoprophylactic activity and dose/exposure-response relationship of single 
doses of M5717 administered after DVI of P. falciparum sporozoites (PfSPZ challenge) to healthy 
malaria-naïve male and female participants, 18 to 45 years of age.  
Number of Participants:  
The study will involve up to a maximum of 50 healthy adult men and women (between 4 and 12 
healthy participants per dose group, with up to 5 cohorts). 
Given the exploratory nature of this study, the sample size will not be based on power calculations. 
Historically, 8 to 12 participants in a dose cohort have provided sufficient data to characterize the 
chemoprophylactic activity of a drug on malaria parasite load following induction in healthy 
participants using DVI with PfSPZ. This number is comparable with previously published 
experiences (Sulyok 2017).  
As the exact number of participants who might show recrudescence is unknown, 4 to 5 cohorts are 
planned to be able to evaluate adapted doses of the study intervention to collect sufficient data on 
participants who are cured and participants with recrudescence, to explore the dose-exposure-
response relationship.  
The number of participants in the current study will be 4 to 12 participants per cohort with an 
active to placebo ratio of 3:1 and a block size of 4 (e.g. 4 [3 active:1 placebo], 8 
[6 active:2 placebo] or 12 [9 active:3 placebo]). The number of participants for a subsequent dose 
group will be based on available PD (cured/not-cured) and PK data from the actual/preceding dose 
groups. Once the efficacious dose level for the early liver stage has been identified, a cohort of 12 
participants will be evaluated whether this dose is also efficacious on the late liver stage 
(administration of M5717 at Day 5 after PfSPZ challenge). 
A screening failure rate of 30% is expected and therefore about 70 participants should be screened. 
With 3 actively treated participants, the probability that the protection rate is 50% or greater was 
calculated using the Bayesian method. The assumption is that the protection status follows a 
binomial distribution with parameter θ (true protection rate) which follows a non-informative prior 
distribution beta (0.5, 0.5). The posterior probability that the true protection rate is ≥ 50% given 
various situations to be observed from Cohort 1, are tabulated below: 
 
Number of actively treated 
participants  
Number of protected participants 
observed 
Posterior probability (true 
protection rate ≥ 50%) 
3 
3 
97% 
3 
2 
71% 
3 
1 
29% 
3 
0 
3% 
If ≥ 2 protected participants out of 3 actively treated participants are observed in the first cohort, 
it is likely (probability ≥ 71%) that the true protection rate is greater than 50%, so in the next cohort 
the cohort will be expanded in order to identify the dose for a 50% protection rate. 


M5717 
 
Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model 
MS201618_0003 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
15/119 
 
 
Study Intervention Groups and Duration:  
A maximum 28-day screening period is foreseen for each participant. 
Dose-finding ‘early liver stage’: Participants that will be dosed on Study Day 1 will be admitted 
at the site on Study Day -1. For COVID-19 risk assessment measures upon admission, see 
Appendix 11. Randomization will occur either on Study Day -1 or Day 1; PfSPZ IV inoculation 
and study intervention administration will occur on Study Day 1 after randomization. Participants 
will be hospitalized for 2 nights from Study Day -1 to Day 2, which includes 24 hours post study 
intervention administration. Thereafter they will enter an ambulatory visit period from Study Day 
3 to Day 28. During this period, they will return as outpatients for serial PK samplings, qPCR tests 
and evaluation of the malaria clinical score, as scheduled. In case blood-stage parasite growth is 
noted, the participant will be given rescue medication immediately. Participants will be contacted 
daily either during a visit to the unit or via phone calls from the site while being outpatient, from 
Study Day 3 to Day 33, for a safety check and for compliance with the rescue medication use. On 
Study Days 3, 4, 5, 12, 18, 21, 23, 25 and 27 ambulatory visits by phone call only are planned.  
Once participants are discharged from the clinic, they need to keep a diary about their health status 
that will be checked every time they report back to the clinic. The End of Study visit will be 
performed on Study Day 33 (+ 3). In case rescue medication is given before Study Day 28, an 
adapted visit schedule might apply.  
‘Late liver stage’: Following randomization either on Study Day -1 or Day 1 and PfSPZ IV 
inoculation on Study Day 1, participants will be admitted at the site on Study Day 4 and will be 
dosed on Study Day 5 (equal to study intervention administration Day 1). For COVID-19 risk 
assessment measures upon admission, see Appendix 11. They will also be hospitalized for 2 nights 
from Study Day 4 to 6 (equal to study intervention administration Day -1 to 2), which includes 24 
hours post study intervention administration. Thereafter, participants will enter an ambulatory visit 
period similar to that of participants dosed on Study Day 1, as described above.  In case blood-
stage parasite growth is noted, the participant will be given rescue medication immediately, 
otherwise rescue medication will be administered on Study Day 32 (which represents study 
intervention administration Day 28).  The End of Study visit for this cohort will be on Study 
Day 36 (+ 3). 
Involvement of Special Committee(s):  
A Safety Monitoring Committee (SMC) will be established before enrolment of the first participant 
to review the data after each cohort is completed, and to decide on the dose, dose regimen, and 
number of participants for the next cohort as per protocol. The SMC will include the Chairperson 
(Global Patient Safety Product Responsible), core sponsor members (Medical Responsible, 
Clinical Pharmacology Representative, and Biostatistician). The following external members will 
be included: Principal Investigator (and Sub-Investigator(s)), CRO representative, and an 
independent external expert (if applicable). Only Merck members and the investigators will be 
voting members, and, as applicable, the independent external expert. Further persons may be 
represented on the team if their input is required. Details regarding SMC roles, responsibilities, 
activities, procedures to reduce potential bias, and possible SMC recommendations will be 
provided in a separate SMC charter. 


M5717 
 
Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model 
MS201618_0003 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
16/119 
 
 
1.2 
Schema 
The overall design of the study per cohort for dose finding, from Screening, direct intravenous 
inoculation (DVI, i.e. bolus) with malaria sporozoites, study intervention administration, medical, 
quantitative polymerase chain reaction (qPCR) and pharmacokinetic monitoring, to discharge and 
rescue treatment, is summarized in Figure 1.   
After discharge participants will visit the study site on a daily basis for serial qPCR, 
pharmacokinetics (PK) and safety assessments as scheduled, until study intervention 
administration Day 28 when rescue medication will be administered. When indicated and deemed 
safe by the Investigator, participants may also visit on a less regular basis from study intervention 
administration Day 20 until Day 28. However, on the days that the participants do not visit the 
study site, the participant will be contacted by telephone, SMS or email by site staff. Once they 
are discharged from the clinic, the participants need to keep a diary about their health status that 
will be checked every time they report back to the clinic. The End of Study visit (including safety 
examinations, PK and qPCR) will be done at study intervention Day 33 (+ 3). In case blood-stage 
parasite growth is noted and confirmed; the participant will have a blood sample taken for P. 
falciparum genotyping and be given rescue medication immediately. Blood-stage parasite growth 
is defined as an increase of parasite load compared to the load measured at first parasitaemia. If no 
blood-stage growth develops before study intervention administration Day 28, participants will 
receive rescue treatment on study intervention administration Day 28. In the first 3 or 4 cohorts 
enrolled, the study intervention will be administered 2 hours after PfSPZ challenge so that the 
sporozoites can be deposited in the liver without any interference by M5717, and the effect of the 
study intervention on the (pre-erythrocytic) intracellular liver stages can be evaluated. Based on 
(PK)/pharmacodynamics (PD) and safety analysis of the previous cohorts, subsequent cohorts (up 
to 5 cohorts in total) will be initiated with the same and/or an adaptive study design (i.e. changes 
in either doses or time interval between DVI and M5717 administration; see Section 4.3.2).  
Figure 1 
Overall Study Design per Cohort for Dose Finding  
 
IV = intravenous; PfSPZ = Plasmodium falciparum sporozoite; PK = pharmacokinetic; qPCR = quantitative polymerase 
chain reaction. 
1.3 
Schedule of Activities 














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Table 5 
Allowed Time Windows for Scheduled Time Points 
Time Point 
Tolerance Window 
Pharmacokinetic/Pharmacodynamic (blood samples) 
Predose 
 
- 60 min to 0 h 
0.5 h to 1.0 h post 
± 3 min 
2 h to 3 h post 
± 3 min 
6 h to 24 h post 
± 10 min 
120 h to 192 h post 
± 6 h 
600 h and 768 h post 
± 72 h 
12-Lead Electrocardiogram/Vital Signs/Respiratory Rate/Temperature/Safety Laboratory Samples 
Predose 
- 150 min to 0 h 
24 h post 
± 10 min 
120 h to 408 h post 
± 6 h 
504 h post 
± 24 h 
648 h and 768 h post 
± 72 h 
 


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2 
Introduction 
M5717 is a first-in-class New Chemical Entity (NCE) targeting the Plasmodium cytosolic protein 
synthesis “elongation factor 2”. This target is involved in the guanosine triphosphate-dependent 
translocation of the ribosome and is essential for protein synthesis. From preclinical and human 
data, M5717 seems to be highly selective for the Plasmodium species and no effects on protein 
synthesis in humans are to be expected. 
The molecule is intended to be developed in combination with a partner molecule as a single dose 
for the treatment of uncomplicated malaria and/or the prevention of malaria in endemic 
populations and travelers. M5717 is highly efficacious against multiple life-cycle stages of the P. 
falciparum and P. vivax malaria parasites, including the erythrocytic, the liver schizont, and the 
gametocyte stages of the parasite (Figure 2). 
Figure 2 
Plasmodium Life Cycle: Sporogony in Mosquito (Sexual Cycle) and 
Human Stages (Asexual Cycle) 
 
Potent prophylactic activity of M5717 has been demonstrated in preclinical models. The safety 
and tolerability of M5717 has been monitored closely in preclinical studies, and in completed and 


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Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model 
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(Malarone®) and recently tafenoquine (ArakodaTM, 60 Degrees Pharmaceuticals, Washington, DC, 
USA) have been registered for chemoprophylaxis in the traveler population, there are limited 
preventive chemotherapy options available for extended use by the populations in endemic areas 
and migrants. Chemoprophylactic agents are mainly based on the repurposing of drugs used for 
treatment and all of these agents are facing emerging or established resistance.  
The development of new treatments in malaria targeting prophylaxis and transmission is becoming 
increasingly important. Target Product Profiles have been defined in the malaria drug development 
field to address future cure and chemoprophylaxis compound profiles, consistent with the strong 
recommendation from WHO to develop only combination therapies, to minimize the risk of 
emerging resistance (Burrows 2013). 
M5717 is a first-in-class compound with a new mode of action (i.e., inhibition of plasmodial 
protein synthesis by targeting the Plasmodium eukaryotic translation Elongation Factor 2 [PeEF2]) 
and shows excellent activity against malaria blood-stages (including clinical isolates and drug-
resistant strains), liver-stages, and in transmission blocking assays in preclinical investigations. 
M5717 displayed a long half-life and an effective exposure with high potency against all forms of 
the parasite. This allows for administration of a single oral dose and maintaining protection over 
an extended period of time. 
In the view of accelerating the development of new antimalarial medications, CHMI studies have 
been established, involving infection of participants with low numbers of malaria parasites, either 
through injection of sporozoites and allowing the development of pre-erythrocytic stages, or 
injection of malaria-infected erythrocytes (blood stage). These models are well-accepted, their 
safety profile is well understood, and their overall benefit was demonstrated in terms of reduction 
of development times and limiting the number of participants in Phase II dose-finding studies.  
The DVI of P. falciparum sporozoites (PfSPZ) is a validated and standardized model for 100% 
induction of malaria infection in healthy participants (Mordmüller 2015). DVI of 3200 PfSPZ has 
been implemented for testing efficacy of malaria vaccines (Jongo 2018, Mordmüller 2017) and 
more recently for evaluating efficacy of antimalarial drugs (Murphy 2018, Sulyok 2017). 
The aim of this study is to assess the chemoprophylactic activity and to explore the dose-exposure-
response relationship of single oral doses of M5717 administered immediately (early liver stage) 
or few days after (late liver stage) DVI of PfSPZ Challenge in malaria-naïve, healthy participants 
in the CHMI model. 
2.3 
Benefit/Risk Assessment 
Benefits are mainly to society for the potential availability of a more convenient product for 
chemoprophylaxis of malaria in travelers and populations in endemic settings.  
Potential risks to participants in the PfSPZ Challenge model include development of 
mild/moderate symptoms associated with PfSPZ inoculation and the subsequent infection with 
malaria parasites, as well as the adverse effects of M5717 and the approved malaria rescue 
medications atovaquone/proguanil (Malarone 250 mg/100 mg, Glaxo Wellcome S.A.) and 
artemether/lumefantrine (Riamet® 20 mg/120 mg, Novartis). The risk to develop malaria 
symptoms is minimized, as the rescue treatment will be started at a low parasitemia level. 


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There have been three cardiac adverse events in previous controlled human infection studies of 
which two were published as case reports (Nieman 2009, Van Meer  2014). A third case happened 
in the BMGF1 study (NL48301.91.14). All cases were reported to the regulatory authorities 
concerned.  Although the relation with the malaria infection was not resolved, the temporal 
relationship makes an association with CHMI likely.  
No such events are expected in the present study however as treatment will be initiated at very low 
levels of parasitemia. Rescue treatment in the present study is initiated when blood-stage growth 
is detected after a first parasitemia of just > 100 asexual parasites/mL as measured by qPCR and 
provided that the subsequent qPCR shows higher parasitemia than the first positive qPCR, or on 
Day 28 if qPCR outcome remains below this threshold (see Section 6.5.1). To compare, the 
23-year-old male in the TIP5 study had 13,293 parasites/ml on the day of treatment, measured by 
qPCR retrospectively after a positive thick blood smear triggered rescue treatment. Thick blood 
smears become positive at much higher levels of parasite load compared to qPCR. 13,293 is not 
an unusual level for a first positive thick blood smear. In fact, the detection threshold of a thick 
blood smear is estimated to be at 4-20 parasites/ul (= 4000 – 20 000 p/ml). All three cardiac cases 
occurred in studies where a positive thick blood smear was the trigger for rescue treatment. 
Moreover, these previous studies were done with bites of P. falciparum infected mosquitoes of 
which the load of initial parasite exposure is less reliably estimated when compared to DVI of 
PfSPZ parasites. 
Currently, for controlled human malaria infection studies, the use of qPCR with a treatment 
threshold of 100 parasites/ml is highly sensitive and specific and improves safety (Walk 2016).  
Moreover, frequent Hs-Troponin T testing (a marker for cardiac necrosis) is incorporated as part 
of the safety labs in the present study.  
The risk to participants in this study will be minimized by an adequate selection of eligibility 
criteria, a dense schedule of medical monitoring of admitted participants, including ambulatory 
follow up, and administration of standard of care (SoC) medication to participants. Since infection 
with malaria parasites may lead to transiently increased levels of liver enzymes in some 
participants (Woodford 2018), close monitoring of liver function and other relevant clinical 
laboratory parameters will be assessed regularly as part of the safety monitoring in this study.  Of 
note, no additional effects on liver enzymes were observed by administration of M5717 to 
participants challenged with infected erythrocytes in the CHMI part of the Phase I study (refer to 
the IB).  
In repeat-dose toxicity studies in dogs and rats, the main target organs of toxicity of M5717 were 
the liver, the lymphatic system, and the epithelia of the gastrointestinal tract. Thus, the following 
potential risks of the investigational product were identified as:  
• Change in hematology (test abnormal) and biochemistry parameters (e.g., decrease in 
reticulocytes, platelet increase, liver enzymes [alanine aminotransferase (ALT)/ aspartate 
aminotransferase (AST)/ Bilirubin] increases), 
• Leukocyte vacuolization, 
• Gastrointestinal symptoms (nausea, vomiting, diarrhea), 
• Photosensitivity/light sensitivity (cutaneous reactions), 
• Drug-drug interactions. 


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In vitro safety pharmacology studies included off-target receptor profiling (employing 
145 radioligand binding and enzyme assays), activity testing on cardiac ion channels, and 
measuring of refractory period in isolated guinea pig papillary muscle. Results showed that M5717 
did not induce relevant off-target effects at 10 μM (= 4630 ng/mL) a concentration that is higher 
than the concentrations reached in the FIH study. At a dose of 800 mg, where 8/8 participants 
achieved full cure in an induced human blood stage model (IBSM), the highest concentration 
observed was 615 ng/mL. Based on these data, the probability for off-target effects at the expected 
pharmacologically relevant concentration is considered to be low.   
As of 08 May 2019, single ascending doses of M5717 up to 2100 mg (as succinate) have been 
administered. Overall, across all cohorts, M5717 showed a favorable safety profile, with no 
treatment emergent adverse events (TEAEs) leading to death, discontinuation or withdrawal. 
Drug-related TEAEs were mostly mild, transient in nature, and resolved without sequelae. High 
doses of 1800 and 2100 mg M5717 succinate showed mild to moderate neurological effects 
(headache, blurred vision, dizziness) in a few participants, but these adverse events (AEs) resolved 
spontaneously and without sequelae. The doses intended to be used in this study will be lower or 
within the dose range (200 to 800 mg M5717) showing different grades of efficacy in the IBSM 
model in the FIH study and will not exceed 1250 mg. 
Periodic blood draws will be needed to monitor the participants’ safety, to perform qPCR for early 
detection of P. falciparum parasitemia, and for PK analysis. Throughout the whole study, the 
amount of blood collected over the course of 2 months will be less than 450 mL. 
Furthermore, 
the 
participants 
will 
be 
prescribed 
curative 
therapy 
for 
malaria: 
atovaquone/proguanil or artemether/lumefantrine for final clearance of the parasite at the end of 
the study. A full discussion of the potential risks from atovaquone/proguanil and 
artemether/lumefantrine may be found in the respective approved manufacturer’s prescribing 
information (see Appendix 8 for package inserts of Malarone and Riamet). 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of M5717 may be found in Section 4.2 and the IB. 
Based on the available nonclinical and clinical data to date, the conduct of the study, as specified 
in this protocol, is considered justifiable. 
Due to the currently ongoing threat of the SARS-CoV-2 pandemic, additional COVID-19 related 
risk assessment measures were implemented. See Appendix 11. 
3 
Objectives and Endpoints 
The study objectives and endpoints are listed in Table 6 below. See Section 9.4 (Statistical 
Analysis) for the statistical aspects of the endpoints. 


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4 
Study Design 
4.1 
Overall Design 
This is a Phase Ib, single center, sequential, double-blind, randomized, placebo controlled study 
to investigate the chemoprophylactic activity and dose-exposure-response relationship of single 
doses of M5717 administered after DVI of P. falciparum sporozoites (PfSPZ challenge) to healthy 
malaria-naïve male and female participants (see Section 2 for more details). 
The study will involve up to a maximum of 50 healthy adult men and women (between 4 and 12 
healthy participants per dose group, with up to 5 cohorts), 18 to 45 years of age and all receiving 
PfSPZ challenge. The sequence of cohorts (dose escalation or de-escalation and time interval 
between DVI with PfSPZ and M5717 administration) will depend on Safety Monitoring 
Committee (SMC) review for safety and PK/PD (Figure 3). 
Figure 3 
Overall Study Design Assuming 5 Cohorts for Dose-Finding 
 
SD=study dose, PD=pharmacodynamics, PK=pharmacokinetics. 
PK-PD data analysis will be performed as needed on the basis of the PD results of the respective cohort(s) and 
according to the algorithm for adaptive dose selection as shown in Figure 4.  
For each cohort, between 4 and 12 participants will be randomly assigned to receive a single dose 
of M5717 or placebo at a pre-defined ratio of 3:1 and a block size of 4. Number of participants 
may be adapted (e.g., 4 [3 active:1 placebo], 8 [6 active:2 placebo], or 12 [9 active:3 placebo]) for 
the subsequent dose group based on available PD (cured/not-cured) and PK data from the 
actual/preceding dose groups. This approach allows for a data-driven assessment of the 
chemoprophylactic activity of M5717 and the PK/PD relationship. As such, subsequent dose level 
(up to a total of 5) and/or time interval will be suggested based on the available PK/PD and safety 
data, and decided by the SMC, with the goal to identify the dose (exposure) level achieving full 
prophylaxis on Day 1. Once the efficacious dose level for the early liver stage has been identified, 
a cohort with 12 participants will be evaluated whether this dose is also efficacious on the late liver 
stage (administration of M5717 at Day 5 after PfSPZ challenge). 
The placebo control will facilitate the identification of effects related to administration of M5717 
in the active group rather than to the study procedures or situation, i.e. to minimize bias. The 
placebo treatment will also allow confirmation of biological activity of the DVI PfSPZ challenge 
and the determination of shortest time to first qPCR positivity as part of the primary endpoints. 
No participant will be enrolled in more than 1 cohort in the study. 


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base (rounded to 200 mg), at which 50 % of the participants are expected to have an exposure 
above 530 ng/mL*h. 
It is recognized that there are many assumptions regarding this first dose level and therefore the 
study follows a sequential adaptive design to be able to escalate or de-escalate the dose in the 
subsequent cohorts, to find a dose that leads to protection in the majority of the participants. By 
exploring the dose-exposure-response relationship via population PK/PD modeling approaches, it 
is envisaged that effective Phase II doses and dosing regimen can be extrapolated. For dosing 
considerations, see Section 6.6. 
The proposed starting dose of 200 mg in this study was shown to be safe in the FIH study 
(MS201618-0013) and is well below the highest dose that was assessed in the FIH SAD study 
(2100 mg).  
4.3.2 
Selection of Further Doses 
The decision to proceed to the next cohort (either an increase or a decrease of M5717 single, oral 
dose or change in time interval between DVI with PfSPZ and M5717 administration) will be made 
by the SMC based on all available safety, tolerability and PD data. PK data will be included if 
appropriate.  Due to a high uncertainty in the dose setting for the human situation, the single, oral 
dose will be adjusted for subsequent cohorts. Considering preclinical data from animal models it 
is expected that the dose for prophylaxis is lower than the dose for cure. The effective dose range 
in the IBSM model for cure in the FIH study was about 200 mg – 800 mg M5717. Therefore, the 
highest dose in this protocol is deemed not to exceed 1250 mg M5717.  SMC guidance on dose 
selection and modification will follow the algorithm for adapted dose selection as shown in Figure 
4 and taking into account the available safety data. Details will be described in the SMC charter 
(see Appendix 2 Study Governance).  
The number of participants per dose group will be flexible and depend on the uncertainty of the 
prediction. The first dose group(s) will contain few participants (3 active:1 placebo). When there 
is more certainty on efficacious AUC exposures, the number of participants per group can be 
increased to 8 (6 active:2 placebo) or 12 (9 active:3 placebo). 
Once an efficacious dose and AUC is identified and sufficient data are available for evaluating the 
exposure-dose response relationship, another cohort will be initiated and dosed with M5717 at a 
later time-point, i.e., 4 days after DVI, to assess the effect of M5717 on late liver stages. 
The decision to proceed to the next cohort will be made by the SMC. See Figure 4 for a summary 
of possible adaptive designs after evaluation of the first and/or second cohort. Decisions for the 
next cohorts will follow a comparable algorithm. If 100% cure is observed in 3/3 active participants 
(assuming the placebo will not be cured), the dose will be halved, and another 4 participants will 
be treated with a lower dose. If again 100% cure is observed at this lower dose it is at the discretion 
of the SMC to propose a lower dose for the next cohort. For example, the following scenario could 
be possible: 200 mg – 100 mg – 60 mg – 30 mg, taking into account available dose strengths of 
the study intervention. 
If 1 or 2 active participants show cure, the cohort will be expanded at that dose with another 8 
participants (6 actives). Subsequently, the PK data of all 12 participants (9 actives) will be 
analyzed. The goal is to see whether a PK parameter can be identified that predicts cure and to 
propose a subsequent dose that will lead to around 50% cured participants in the next cohort. 


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For example, if the assumption AUC0-24 ≥ 530 ng/h*mL, in all cured participants is confirmed, 
another cohort of 12 participants can be added with a lower or higher dose assumed to reach about 
50% of cured participants to provide sufficient data for determination of the dose-
exposure-response relationship. Once this has been accomplished the SMC can decide to evaluate 
administration of M5717 on Day 5 after PfSPZ inoculation. 
In case of uncertainty in the goal of reaching 50% of cured participants, the SMC might propose 
to evaluate less than 12 participants (4 or 8) or propose to explore 2 doses in the next cohort. 
In case there are cured participants that have an AUC0-24 < 530 ng/h*mL it means that the initial 
assumption is not valid, or it could also mean that AUC0-24 is not the correct parameter. In this case 
modeling and simulation should evaluate whether another threshold can be identified, or whether 
another PK parameter can be defined and inform the SMC accordingly on possible doses.   
Similarly, if no participants are cured at the first dose, the dose will be doubled if safety allows. If 
after the second dose again none of the participants is cured the SMC can propose another increase 
of the dose taking into consideration the observed safety signals. This can be repeated until 1 or 2 
active participants show cure, then that dose will be expanded, or until a dose of 1250 mg is 
reached.   
Figure 4 
Summary of Adaptive Design Steps after Evaluation of First and Second 
Cohort 
 
The available formulations for the study intervention are 30 mg and 100 mg M5717 free base 
capsules. The participants will receive the content of capsules of 30 and/or 100 mg or placebo. 


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4.4 
End of Study Definition 
A participant has completed the study if he/she has completed all study parts, including the last 
study visit (End of Study visit).  
The end of the study is defined as the date of the last visit of the last participant. 
5 
Study Population 
The criteria in Sections 5.1 and 5.2 are designed to enroll only participants, who are appropriate 
for the study; thereby, ensuring the study fulfills its objectives. All relevant medical and 
nonmedical conditions should be taken into consideration when deciding whether a participant is 
suitable for this study. 
Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Before performing any study assessments that are not part of the participant’s routine medical care, 
the Investigator will confirm that the participant or the participant’s legal representative has 
provided written informed consent, as indicated in Appendix 2 Study Governance. 
The study population comprises healthy, malaria-naïve, male and female, adult participants. 
Following approval by the accredited institutional review board (IRB)/IEC, potential participants 
will be contacted by email and telephone from the site’s database of healthy participants and 
through study-specific advertisement including print-, social-, and online media, including 
websites such as proefpersoon.nl, controlledhumaninfection.nl or the site’s website. In addition, 
short presentations may be given to students before lectures. Only persons meeting all inclusion 
criteria and none of the exclusion criteria may be enrolled into the study as participants. The criteria 
have to be checked at Screening, and on the day of DVI of PfSPZ. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
Age 
1. Are between 18 and 45 years of age at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Are overtly healthy as determined by medical evaluation, including no clinically significant 
abnormality identified on physical examination or laboratory evaluation and no active 
clinically significant disorder, condition, infection or disease that would pose a risk to 
participant safety or interfere with the study evaluation, procedures or completion.  
Weight 
3. Have a body weight within 50 to 100 kg and body mass index within the range 19.0 to 
29.9 kg/m2 (inclusive). 
Sex 
4. Are male or female  


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Contraceptive use by males or females will be consistent with local regulations on contraception 
methods for those participating in clinical studies. 
• Male Participants: 
Agree to the following during the study intervention period and for at least 120 days after 
the day of the study intervention dose (covering a full sperm cycle of 90 days starting after 
5 half-lives of last dose of study intervention: 
• 
Refrain from donating sperm 
PLUS, either: 
• 
Abstain from intercourse with a woman of childbearing potential 
OR 
• 
Use a male condom: 
• When having sexual intercourse with a woman of childbearing potential, who is 
not currently pregnant, and advise her to use a highly effective contraceptive 
method with a failure rate of < 1% per year, as described in Appendix 3
 Contraception, since a condom may break or leak. 
• Female Participants: 
• Have a negative serum test at Screening and a highly sensitive urine pregnancy test 
within 24 hours before the first study intervention (DVI) and within 24 hours before 
the second study intervention (M5717) administration, as required by local regulations. 
[If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive]. 
• Are not pregnant or breastfeeding, and at least one of the following conditions applies: 
• Not a woman of childbearing potential 
− At least 1 year post-menopausal (amenorrhea ≥ 12 months and follicle-
stimulating hormone (FSH) ≥ 40 mIU/mL) at Screening; 
− Surgically sterile (bilateral oophorectomy, hysterectomy or bilateral 
salpingectomy; tubal ligation alone is not sufficient). 
OR 
• If a woman of childbearing potential, use a highly effective contraceptive method 
(i.e., with a failure rate of < 1% per year), preferably with low user dependency, as 
described in Appendix 3 for the following time periods: 
• Before the first dose of the study intervention(s), if using hormonal 
contraception: 
− Has completed at least one 4-week cycle of an oral contraception pill and 
either had or has begun her menses 


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OR 
− Has used a depot contraceptive or extended-cycle oral contraceptive for at 
least 28 days and has a documented negative pregnancy test using a highly 
sensitive assay. 
• During the intervention period 
• After the study intervention period (i.e., after the last dose of study intervention is 
administered) for at least 62 days, corresponding to the time needed to eliminate 
any study intervention(s) (5 times terminal half-live of 155 hours) plus 30 days (a 
menstrual cycle) after the last dose of study intervention (and agree not to donate 
eggs (ova, oocytes) for reproduction during this period). 
• Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.2.4.  
• The investigator reviews the medical history, menstrual history, and recent sexual 
activity to decrease the risk for inclusion of a female with an early undetected 
pregnancy. 
Informed Consent 
5. Capable of giving signed informed consent, as indicated in Appendix 2 
Study 
Governance, which includes compliance with the requirements (including mandatory intake 
of rescue medication to participants who have been administered the investigational P. 
falciparum sporozoite challenge) and restrictions listed in the informed consent form (ICF) 
and this protocol. 
Other Inclusions 
6. A non-smoker or ex-smoker for more than 90 days prior to Screening, or a smoker of no 
more than 5 cigarettes per day or nicotine products (spray, patch, e-cigarette, etc.) equivalent 
of no more than 5 cigarettes per day. Participants must agree to abstain from smoking while 
in the study. 
7. Willing to adhere to the prohibitions and restrictions (see Section 6.5.3) specified in this 
protocol, including willingness to stay confined to the inpatient unit for the required 
duration and willingness to avoid extensive travelling during the study period. 
8. Different ways of being reachable 24 hours per day, 7 days per week (e.g., by mobile phone, 
regular phone or electronic mail) during the whole study period.  
9. Does not live alone (from start of DVI with malaria sporozoites until at least the end of the 
antimalarial drug treatment), willing to provide contact details of a person living with 
him/her who is contactable and available for the duration of the study. 
See Appendix 11 for COVID-19 related Inclusion Criteria. 
5.2 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 


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Medical Conditions 
1. 12-Lead electrocardiogram (ECG) outside normal range (QTcF > 450 ms, PR interval  > 
215 ms, or QRS > 120 ms) and deemed clinically relevant by the Investigator.  
2. Supine systolic blood pressure > 140 or < 90 mmHg, diastolic blood pressure > 90 or 
<  50 mmHg, and pulse rate > 90 or < 50 beats per minute (min) at Screening and at 
Admission on Day -1 (Any abnormal blood pressure or pulse rate results may be repeated 
once and if the repeat result is within the normal range, it is not considered to have met the 
exclusion criterion). 
3. Seropositive for human immunodeficiency virus (HIV) I and II antibody or antigen), 
hepatitis B virus (HBV; hepatitis B surface antigen [HBsAg]), or hepatitis C virus (HCV; 
antibody) tests.  
4. Liver function tests (see Appendix 5 
Liver Safety: Suggested Actions and Follow-up 
Assessments) above the upper limit of normal (ULN) (> 3xULN) (as specified in the 
Laboratory Manual) the day before DVI / study intervention administration (Day -1). 
5. History or presence of diagnosed food or known drug allergies (including but not limited to 
allergy to any of the antimalarial rescue medications to be used in the study), or history of 
anaphylaxis or other severe allergic reactions.  
Note: Participants with seasonal allergies/hay fever, house dust mite allergy, or allergy to 
animals that are untreated and asymptomatic at the time of dosing can be enrolled in the 
study. 
6. History of a serious psychiatric condition that may affect participation in the study or 
preclude compliance with the protocol.  
7. Any surgical or medical condition possibly affecting drug absorption (e.g. cholecystectomy, 
gastrectomy, bowel disease), distribution, metabolism or excretion. 
8. Any history of gallbladder disease, including cholecystitis and/or cholelithiasis. 
9. Any condition that in the opinion of the investigator would jeopardize the safety or rights 
of a person participating in the study or would render the person unable to comply with the 
protocol. 
10. Frequent headaches of clinical relevance and/or migraine, recurrent nausea, and/or vomiting 
(> 2 times per month). 
11. Ingestion of any poppy seeds within 24 hours prior to each Drug Abuse Screening. 
12. Personal history of malaria or medical history of possible exposure to malaria. 
13. Presence of acute infectious disease or fever (i.e., sublingual temperature ≥ 38.0°C) within 
the 5 days prior to DVI with malaria sporozoites. 
Prior/Concomitant Therapy 
14. Use of medications known to interact with atovaquone-proguanil (Malarone) or artemether-
lumefantrine (Riamet) such as cimetidine, metoclopramide or antacids, or an anticipated 
requirement for the use of these at any point during the study period (see also Section 5.1).  


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15. Use of systemic antibiotics with known antimalarial activity within 30 days (or 5 half-lives 
whichever is longer) of first study intervention administration (e.g. trimethoprim-
sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones 
or azithromycin) or an anticipated requirement for the use of these during the study period. 
16. Use of any prescription drugs, herbal supplements (e.g., St John's Wort) or over-the-counter 
medication within 7 days or five half-lives (whichever is longer) prior to the first study 
intervention administration, or an anticipated requirement for the use of these during the 
course of the study. 
Note: If necessary, the incidental use of non-steroidal anti-inflammatory drugs (NSAIDs), 
paracetamol (2 g/day, 10 g/week), vitamins and topical treatments may be acceptable after 
approval by the Investigator 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 or 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. 
Prior/Concurrent Clinical Study Experience 
17. Participation in an investigational drug or device study within 3 months prior to first dosing 
or more than 4 times a year or plans to participate in other investigational drug or vaccine 
research during the study period. 
Diagnostic Assessments 
None. 
Other Exclusions 
18. 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 or students of the departments involved. 
19. Intake of grapefruit, Seville oranges, cranberries, star fruit or juices of these fruits, as well 
as quinine-containing food/beverages (e.g., tonic water, bitter lemon), within 14 days prior 
to study intervention administration until the end of the ambulatory period.  
20. Participant has travelled to or lived in a malaria-endemic area for more than 4 weeks during 
the 12 months prior to first study intervention administration or spent any time in an 
endemic area during the 4 weeks prior to first study intervention administration. 
21. Plans to travel to a malaria-endemic region during the study period up to last Follow-Up 
(FU) visit. 
22. Previous participation in any malaria vaccine or CHMI study. 
23. Participant with a whole blood donation or loss of > 450 mL within 60 days before 
administration of study drug or unwilling to defer blood donations for 6 months. 
See Appendix 11 for temporary exclusion criteria for participants with a risk factor for a COVID-
19 infection. 


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6.1 
Study Intervention(s) Administration 
 
Study Intervention 
Study Intervention Name: 
M5717 
Dose Formulation: 
M5717: Capsules containing 30 or 100 mg of M5717 powder.  
Placebo: Capsules containing 100 mg of placebo matched to a similar 
number of capsules with M5717. 
Unit Dose Strength(s)/ Dosage 
Level(s): 
First dose 200 mg (2 x 100 mg); other doses to be decided based on SMC 
recommendation 
Route of Administration: 
Oral 
Dosing Instructions: 
The number of capsules will be dependent on the dose to be administered 
and will be calculated by the pharmacist. For the first cohort, the participants 
will receive 2 capsules (100 mg each) in total. The appropriate number of 
M5717 or placebo capsules will be opened, the content will be transferred 
into 20 mL water (if the dose is between 30-90 mg) or 50 mL water (if the 
dose is above 90 mg) and the suspension will be swallowed by the 
participant. The beaker will be rinsed with another 10 or 50 mL of water that 
is also to be swallowed by the participant. If a low dose is given, participants 
need to drink an additional 70 mL thereafter in order to have a comparative 
total volume intake of 100 mL.   
For further details, refer to Pharmacy Manual. 
Other study interventions: PfSPZ Challenge 
1. 
Malaria inoculum 
Study Intervention Name: 
Purified, aseptic, cryopreserved P. falciparum sporozoites, strain NF54 
(PfSPZ Challenge; Sanaria Inc, Rockville, MD, USA) 
Dose Formulation: 
Cryopreserved sporozoites 15,000/20µL/vial 
Unit Dose Strength(s)/ Dosage 
Level(s): 
3200 sporozoites per injection 
Route of Administration: 
Intravenous/Bolus 
Dosing Instructions: 
According to the instructions supplied by Sanaria Inc. 
For further details see pharmacy manual. 
2. 
Rescue medications 
Each participant will receive rescue treatment as specified in Section 6.5.1: 
- 
Atovaquone/proguanil (Malarone) as first line rescue treatment in case of any intolerance. 
- 
Artemether/lumefantrine (Riamet) as back-up rescue medication. 
- 
Intravenous artesunate will be used in case of suspicion of severe malaria. 
PfSPZ=Plasmodium Falciparum Sporozoites, SMC=Safety Monitoring Committee. 
6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability 
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study intervention accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). 
• Upon receipt of the study intervention(s), the Investigator or designee must confirm appropriate 
temperature conditions have been maintained during transit and any discrepancies are reported 
and resolved before use. Also, the responsible person will check for accurate delivery. Further 


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guidance and information for study intervention accountability are provided in the Pharmacy 
Manual. 
• Only participants enrolled in the study may receive study intervention(s) and only authorized 
site staff may supply it. All study intervention(s) must be stored in a secure, environmentally-
controlled, and monitored (manual or automated) area, in accordance with the labeled storage 
conditions, and with access limited to the Investigator and authorized site staff. 
• Dispensing will be recorded on the appropriate accountability forms so that accurate records 
will be available for verification at each monitoring visit. 
• Study intervention(s) accountability records at the study site will include the following: 
• Confirmation of receipt, in good condition and in the defined temperature range. 
• The inventory provided for the clinical study and prepared at the site. 
• The dose(s) each participant used during the study. 
• The disposition (including return, if applicable) of any unused study intervention(s). 
• Dates, quantities, batch numbers, container numbers, expiry dates, and the participant 
numbers. 
• The Investigator site will maintain records, which adequately documents that participants were 
provided the doses specified in this protocol, and all study intervention(s) provided were fully 
reconciled. 
• Unused study intervention(s) must not be discarded or used for any purpose other than the 
present study. No study intervention that is dispensed to a participant may be re-dispensed to a 
different participant. 
• A Study Monitor will periodically collect the study intervention(s) accountability forms. 
Further guidance and information for the final disposition of unused study intervention(s) are 
provided in the Pharmacy and Monitoring Manuals. 
6.3 
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding 
6.3.1 
Study Intervention Assignment 
After confirmation of participant’s eligibility and at the last practical moment prior to study 
intervention administration, participants will be centrally allocated to either M5717 or placebo in 
a 3:1 ratio using an Interactive Web Response System (IWRS), which forms part of the built-in 
functionality of the clinical data management system, and per a computer-generated randomization 
list. 
The IWRS will be used to assign unique participant numbers, allocate participants to study 
intervention group at the randomization visit, and study intervention to participants at each study 
intervention visit. 


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Before the study is initiated, the log in information and directions for the IWRS will be provided 
to the site. The site will randomize any eligible participant in the database on Study Day -1 or 
Study Day 1, prior to DVI PfSPZ and to starting study intervention administration for each 
participant.  
Participants will be assigned at a randomization ratio of 3:1 to M5717:placebo treatment. Cohorts 
will be expanded in multitudes of 4, i.e. a cohort will start off with 4 participants (assigned 3:1) 
and may then be expanded to include either 8 or 12 participants (with the randomization ratio kept 
fixed at 3:1). The randomization code will be generated using SAS 9.4 for Windows or newer 
(SAS Institute Inc., Cary, NC, USA) by a study-independent statistician. 
Code-break envelopes will be provided to the site in case an emergency unblinding of an individual 
participant’s study intervention is required. 
Participants who are withdrawn from the study by the Investigator due to AEs after the start of 
administration of the study intervention will not be replaced. Participants who withdraw for any 
other reason may be replaced after discussion with the Sponsor. Replacement participants, if 
utilized, will receive the same treatment as the participants they are replacing, using randomization 
replacement numbers. 
6.3.2 
Blinding 
Blinding Method 
The study will be double-blind. Blinding will be maintained throughout the duration of the study 
for the participants and for the investigator, i.e., until final database lock. After initiating the rescue 
medication of all participants in each cohort, the SMC will perform a blinded data review. The 
SMC will remain blinded throughout the study. Only the unblinded PK/PD scientist and 
Pharmacometrician  of the Sponsor and the responsible analyst from the Contract Research 
Organization (CRO) performing the PK/PD evaluation will analyze the unblinded PK/PD data, 
and will provide the PK/PD results in a blinded manner only to the SMC in order to decide on the 
dose and number of participants, as well as the timing of the study intervention in relation to the 
DVI challenge for the next. Only when the study is completed, database locked, data file verified, 
and protocol deviations determined, will the drug codes be broken and made available for final 
data analysis. 
Details including but not limited to SMC membership, meeting frequencies, and responsibilities 
will be provided in the SMC charter.  
Assignment Method Retention 
The randomization list is to be kept strictly confidential, accessible only to authorized persons 
(e.g., randomization statistician, pharmacists, and the bioanalytical laboratories that prepare and 
analyze relevant samples), until the time of unblinding. The study blind may be broken for an 
individual participant only if knowledge of the study intervention is essential for clinical 
management of the participant. The Investigator or designee will unblind the participant using the 
individual code-break envelope provided by the randomization statistician. The Investigator must 
promptly explain the reason for any unblinding of an study intervention to the Sponsor without 
revealing the result to any Sponsor employee except the designated Drug Safety representative 
(using the Emergency Unblinding Notification Form, see Section 6.3.3). 


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Unblinding Clinical Studies for Sample Analysis of Special Data 
For the purposes of the SMC, safety data listings will use the participant identification numbers as 
entered in the electronic Case Report Form (eCRF). The unblinded PK/PD scientist and 
Pharmacometrician of the Sponsor and the responsible analyst from the CRO performing the 
PK/PD evaluation will analyze the unblinded PK/PD data and will provide the PK/PD results in a 
blinded manner to the SMC for decision making. A process for SMC data review will be 
established to describe the process of data flow for SMC meetings and the requirements for SMC 
presentation.  
The bioanalytical laboratory for measurement of M5717 concentrations will be unblinded since 
obtaining the concentration data reveals the study intervention arm for the participant. This is 
acceptable, as this function is not involved in the SMC decision making process. M5717 
concentration information that may unblind the study will not be reported to investigative sites or 
blinded personnel until the study has been unblinded. 
6.3.3 
Emergency Unblinding 
In an emergency, the Investigator is solely responsible for determining if unblinding of a 
participant’s study intervention assignment is warranted. Participant safety must always be the first 
consideration in this decision. If the Investigator decides that unblinding is warranted, the 
Investigator should make every effort to contact the Sponsor prior to the unblinding, unless this 
could delay emergency treatment. The Sponsor must be notified within 24 hours after unblinding. 
The Investigator must provide the Sponsor the reason for unblinding without revealing the study 
intervention, except to the designated drug safety representative via the Emergency Unblinding 
Notification Form. The date of and reason for unblinding must be recorded in the source documents 
and eCRF. Contact information for unblinding in an emergency is given on the participant 
emergency card provided to each participant, as noted in Appendix 2 Study Governance. 
The Sponsor’s drug safety department will submit any Suspected Unexpected Serious Adverse 
Reactions (SUSAR) reports to regulatory authorities and ethics committees with unblinded 
information, per applicable regulations. Only blinded information will be provided to the study 
team. 
6.4 
Study Intervention Compliance 
The study intervention will be administered by the study site personnel within the confines of the 
study site. A mouth and hand check will be performed after study intervention dose administration 
to ensure that it has been swallowed. 
Diary cards will be provided to participants for collection of data related to their daily physical 
activity, daily alcohol consumption and their oral (sublingual) temperature. Participants will bring 
their completed diary cards to the study site for all Ambulant and the End of Study visits. 
6.5 
Concomitant Therapy 
Record in the eCRF all concomitant therapies (e.g., medicines or nondrug interventions) used from 
the time the participant signs the informed consent until completion of the study, including any 
changes. Changes in concomitant procedures and concomitant medication or other interventions 


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need to be recorded. For prescription and over-the-counter medicines, vaccines, vitamins, and 
herbal supplements, record the name, reason for use, dates administered, and dosing information. 
Contact the Medical Monitor for any questions on concomitant or prior therapy.  
Medication history (3 months prior to Screening) must be recorded, noting the generic name, 
galenic form, dose and route of administration, duration and indication for each drug. 
Participants must abstain from taking prescription or nonprescription drugs (including vitamins 
and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) before the start of study intervention until completion 
of the End of Study visit, unless, in the opinion of the Investigator and Sponsor, the medication 
will not interfere with the study.  
Ibuprofen, at doses of ≤ 1 g/24 hours, is permitted for use at any time during the study; other 
concomitant medication may be considered on a case-by-case basis by the Investigator. If 
necessary, the incidental use of NSAIDs, paracetamol (2 g/day, 10 g/week), vitamins and topical 
treatments may be acceptable after approval by the study Sponsor and will be documented in the 
eSource system. 
6.5.1 
Rescue Medicine 
Rescue medication(s) will be administered mandatorily to participants who have been 
administered the P. falciparum sporozoite challenge to ensure participants’ safety and complete 
cure from the investigational malaria challenge. Rescue medication will be given either (i) after 
confirmation that the first qPCR outcome is equal or greater than 100 asexual parasites per mL of 
blood and provided that the subsequent qPCR shows higher parasitemia than the first positive 
qPCR, or (ii) on study intervention administration Day 28 after study intervention administration 
if qPCR outcome remains below this threshold. An additional blood sample will be drawn for the 
analysis of emerging genetic mutations for resistance in the parasites. In any case, safety 
assessments must be performed prior to starting rescue medication, as indicated in the SoA (Table 
1 through 


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Table 4). With the start of rescue medication, daily qPCR is to be performed until the qPCR is 
negative and remains negative for 48 hours. 
See Appendix 11 for the COVID-19 contingency plan if any participant presents with COVID-19 
related symptoms and/or has a positive SARS-CoV-2 PCR test. 
The study site will supply all rescue medication. The investigator or a qualified designee will 
ensure that the received drugs are of the specified formulation. The site pharmacist or a qualified 
designee is responsible for maintaining an accurate inventory and accountability record of drug 
supplies for this study. Participants will be prescribed an approved regimen for curative therapy 
for malaria, to assure final parasite clearance, at recrudescence or at the end of the study on study 
intervention administration Day 28. All participants will receive the following rescue medication 
as first choice, atovaquone-proguanil (Malarone): 
1. Malarone (250 mg atovaquone/100 mg proguanil hydrochloride) oral tablets, film coated. 
Atovaquone-proguanil has two uses: (i) to prevent malaria, and (ii) to treat malaria.  
2. Riamet (20 mg artemether/120 mg lumefantrine) oral tablets. Artemether-lumefantrine is 
used for the treatment of acute uncomplicated malaria infections caused by P. falciparum.  
Rescue treatment will be administered according to standard protocols for treatment of CHMI 
malaria at the clinical site. In case of a known allergy or intolerance to artemether and/or 
lumefantrine or any of the ingredients of Riamet, another artemisinin-derivative combination 
therapy will be administered in accordance with the WHO Guidelines for the Treatment of Malaria. 
Treatments mentioned are in accordance with Stichting Werkgroep Antibiotica Beleid guidelines 
for non-severe P. falciparum malaria. 
In case of suspicion of severe malaria: intravenous/intramuscular artesunate for at least 24 hours.  
Once a patient has received at least 24 hours of parenteral therapy and can tolerate oral therapy, 
complete treatment with 3 days of artemisinin-based combined therapy (ACT). 
6.5.2 
Permitted Medicines 
The only permitted medications are the following: 
1. Ibuprofen is the preferred symptomatic treatment for pain relieve or fever, if needed during 
the study. 
2. Paracetamol, which may facilitate liver enzyme elevations in the context of PfSPZ DVI in 
nonimmune participants, should be avoided. Doses of paracetamol up to ≤ 2 g/24 hours, at 
the discretion of the Investigator, may be allowed but only if ibuprofen is contraindicated 
or considered insufficient to treat the symptoms. 
3. No other concomitant medication or over-the-counter products should be administered 
unless deemed necessary by the Investigator. Any medications that are considered necessary 
to protect participant welfare and will not interfere with the study intervention may be given 
at the Investigator’s discretion. 
Any medicines that are considered necessary to protect the participant’s welfare in emergencies 
may be given at the Investigator’s discretion, regardless if it results in a protocol deviation. 


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• Refrain from alcohol use for 1 week prior to study treatment. After release of confinement from 
the study site, participants will be requested not to consume more than 1 drink (2 units) of 
alcohol per day until the End of Study visit 
• Refrain from taking up any new unaccustomed exercise from Screening until the End of Study 
visit. 
Compliance checks will be performed and documented at each visit following discharge from the 
study site. Additional checks for drug and/or alcohol abuse can be done at the discretion of the 
investigator. 
6.9 
Management of Adverse Events of Interest 
No adverse events of special interest are defined for this study. 


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7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1 
Discontinuation of Study Intervention 
As only a single dose of M5717 will be given, study intervention cannot be discontinued, but 
participants can be withdrawn from the study (see Section 7.2). 
In any case, rescue medication(s) (see Section 6.5.1) will be administered mandatorily to 
participants who have been administered the investigational P. falciparum sporozoite challenge, 
independent of whether the scheduled M5717 administration took place or not, to ensure 
participants’ safety and proof of complete cure (i.e. absence of parasitemia) from the 
investigational malaria challenge.  
The SoA (Section 1.3) specifies the data to collect at study intervention discontinuation and follow-
up, and any additional evaluations that need to be completed. 
7.1.1 
Temporary Discontinuation 
Not applicable. 
7.1.2 
Rechallenge 
Not applicable. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
A participant must be withdrawn if any of the following occur during the study: 
• A participant may withdraw from the study at any time, at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons. 
• The participant may be withdrawn by the Investigator due to participation in another clinical 
study. 
• Use of a nonpermitted concomitant medication. However, any medications that are considered 
necessary for the participant’s wellbeing may be given at the discretion of the Investigator. 
• Protocol noncompliance judged as significant by the Investigator, including noncompliance to 
the required study considerations (e.g., caffeine intake/food/diet requirements/alcohol and/or 
drug abuse). 
• Participant lost to follow-up. 
• Any events that unacceptably endanger the safety of the participant (e.g., occurrence of a SAE). 
• At the time of discontinuing from the study, if possible, a discontinuation visit will be 
conducted, as listed in the SoA. The SoA specifies the data to collect at study discontinuation 
and follow-up, and any additional evaluations that need to be completed. 


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• Withdrawal from the study for any reasons after having received the PfSPZ challenge must be 
followed mandatorily by rescue medication and proof of absence of parasitemia. 
• If the participant withdraws consent for future involvement in the study, any data collected up 
to that point may still be used, but no future data can be generated, and any biological samples 
collected will be destroyed. 
• A participant has the right at any time to request destruction of any biological samples taken. 
The investigator must document this in the site study records. 
Please see Appendix 11 for participant withdrawal/discontinuation procedures for participants who 
test positive for a SARS-CoV-2 infection. 
In case liver function test derangements are observed, the SMC would need to review the data; the 
participants who have been treated with M5717 will be followed up and might remain on the study, 
rather than being withdrawn, unless a decision is made otherwise by the Investigator or the SMC. 
If a participant has failed to attend scheduled study assessments, the Investigator must determine 
the reasons and the circumstances as completely and accurately as possible. If there is a medical 
reason for the withdrawal, the participant will remain under the supervision of the Investigator 
until satisfactory health has returned or care has been transferred to the participant’s general 
practitioner or to a hospital consultant. In case a participant has to be withdrawn from the study, 
the Study Monitor and Clinical Study Leader at the Local and Funding Sponsors will be informed 
immediately. 
7.3 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain if the participant wants to or should continue in the study. 
• Before a participant is deemed “lost to follow-up”, the Investigator or designee must make every 
effort to regain contact with the participant: 1) where possible, make 3 telephone calls; 2) if 
necessary, send a certified letter (or an equivalent local method) to the participant’s last known 
mailing address, and 3) if a participant has given the appropriate consent, contact the 
participant’s general practitioner for information. These contact attempts should be documented 
in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study. 
8 
Study Assessments and Procedures 
• Study assessments and procedures and their timing are summarized in the SoA (see 
Section 1.3). 


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• No protocol waivers or exemptions are allowed. 
• Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• All Screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a Screening log to record details of 
all participants screened, to confirm eligibility, and if applicable, record reasons for Screening 
failure. 
• Prior to performing any study assessments that are not part of the participant’s routine medical 
care, the Investigator will obtain written informed consent as specified in Appendix 2
 
Study Governance). 
• Procedures conducted as part of the participant’s routine medical care (e.g., blood count) and 
obtained before signing of the ICF may be used for Screening or baseline purposes provided 
the procedures met the protocol-specified criteria and were performed within the time frame 
defined in the SoA. 
8.1 
Efficacy Assessments and Procedures 
The primary efficacy assessment will be of the chemoprophylactic effect of M5717, defined as 
number of participants with absence of parasitemia by qPCR from PfSPZ Challenge up to Day 28.  
The time from DVI PfSPZ Challenge to the first positive qPCR outcome, defined as equal or 
greater than 100 asexual parasites per mL of blood (time frame: number of days from PfSPZ DVI 
challenge to positive parasitemia, or 28 days) is also going to be measured. 
The malaria clinical score is defined in Appendix 6 Malaria Clinical Score for Treatment 
Initiation and needs to be assessed in case any malaria-related symptoms emerge. 
Efficacy examinations will be scheduled according to the applicable SoA (Table 1 through 


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Table 4). 
8.2 
Safety Assessments and Procedures 
The safety profile of the study intervention will be assessed through the recording, reporting and 
analysis of baseline medical conditions, AEs, physical examination findings, vital signs, 
electrocardiograms, and laboratory tests. 
Comprehensive assessment of any potential toxicity experienced by each participant will be 
conducted starting when the participants give informed consent and throughout the study. The 
Investigator will report any AEs, whether observed by the Investigator or reported by the 
participant; the reporting period is specified in Section 8.3.1. 
8.2.1 
Physical Examinations 
A complete physical examination, including examination of all body systems, will be performed 
at Screening and the End of Study visit (Day 33 + 3 days). At other time points an abbreviated 
physical examination can be performed. Additional physical examinations may be performed as 
deemed necessary, per the Investigator’s discretion. 
A complete physical examination will include, at a minimum, assessments of all body systems 
(including general appearance, skin, head, neck [including thyroid], eyes, ears, nose, throat, 
cardiovascular and pulmonary system, abdomen, neurological, peripheral vascular, and 
musculoskeletal system).  
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.2 
Vital Signs 
Measurement of Vital Signs will be done at the time points as indicated in the SoA, Table 1 
through 


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Table 4. On Day 1 Vital signs assessment will be done prior to administration of malaria inoculum 
as well as 1-hour post-DVI. 
• Height and weight will be measured and recorded at Screening, and weight at the End of Study 
visit. 
• Tympanic temperature, pulse rate, respiratory rate, and blood pressure will be assessed. Oral 
temperature may be used if in the opinion of the investigator the reading is more reliable than 
the tympanic measurement. For SARS-CoV-2 symptoms screening, see Appendix 11. 
• Blood pressure and pulse measurements will be assessed with the participant in the supine 
position, with a completely automated device. Manual techniques will be used only if an 
automated device is not available. Blood pressure will be assessed once again after 5 minutes 
with the participant in the supine position. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones). 
• Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
3 blood pressure measurements (3 consecutive blood pressure readings will be recorded at 
intervals of at least 1 minute). The average of the 3 blood pressure readings will be recorded on 
the eCRF. 
8.2.3 
Electrocardiograms 
Single 12-lead ECG will be obtained as outlined in the SoA using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, and QT intervals. The ECG done 
during Screening will be used to determine eligibility and during study conduct as part of the safety 
assessments. At visits where multiple assessments and procedures are to be done at the same time 
point the ECG should be done after vital sign assessment and before blood sampling. 
Safety 12-lead ECGs will be read locally and monitored in real time. ECG printouts should be 
signed and dated by the person performing the ECG. The 12-lead ECG will be analyzed, assessed 
for plausibility and clinical relevance, and signed by the Investigator.  
Additional ECGs during the course of the study are at the discretion of the Investigator.  
8.2.4 
Clinical Safety Laboratory Assessments 
Blood (fasting state mandatory during Screening, Day 1 Predose and Study Intervention 
Administration Day 2 visits for Cohorts 1 to 4, and mandatory during Screening, Day 1 Predose 
and Study Intervention Administration Day 5 visits for Cohort 5; fasting will be optional from 
Days 6 to 33) and urine samples will be collected for the clinical laboratory tests listed in Appendix 
7 Clinical Laboratory tests at the time points listed in the SoA. All samples should be clearly 
identified.  
Additional tests may be performed at any time during the study, as determined necessary by the 
Investigator or required by local regulations. Cholesterol, Triglycerides, HDL cholesterol and 
glucose tested during Screening must be collected in a fasted state. The participant must be fasted 
for at least 8 hours prior to sample collection. 


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Additional serum or highly sensitive urine pregnancy tests may be conducted, as determined 
necessary by the investigator or required by local regulation, to establish the absence of pregnancy 
at any time during the study. 
The tests will be performed by a local laboratory. Details on process for collection and shipment 
of these samples are in the Laboratory Manual.  
The Sponsor must receive a list of the local laboratory normal ranges before shipment of study 
intervention(s). Any changes to the ranges during the study must be forwarded to the Sponsor. 
The Investigator must review each laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. 
Laboratory results that could unblind the study will not be reported to investigative sites or other 
blinded personnel until the study has been unblinded. 
8.2.5 
Suicidal Risk Monitoring 
Not applicable. 
8.3 
Adverse Events and Serious Adverse Events 
The definitions of an AE and a SAE are in Appendix 4 
Adverse 
Events: 
Definitions 
and 
Procedures for Recording, Evaluating, Follow-up, and Reporting. 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information 
The AE reporting period for safety surveillance begins when the participant is initially included in 
the study (date of first signature of informed consent/date of first signature of first informed 
consent) and continues until the End of Study Visit. 
Any SAE assessed as related to study intervention must be recorded and reported, as indicated in 
Appendix 4 
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting, whenever it occurs, irrespective of the time elapsed since the last administration 
of study intervention. 
The method of recording, evaluating, and assessing causality of AEs (including SAEs) and the 
procedures for completing and transmitting SAE reports are in Appendix 4 Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting.  
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events 
At each study visit, the participant will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the participant’s condition will be recorded as AEs, 
regardless if reported by the participant or observed by the Investigator. 


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Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the eCRF. 
All SAEs must be additionally documented and reported using the appropriate Report Form as 
specified in Appendix 4 Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting. 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events 
AEs are recorded and assessed continuously throughout the study, as specified in Section 8.3.1 
and are assessed for their outcome at the End of Study Visit. All SAEs ongoing at the End of Study 
Visit must be monitored and followed up by the Investigator until stabilization or until the outcome 
is known, unless the participant is documented as “lost to follow-up”. Reasonable attempts to 
obtain this information must be made and documented. It is also the responsibility of the 
Investigator to ensure that any necessary additional therapeutic measures and follow-up procedures 
are performed. Further information on follow-up procedures is given in Appendix 4 
Adverse 
Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events 
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations. 
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving study participants to the IEC/IRB that approved 
the study. 
In accordance with ICH GCP, the Sponsor/designee will inform the Investigator of findings that 
could adversely affect the safety of participants, impact the conduct of the study or alter the 
IEC’s/IRB’s approval/favorable opinion to continue the study. In line with respective regulations, 
the Sponsor/designee will inform the Investigator of AEs that are both serious and unexpected and 
considered to be related to the administered product (“suspected unexpected serious adverse 
reactions” or SUSARs). The Investigator should place copies of Safety Reports in the Investigator 
Site File. National regulations regarding Safety Report notifications to Investigators will be 
considered. 
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records of 
these notifications. When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IEC/IRB of 
any Safety Reports provided by the Sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File. 
For studies covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with that 
Directive and with the related Detailed Guidance documents. 


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8.3.5 
Pregnancy 
Only pregnancies the Investigator considers to be related to the study intervention (e.g., resulting 
from a drug interaction with a contraceptive method) are AEs. However, all pregnancies with an 
estimated conception date during the period defined in Section 8.3.1 must be recorded in the AE 
page/section of the eCRF for both pregnancies in female participants and pregnancies in female 
partners of male participants. The Investigator must notify the Sponsor/designee in an expedited 
manner of any pregnancy using the Pregnancy Report Form, which must be transmitted by the 
same process specified for SAE reporting in Appendix 4 Adverse 
Events: 
Definitions 
and 
Procedures for Recording, Evaluating, Follow-up, and Reporting, section on Reporting Serious 
Adverse Events. 
Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the participants are withdrawn from the study. 
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form will be used if the participant sustains 
an event and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains an 
event. Any abnormal outcome (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) must be reported in an expedited manner, as specified in Section 
8.3.1, while normal outcomes must be reported within 45 days after delivery. 
In the event of a pregnancy in a participant occurring during the study, the participant must be 
discontinued from study intervention. The Sponsor/designee must be notified without delay and 
the participant must be followed as indicated above. 
8.4 
Treatment of Overdose 
For this study, any dose greater than the highest daily dose included in a clinical study protocol or 
planned for an individual participant enrolled in the study is considered an overdose.  
Even if it is not associated with an AE or a SAE, any overdose is recorded in the eCRF and reported 
to drug safety in an expedited manner. Overdoses are reported on a SAE Report Form, following 
the procedure in Appendix 4 Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting, section on Reporting of Serious Adverse Events.  
The effects of an M5717 overdose are unknown, and therefore no standard treatment is currently 
established. In the event of an overdose, the Investigator or treating physician should use 
appropriate clinical judgment for the evaluation and management of any clinical signs, symptoms, 
and laboratory results. 
See package inserts of the rescue medication in Appendix 8 for details regarding the effects and 
management of an overdose. 
8.5 
Pharmacokinetics 
8.5.1 
Pharmacokinetic Samples 
Blood samples for measurement of M5717 concentrations in whole blood will be collected at the 
time points indicated in the SoA (Table 1 through Table 4). Metabolite concentrations, as 


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applicable, may also be measured in blood samples. Remaining samples collected for measurement 
of M5717 may also be used for testing of bioanalytical standards. 
Actual date and time of the PK sampling, as well as date/time of drug administration, will be 
recorded in the eCRF. Samples and assessments obtained outside the allowed time window (see 
Table 5) from dosing will be captured as a minor protocol deviation, if the exact time of the 
assessment/sample collection is noted on the source document and data collection tool (e.g., 
eCRF).  
Volume of blood taken per treatment timepoint and the total volume will be listed in a separate 
Laboratory Manual. 
For PK sample analysis, liquid whole blood levels of M5717 will be analyzed by the analytical 
laboratory selected under responsibility of the Sponsor, using an appropriate validated 
bioanalytical method. Full details of the bioanalytical method used will be described in a separate 
bioanalytical report. For participants randomized to placebo treatment, no PK samples will be 
analyzed unless deemed necessary by the Investigator and/or Sponsor. Details on blood sample 
collection, preparation for processing, and shipment will be specified in a separate Laboratory 
Manual. 
8.5.2 
Pharmacokinetic Calculations 
For each participant with evaluable whole blood PK data, PK parameters will be calculated from 
M5717 whole blood concentrations generated from the validated bioanalytical assays. 
• The following PK parameters will be calculated, when appropriate: 


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Table 7 
Definition of Individual PK Parameters 
Symbol 
Definition 
AUC0-t 
Area under the blood concentration-time curve (AUC) from time zero to the last sampling time at 
which the concentration is at or above LLOQ, calculated according to the mixed log linear 
trapezoidal rule (i.e., linear up, log down) 
AUC0-∞ 
The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the 
concentration at tlast , as estimated using the linear regression from λz determination. AUC0-
∞=AUC0-t+Clast pred/ λz 
AUC0-24 
The AUC from time zero (= dosing time) to 24 hours post dose. Calculated using the mixed log 
linear trapezoidal rule (linear up, log down) using the nominal dosing interval. The actual dosing 
interval calculated from CRF time data should not be used. 
AUC0-168 
The AUC from time zero (= dosing time) to 168 hours post dose. Calculated using the mixed log 
linear trapezoidal rule (linear up, log down) using the nominal dosing interval. The actual dosing 
interval calculated from CRF time data should not be used. 
Cmax 
Maximum blood concentration observed 
C24 
Blood concentration at 24 hours 
C168 
Blood concentration at 168 hours 
tmax  
Time to reach the maximum blood concentration (1st occurrence in case of multiple/identical Cmax 
values) 
t1/2 
Apparent terminal half-life, calculated as ln2/λz 
λz  
Terminal first order (elimination) rate constant. Determined from the terminal slope of the log-
transformed concentration curve using linear regression on terminal data points of the curve 
CL/f  
Total body clearance of drug from blood following oral administration, calculated as Dose/AUC0-∞. 
The predicted AUC0-∞ should be used. 
Vz/f  
Apparent volume of distribution during the terminal phase following extravascular administration. 
The predicted AUC0-∞ should be used. 
AUCextra% 
The AUC from time tlast extrapolated to infinity given as percentage of AUC0-.  
AUC0-t/ Dose  
The Dose normalized AUC from time zero to the last sampling time (tlast) at which the 
concentration is at or above the lower limit of quantification. Normalized using the actual dose, 
using the formula AUC0-t /Dose. 
AUC0-∞/Dose 
The Dose normalized AUC from time zero extrapolated to infinity. Normalized using actual dose 
and AUC0-∞, using the formula AUC0-∞ /Dose. 
Cmax/Dose 
Dose-normalized Cmax 
LLOQ=lower limit of quantification, CRF=case report form.  
Additional PK parameters might be added based on emerging data and detailed in the Integrated 
Analysis Plan. 
• For measurement of whole blood concentrations of M5717, as specified in the SoA. The actual 
date and time (24-hour clock time) of each sample will be recorded to calculate actual time 
elapsed since the prior dose administration. 
• The quantification of M5717 in whole blood will be performed using a validated assay method. 
Concentrations will be used to evaluate the PK of M5717. 
• Remaining samples collected for analyses of M5717 concentration may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study. 


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Table 9 
Analysis Populations 
Analysis Set 
Description 
Screening (SCR) 
All participants who provided informed consent, regardless of the participant’s 
randomization and study intervention status in the study. 
Intention-to-Treat (ITT)  
All participants, who were randomized to study intervention. Analyses performed on 
the ITT population will consider participants’ allocation to study intervention groups as 
randomized. 
Safety (SAF)  
All ITT participants, who have been inoculated using a DVI of PfSPZ and who were 
administered one dose of study intervention (M5717 or placebo). 
All Safety analyses will be based on this analysis set. Analyses will consider 
participants as treated. 
Per-Protocol (PP) 
All SAF participants who comply with the protocol and meet no criteria that could 
impact the proper evaluation of key objectives of the study (as will be defined in the 
Integrated Analysis Plan and approved at the Data Review Meeting). Participants who 
meet one of the following criteria will be excluded from the PP: 
• 
Incorrect study intervention group allocation, different to assignment at 
randomization. 
All Efficacy analyses will be based on this analysis set. 
Pharmacokinetic (PK)  
All participants, who receive one dose of M5717, have no clinically important protocol 
deviations or important events affecting PK, and provide at least one measurable post-
dose concentration. Participants will be analyzed per the actual study intervention they 
received. 
All PK analyses will be based on the PK analysis set. 
DVI=direct 
intravenous 
inoculation, 
ITT=intention-to-treat, 
PfSPZ=Plasmodium 
Falciparum 
Sporozoites, 
PK=pharmacokinetic, PP=per-protocol, SCR=screening, SAF=safety. 
9.4 
Statistical Analyses 
The following descriptive statistics will be used as applicable to summarize study data by actual 
dose or study intervention, unless otherwise specified: 
• Continuous variables: number of non-missing observations, mean, standard deviation, median, 
first and third quartiles, minimum, and maximum 
• Categorical variables: frequencies and percentages.  
No formal statistical hypothesis testing will be performed. Missing data will not be imputed. A 
participant who withdraws prior to the last planned observation in a study period will be included 
in the analyses up to the time of discontinuation. 
All participants will be included in individual participant data listings. All derived data will also 
be listed.  
The Baseline measurement is defined as the pre-dose value reported on Day 1 or the Screening 
value as relevant in accordance with the SoA. 
Data will be presented by dose cohort and data of participants who received placebo may be pooled 
across dosing cohorts. 
Further details on all statistical analyses will be presented in the Integrated Analysis Plan that will 
be finalized before database lock.  


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Changes in the conduct of the study or planned analyses will be reported in the corresponding 
section of the Integrated Analysis Plan, if applicable, and in the clinical study report.  
A separate statistical analysis plan for SMC purposes will be established to document technical 
and detailed specifications for the analyses to be provided to the SMC members as defined in the 
SMC charter and will be finalized before the first SMC meeting. 
9.4.1 
Efficacy Analyses 
All efficacy analyses will be performed on the Per-Protocol Analysis population. Efficacy 
endpoints will be compared between participants who received M5717 and placebo within the 
same cohorts and overall (pooling all participants receiving placebo across cohorts). Protection 
rate, defined as 1 minus the proportion of participants with positive parasitemia qPCR outcome 
equal or greater than 100 asexual parasites per mL of blood within 28 days of PfSPZ Challenge 
will be summarized. Clopper-Pearson confidence interval (CI) (nominal 95%) for the protection 
rate will be provided.  
Kaplan-Meier curves and median estimates (with 95% CI) of the time from DVI PfSPZ to positive 
parasitemia will be generated. Efficacy endpoints are the presence or absence of clinical signs and 
symptoms of malaria until Day 28 (Table 10). 
Table 10 
Statistical Analysis Methods Used for Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
 
• 
Number of participants over time with positive 
parasitemia defined as first positive qPCR 
outcome equal or greater than 100 asexual 
parasites per mL of blood within 28 days of PfSPZ 
challenge  
• 
Time to parasitemia, defined as time from PfSPZ 
DVI to the first qPCR outcome equal or greater 
than 100 asexual parasites per mL of blood (time 
frame: number of days from PfSPZ DVI challenge 
to positive parasitemia, or 28 days)  
• 
Number of participants with documented blood 
stage parasite growth, defined as an increase of 
qPCR measured asexual parasites per mL 
compared to the first parasitemia measurement, 
within 28 days of PfSPZ DVI 
• 
To explore the dose/exposure-response 
relationship of M5717 and liver stage or blood 
stage breakthrough 
• 
Descriptive statistics of the protection rate. Clopper-
Pearson confidence interval will be provided. 
• 
Kaplan-Meier curves and median estimates (with 
nominal 95% CI) of the time from DVI PfSPZ to 
positive parasitemia will be generated. 
• 
Clinical signs and symptoms of malaria 
• 
The malaria clinical score for treatment initiation will 
be listed and summarized by cohort and treatment 
group. 
CI=confidence interval, DVI=direct intravenous inoculation, qPCR=quantitative polymerase chain reaction, 
PfSPZ=Plasmodium Falciparum Sporozoites. 


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9.4.2 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis population (Table 11). 
Table 11 
Statistical Analysis Methods Used for Safety Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
No primary Safety endpoints 
Secondary 
Nature, occurrence, and 
severity of treatment-
emergent adverse events 
(TEAEs) 
The number and percentage of participants experiencing at least 1 TEAE will be 
summarized by treatment and the number of events. Tables by relationship to 
study drug and by severity will be generated. AEs will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) terminology. 
Change from Baseline in 
safety laboratory 
parameters 
All laboratory data will be reported with SI units. Laboratory parameters will be 
summarized using descriptive statistics for absolute values and change from baseline 
over time, by postdose shifts relative to baseline, and data listings of abnormalities. 
Absolute values and 
change from Baseline in 
vital signs 
Vital signs data will be summarized by changes-from-baseline values by treatment 
using descriptive statistics. 
Absolute and change 
from Baseline in 12-lead 
safety ECGs 
ECG data will be summarized by changes-from-baseline values by treatment using 
descriptive statistics. Clinical noteworthy ECG findings for individual participants will 
be listed and summarized as appropriate. 
AE=adverse 
event(s), 
ECG=electrocardiogram, 
MedDRA=Medical 
Dictionary 
for 
Regulatory 
Activities, 
TEAE=treatment-emergent adverse event(s). 
9.4.3 
Other Analyses 
PK analyses will be specified in the Integrated Analysis Plan.  
M5717 concentrations in blood, along with the prespecified PK and PD parameters, will be 
presented in tables and descriptively summarized by dose level and/or nominal time point, as 
appropriate, using count (n), arithmetic mean, standard deviation, median, minimum, maximum, 
and coefficient of variation. Values below the lower level of quantification will be taken as zero 
for descriptive statistics of PK concentrations. Descriptive statistics of PK parameters will 
additionally show the geometric mean, geometric coefficient of variation, and the 95% confidence 
interval for the geometric mean. Graphical displays will be provided, where appropriate. 
Estimation of Individual PK Parameter 
Pharmacokinetic parameters will be calculated by the CRO and overseen by the Clinical PK/PD 
Group of Quantitative Pharmacology, Merck Healthcare KGaA, Darmstadt, Germany, using 
standard non-compartmental methods and the actual administered dose. PK parameters will be 
calculated using the actual elapsed time since dosing, given with a precision of 14 significant digits 
or the SAS format Best12. When the actual sampling time is missing, calculations will be 
performed using the scheduled time. Otherwise, there will be no further imputation of missing 
data.  


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10 
References  
Adegnika AA, Verweij JJ, Agnandji ST, et al. Microscopic and sub-microscopic Plasmodium 
falciparum infection, but not inflammation caused by infection, is associated with low birth weight. 
Am J Trop Med Hyg. 2006; 75(5):798-803. 
Baragaña B, Hallyburton I, Lee MC, et al. A novel multiple-stage antimalarial agent that inhibits 
protein synthesis. Nature. 2015; 522(7556):315-20.  
Burrows JN, van Huijsduijnen RH, Möhrle JJ, et al. Designing the next generation of medicines 
for malaria control and eradication. Malaria J. 2013 Jun 6; 12:187. 
Chalon S, Akakpo S, Duparc S, et al. Moderate and severe LFT elevations in controlled human P. 
falciparum malaria infection model: recent experience, literature review and mechanistic 
hypotheses. 2016: Abstract #1540 ASTMH. 
Hermsen CC, Telgt DS, Linders EH, et al. Detection of Plasmodium falciparum malaria parasites 
in vivo by real-time quantitative PCR. MolBiochemParasitol. 2001; 118(2):247-51. 
Jongo SA, Shekalaghe SA, Church LWP, et al. Safety, immunogenicity, and protective efficacy 
against controlled human malaria infection of plasmodium falciparum sporozoite vaccine in 
Tanzanian adults. Am J Trop Med Hyg. 2018; 99(2):338-349. 
Lee CR. Drug interactions and hormonal contraception. Trends in Urol Gynaecol Sexual Health. 
2009; 14(3):23-26. 
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):21914. 
Mordmüller B, Supan C, Sim KL, et al. Direct venous inoculation of Plasmodium falciparum 
sporozoites for controlled human malaria infection: a dose-finding trial in two centres. Malaria J. 
2015; 14:117. 
Mordmüller B, Surat G, Lagler H, et al. Sterile protection against human malaria by 
chemoattenuated PfSPZ vaccine. Nature. 2017; 542(7642):445-449. 
Murphy SC, Duke ER, Shipman KJ, et al. A Randomized Trial Evaluating the Prophylactic 
Activity of DSM265 Against Preerythrocytic Plasmodium falciparum Infection During Controlled 
Human Malarial Infection by Mosquito Bites and Direct Venous Inoculation. J Infect Dis. 2018; 
217:693-702. 
Nieman AE, de Mast Q, Roestenberg M, et al. Cardiac complication after experimental human 
malaria infection: a case report. Malaria J. 2009; 8:277. 
Nyunt MM, Hendrix CW, Bakshi RP, et al. Phase I/II Evaluation of the Prophylactic Antimalarial 
Activity of Pafuramidine in Healthy Volunteers Challenged with Plasmodium falciparum 
Sporozoites. Am J Trop Med Hyg. 2009; 80(4):528–535. 
Rockett RJ, Tozer SJ, Peatey C, et al. A real-time, quantitative PCR method using hydrolysis 
probes for the monitoring of Plasmodium falciparum load in experimentally infected human 
volunteers. Malaria J. 2011; 10(48). 


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Sulyok M, Rückle T, Roth A, et al. DSM265 for Plasmodium falciparum chemoprophylaxis: a 
randomized, double blinded, phase 1 trial with controlled human malaria infection. Lancet Infect 
Dis. 2017; 17(6):636-644. 
Van Meer MP, Bastiaens GJ, Boulaksil M, et al. Idiopathic acute myocarditis during treatment for 
controlled human malaria infection: a case report. Malaria J. 2014; 13:38. 
Walk J, Reuling IJ, Teelen K, et al. Diagnosis and treatment based on quantitative PCR after 
controlled human malaria infection. Malaria J. 2016; 15:398. 
WHO Malaria report 2018. ISBN 978-92-4-156565-3; World Health Organization 2018. 
Woodford J, Shanks GD, Griffin P, et al. The Dynamics of Liver Function Test Abnormalities 
after Malaria Infection: A Retrospective Observational Study. Am J Trop Med Hyg. 2018 Apr; 
98(4):1113-1119. 


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11 
Appendices 


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HRT 
Hormonal Replacement Therapy 
IB 
Investigator’s Brochure 
IBSM 
Induced Human Blood Stage Model 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intention-to-Treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone-releasing System 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
LAM 
Lactational Amenorrhoea Method 
LLOQ 
Lower Limit of Quantification 
LUMC 
Leiden University Medical Centre 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCE 
New Chemical Entity 
NOAEL 
No-Observed-Adverse-Effect Level 
NSAIDs 
Non-steroidal Anti-inflammatory Drugs 
PCR 
Polymerase chain reaction, a test used to detect the presence of RNA or DNA 
PD 
Pharmacodynamics 
PeEF2 
Plasmodium eukaryotic translation Elongation Factor 2 
PfSPZ 
Plasmodium Falciparum Sporozoites 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PR 
Pulse Rate 
Pre 
Predose 
qPCR 
Quantitative Polymerase Chain Reaction 
RIVM 
Rijksinstituut voor Volksgezondheid en Milieu (Dutch National Institute for 
Public Health and the Environment)   
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAF 
Safety 
SARS-
CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2, the virus causing COVID-
19 


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Appendix 2 
Study Governance 
Financial Disclosure 
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information, as requested, for the Sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. This information is required 
during the study and for 1 year after completion of the study. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative and answer all questions on the study. 
• Participants must be informed that their participation is voluntary. 
• Participants or their legally-authorized representative will be required to sign a statement of 
informed consent that meets the requirements of local regulations; ICH guidelines; Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable; and the 
IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
• If the ICF is updated during their participation in the study, participants must be re-consented 
to the most current, approved version. 
• A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative. 
• The original signed and dated consent will remain at the Investigator’s site and must be safely 
archived so that it can be retrieved at any time for monitoring, auditing and inspection purposes. 
A participant who is rescreened is not required to sign another ICF if the rescreening occurs within 
the Screening period of 28 days from the previous ICF signature date. If rescreening falls outside 
this time period, a new ICF has to be signed. In these cases, the new study number would be noted 
together with the previous number.  
Data Protection 
• The Sponsor will assign a unique identifier to participants after obtaining their informed 
consent. All participant records or datasets transferred to the Sponsor will contain the identifier 
only; participant names or any identifiable information will not be transferred. 
• The Sponsor must inform participants that their personal study-related data will be used per 
local data protection and privacy laws. The level of disclosure must also be explained to the 
participant. 
• The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other Sponsor-appointed, authorized personnel, by appropriate 


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A Safety Monitoring Committee (SMC) will be established before enrolment of the first 
participant, will review the data after each cohort is completed, and decide on the dose, dose 
regimen, and number of participants for the next cohort as per protocol. The SMC will include the 
Chairperson (Global Patient Safety Product Responsible), core sponsor members (Medical 
Responsible, Clinical Pharmacology Representative, and Biostatistician). The following external 
members will be included: Principal Investigator (and Sub-Investigator(s)), CRO representative, 
and an independent external expert (if applicable). Only Merck members and the investigators will 
be voting members, and, as applicable, the independent external expert. Further persons may be 
represented on the team if their input is required. Details regarding SMC roles, responsibilities, 
activities, procedures to reduce potential bias, and possible SMC recommendations will be 
provided in a separate SMC charter.  
All details about the country specific reporting requirements for Individual Case Safety Reports 
(ICSRs) and periodic safety reports to Health Authorities will be described in the Safety 
Management Plan. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and the following: 
• Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• The Investigator must submit the protocol, protocol amendments (if applicable), ICFs, 
Investigator Brochure(s), and other relevant documents (e.g., advertisements) to an IRB/IEC 
and the IRB/IEC must review and approve them before the study is initiated. 
• Any protocol amendments (i.e., changes to the protocol) will be documented in writing and 
require IRB/IEC approval before implementation of changes, except for changes necessary to 
eliminate an immediate hazard to study participants. When applicable, amendments will be 
submitted to the appropriate Health Authorities. 
• The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently per the IRB’s/IEC’s requirements, policies, and procedures. 
• Notifying the IRB/IEC of SAEs or other significant safety findings, as required by 
IRB/IEC procedures. 
• Providing oversight of the study conduct at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations. 
• The protocol and any applicable documentation will be submitted or notified to the Health 
Authorities in accordance with all local and national regulations for each site. 


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Emergency Medical Support 
• The Sponsor or designee will provide Emergency Medical Support cards to participants for use 
during the study. These provide the means for participants to identify themselves as 
participating in a clinical study. Also, these give health care providers access to any information 
about this participation that may be needed to determine the course of medical treatment for the 
participant. The information on the Emergency Medical Support card may include the process 
for emergency unblinding (if applicable). 
• The first point of contact for all emergencies will be the clinical study Investigator caring for 
the participant.  Consequently, the Investigator agrees to provide his or her emergency contact 
information on the card. If the Investigator is available when an event occurs, they will answer 
any questions. Any subsequent action (e.g., unblinding) will follow the standard process 
established for Investigators. 
When the Investigator is not available, the Sponsor provides the appropriate means to contact a 
Sponsor (or designee) physician. This includes provision of a 24-hour contact number at a call 
center, whereby the health care providers will be given access to the appropriate Sponsor (or 
designee) physician to assist with the medical emergency “and to provide support for the potential 
unblinding of the participant concerned”. 
When the Investigator is not available, the Phase I facility will provide the appropriate means to 
contact a physician. This includes the provision of a 24-hour contact number at the facility, 
whereby the health care providers will be given access to an appropriate physician to assist with 
the medical emergency and to provide support for the potential unblinding of the participant 
concerned. 
Clinical Study Insurance and Compensation to Participants 
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions shall meet good local standards, as applicable. 
Clinical Study Report 
After study completion, the Sponsor will write a clinical study report in consultation with the 
Principal Investigator. 
Publication 
• The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows Merck to protect proprietary information and to provide comments.  
• The Sponsor will comply with the requirements for publication of study results. Per standard 
editorial and ethical practice, the Sponsor will generally support publication of multicenter 
studies only in their entirety and not as individual site data. In this case, a coordinating 
Investigator will be designated by agreement. For this single center study, please refer to 
Section 11 of the Clinical Trial Agreement. 


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• Authorship will be determined by agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
Dissemination of Clinical Study Data 
The study results will be disseminated according to Merck’s policy and SOPs. The procedures for 
publication planning will also follow the most recent recommendations from the International 
Committee of Medical Journal Editors. 
The specific study information and data will also be disclosed by the Sponsor publicly by 
registering clinical studies on publicly accessible web platforms such as www.clinicaltrials.gov 
prior to, during and after the completion of the clinical study in manners consistent with applicable 
laws and rules governing protection of patient privacy and intellectual property. In addition, the 
study results will be made publicly available by means of a Clinical Study Report synopsis in 
accordance with privacy legislation and rules. Other researchers can, by following the appropriate 
Merck KGaA processes, gain access to the data for additional analysis or information as part of 
EFPIA/PhRMA commitment to Responsible Data Sharing. Merck KGaA observes stringent data 
protection rules and as such has implemented a strict process whereby external researchers may 
apply for access to the data. All details concerning obtaining access to the clinical study data are 
available 
on 
a 
dedicated 
web 
page 
on 
the 
Merck 
KGaA 
website: 
http://biopharma.merckgroup.com/en/research_development/clinical_trials/commitment_to_resp
onsible_clinical_trial_data_sharing/commitment_to_responsible_clinical_trial_data_ 
sharing.html. 
Healthy participants might be provided with the results of the medical examinations at request. 
After finalization of the study, healthy participants might be provided with the information 
published on ClinicalTrials.gov and/or the European Clinical Trial database at request. 
Data Quality Assurance 
• All participant study data will be recorded on printed or electronic CRFs or transmitted to the 
Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible for 
verifying that data entries are complete, accurate, legible, and timely by physically or 
electronically signing the CRF. Details for managing CRFs are in the CRF Completion 
Guidelines 
• The Investigator must maintain accurate documentation (source data) that supports the 
information in the CRF. 
• The Investigator must permit study-related monitoring, quality assurance audits, IRB/IEC 
review, and regulatory agency inspections and provide direct access to the study file and source 
data. 
• Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are in the Monitoring Plan. 
• The Sponsor or designee is responsible for data management of this study, including quality 
checking of the data and maintaining a validated database. Database lock will occur once quality 


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control and quality assurance procedures have been completed. PDF files of the CRFs will be 
provided to the Investigators at study completion. 
• Study monitors will perform ongoing source data verification to confirm that data in the CRF 
are accurate, complete, and verifiable; that the safety and rights of participants are being 
protected; and that the study is being conducted per the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion, unless local regulations, 
institutional policies, or the Sponsor requires a longer retention. No records may be destroyed 
during the retention period without the Sponsor’s written approval. No records may be 
transferred to another location or party without the Sponsor’s written notification. 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. 
• The Investigator must keep a paper or electronic file (medical file and original medical records) 
at the site for each study participant. The file must identify each participant, contain the 
following demographic and medical information for the participant, and should be as complete 
as possible: 
• Participant’s full name, date of birth, sex, height, and weight 
• Medical history and concomitant diseases 
• Prior and concomitant therapies (including changes during the study) 
• Study identifier (i.e., the Sponsor’s study number) and participant’s study number. 
• Dates of entry into the study (i.e., signature date on the informed consent) and each visit 
to the site 
• Any medical examinations and clinical findings predefined in the protocol 
• All AEs 
• Date that the participant left the study, including any reason for early withdrawal from 
the study or study intervention, if applicable. 
• All source data must be filed (e.g., CT or MRI scan images, ECG recordings, and laboratory 
results). Each document must have the participant number and the procedure date; ideally, 
printed by the instrument used for the procedure. As necessary, medical evaluation of these 
records should be performed, documented, signed and dated by the Investigator.  
• Data recorded on printed or electronic CRFs that are transcribed from source documents must 
be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 


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• The study monitors will use printouts of electronic files (e.g., laboratory reports) for source data 
verification. These printouts must be signed and dated by the Investigator and kept in the study 
file. 
• Source documents are stored at the site for the longest possible time permitted by the applicable 
regulations, and/or as per ICH GCP guidelines, whichever is longer. The Investigator ensures 
that no destruction of medical records is performed without the Sponsor’s written approval. 
• Definition of what constitutes source data is found in ICH GCP Guideline E6 Chapter 1.51. 
Study and Site Closure 
• The Sponsor reserves the right to close the study site or terminate the study at any time and for 
any reason. Study sites will be closed upon study completion. A study site is considered closed 
when all required documents and study supplies have been collected and a site closure visit has 
been completed. 
• The Investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
• Reasons for the early closure of a study site by the Sponsor or Investigator may include: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further development of the Sponsor’s compound. 
 


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Appendix 3 
Contraception 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile, as specified below. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, consider additional evaluation. 
A WOCBP is not: 
1. Premenarchal 
2. A premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Documentation can come from the site personnel’s review of the female’s medical records, 
medical examination, or medical history interview.  
For a female with permanent infertility due to an alternate medical cause other than the 
above, (e.g., mullerian agenesis, androgen insensitivity), investigator discretion applies to 
determine study entry. 
3. A postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• A high follicle-stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in a female not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, more than 1 FSH measurement is required in the 
postmenopausal range. 
• A female on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if she wishes to 
continue her HRT during the study. Otherwise, she must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
A male will be considered eligible for enrolment if he agrees to the following during the study 
intervention period and for at least 120 days after the day of the study intervention dose (covering 
a full sperm cycle of 90 days starting after 5 half-lives of last dose of study intervention): 
• Refrain from donating sperm 
PLUS, either: 
• Abstain from intercourse with a WOCBP 
OR 
• Use a male condom: 


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• When having sexual intercourse with a WOCBP, who is not currently pregnant, 
and advise her to use a highly effective contraceptive method with a failure rate of 
< 1% per year, since a condom may break or leak. 
Contraceptive Guidance 
Highly Effective Methods That Have Low User Dependency 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner: a highly effective contraceptive method provided that the partner is the sole sexual 
partner of a WOCBP, and the absence of sperm has been confirmed. Otherwise, use an additional highly 
effective method of contraception. The spermatogenesis cycle is approximately 90 days. 
Highly Effective Methods That Are User Dependent 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
• 
Injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
• 
Sexual abstinence: a highly effective method only if defined as refraining from intercourse during the entire 
period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study. 
Notes: 
Contraceptive use by men or women is consistent with local regulations on the use of contraceptive methods for 
clinical study participants. 
Highly effective methods are those with a failure rate of <1% per year when used consistently and correctly. 
Typical use failure rates differ from those when used consistently and correctly. 
Hormonal contraception may be susceptible to interaction with the study intervention(s), which may reduce the 
efficacy of the contraceptive method. As such, male condoms must be used in addition to hormonal 
contraception. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for 
this study. Male condom and female condom cannot be used together (due to risk of failure with friction). 
 


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Highly Effective Contraceptive Methods That Are User Dependent  
Failure rate of <1% per year when used consistently and correctly.  
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationb 
• 
oral  
• 
intravaginal  
• 
transdermal  
• 
Progestogen-only hormonal contraception associated with inhibition of ovulationb  
• 
oral  
• 
injectable  
Highly Effective Methods That Are User Independent  
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb 
• 
Intrauterine device  
• 
Intrauterine hormone-releasing system  
• 
bilateral tubal occlusion 
• 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used.)  
• 
Sexual abstinence  
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.)  
NOTES:  
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants participating in clinical studies.  
b) Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case 2 highly effective methods of contraception should be utilized during the 
treatment period and for at least 20 weeks after the last dose of study treatment.  
 
 


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Appendix 4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definitions 
Adverse Event 
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, 
regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, regardless if it is considered related to the medicinal 
product. 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself. 
The Investigator is required to grade the severity or toxicity of each AE. 
Investigators must assess the severity of AEs per the Qualitative Toxicity Scale, as follows: 
Mild: 
The participant is aware of the event or symptom, but the event or symptom is easily 
tolerated. 
Moderate: 
The participant experiences sufficient discomfort to interfere with or reduce his or 
her usual level of activity. 
Severe: 
Significant impairment of functioning: the participant is unable to carry out his or 
her usual activities. 
Investigators must also systematically assess the causal relationship of AEs to study intervention 
(including any other non-study interventions, radiation therapy, etc.) using the following 
definitions. Decisive factors for the assessment of causal relationship of an AE to the M5717, DVI 
or rescue medication include, but may not be limited to, temporal relationship between the AE and 
the product, known side effects of the product, medical history, concomitant medication, course 
of the underlying disease, and study procedures. 
Unrelated: 
Not reasonably related to the study intervention. AE could not medically 
(pharmacologically/clinically) be attributed to the study intervention under study in 
this clinical study protocol. A reasonable alternative explanation must be available. 
Related: 
Reasonably 
related 
to 
the 
study 
intervention. 
AE 
could 
medically 
(pharmacologically/clinically) be attributed to the study intervention under study in 
this clinical study protocol.  
Abnormal Laboratory Findings and Other Abnormal Investigational Findings 
Abnormal laboratory findings and other abnormal investigational findings (e.g., on an ECG trace) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead to 
study intervention discontinuation or are considered otherwise medically important by the 
Investigator. If a laboratory abnormality fulfills these criteria, the identified medical condition 
(e.g., anemia or increased ALT) must be reported as the AE rather than the abnormal value itself. 
Serious Adverse Events 


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An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening. Life-threatening refers to an event in which the participant is at risk of death 
at the time of the event, not an event that hypothetically might have caused death if it was more 
severe. 
• Requires inpatient hospitalization or prolongs an existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is otherwise considered to be medically important. Important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered as SAEs when, based 
upon appropriate medical judgment, they may jeopardize the participant or may require medical 
or surgical intervention to prevent one of the outcomes listed above. Examples of such events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
For the purposes of reporting, any suspected transmission of an infectious agent via a study 
intervention is also considered an SAE, as specified below for reporting SAEs.  
Events that Do Not Meet the Definition of an SAE 
Elective hospitalizations to administer, or to simplify study intervention or procedures (e.g., an 
overnight stay to facilitate intravenous therapy) are not considered SAEs. However, all events 
leading to unplanned hospitalizations or unplanned prolongation of an elective hospitalization (i.e., 
undesirable effects of any administered treatment) must be documented and reported as SAEs. 
Events Not to Be Considered as AEs/SAEs 
Medical conditions present at the initial study visit that do not worsen in severity or frequency 
during the study are defined as Baseline Medical Conditions and are not to be considered AEs. 
Recording and Follow-Up of AE and/or SAE 
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates and also onset and resolution times, when it is important to assess the time of AE 
onset relative to the recorded study intervention administration time), its severity, its causal 
relationship with the study intervention, any other potential causal factors, any treatment given or 
other action taken, including dose modification or discontinuation of the study intervention, and 
its outcome. In addition, serious cases should be identified, and the appropriate seriousness criteria 
documented.  
Specific guidance is in the CRF Completion and Monitoring Guidelines. 


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Reporting Serious Adverse Events  
Serious Adverse Events 
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 HOURS after becoming aware of the event) inform the 
Sponsor or its designee in writing. All written reports should be transmitted using the SAE Report 
Form, which must be completed by the Investigator following specific completion instructions. 
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, a written report must be sent immediately thereafter by fax or e-mail. Names, 
addresses, and telephone and fax numbers for SAE reporting will be included in the study specific 
SAE Report Form.  
Relevant pages from the CRF may be provided in parallel (e.g., medical history, concomitant 
drugs). Additional documents may be provided by the Investigator, if available (e.g., laboratory 
results, hospital report, autopsy report). In all cases, the information provided on the SAE Report 
Form must be consistent with the data about the event recorded in the CRF. 
The Investigator must respond to any request for follow-up information (e.g., additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee and 
(as applicable) to allow the Sponsor to meet strict regulatory timelines associated with expedited 
safety reporting obligations. 
Requests for follow-up will usually be made via the study monitor, although in exceptional 
circumstances the drug safety department may contact the Investigator directly to obtain further 
information or to discuss the event in case of limited provided information. 


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Appendix 5 
Liver Safety: Suggested Actions and Follow-up Assessments  
The drug induced liver injury will be defined as following: 
• an elevated ALT or AST by > 3xULN. Often with ATs much greater: 5-10xULN. 
• an elevated ALT or AST by > 3xULN plus serum total bilirubin (TBL) of > 2xULN, without 
findings of cholestasis (defined as serum alkaline phosphatase activity < 2ULN). 
• no other reason can be found to explain the combination of increased AT and serum TBL, such 
as viral hepatitis, alcohol abuse, ischemia, preexisting liver disease, or another drug capable of 
causing the observed injury. 
An increase of serum ALT to > 3xULN should be followed by repeat testing within 48 to 72 hours 
of all four of the usual serum measures (ALT, AST, ALP, and TBL) to confirm the abnormalities 
and to determine if they are increasing or decreasing. The need for prompt repeat testing is 
especially great if AT is much > 3xULN and/or TBL is > 2xULN.  
If symptoms persist or repeat testing shows AT > 3xULN for participants with normal baseline 
measures, it is appropriate to initiate close observation to determine whether the abnormalities are 
improving or worsening.  
Close observation includes:  
• Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize and the participant is 
asymptomatic,  
• Obtaining a more detailed history of symptoms and prior or concurrent diseases,  
• Obtaining a history of concomitant drug use (including nonprescription medications and herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets,  
• Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune hepatitis; NASH; 
hypoxic/ischemic hepatopathy; and biliary tract disease,  
• Obtaining a history of exposure to environmental chemical agents, 
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., international 
normalized ratio [INR], direct bilirubin),  
• Considering gastroenterology or hepatology consultations. 
All study participants showing possible drug induced liver injury should be followed until all 
abnormalities return to normal or to the baseline state.  
 
 




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Appendix 7 
Clinical Laboratory Tests 
Table 12 
Protocol-Required Clinical Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Hemoglobin 
Hematocrit 
Red blood cell count 
Reticulocytes 
Platelet count 
 
MCV 
MCH 
MCHC 
White Blood Cell 
Count with 
Differentiala: 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
Biochemistry 
Aspartate aminotransferase 
Alanine aminotransferase 
Alkaline phosphatase 
Gamma-glutamyl-transferase 
Lactate dehydrogenase 
Creatine phosphokinasea 
Total Protein 
Albumin 
Bilirubin (total) a 
hs Troponin T 
Cholesterolb 
Triglyceridesb 
HDL cholesterolb 
Amylase 
Lipase 
Uric acid 
Blood Urea Nitrogen 
Creatinine 
Glucose (fasting, fasting 
optional for Days 6 to 33) 
 
Electrolytes: 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Calcium 
• 
Magnesium 
• 
Bicarbonate 
• 
Phosphate 
Coagulationb 
INR  
Activated partial thromboplastin time 
 
a 
In case of abnormal findings manual differential blood count, direct/indirect bilirubin and creatine 
phosphokinase myocardial/brain type fraction or other assessments can be requested by the Investigator. 
b 
Screening only 
Details of liver chemistry stopping criteria and required actions and Follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1 (Discontinuation of Study Intervention) and Appendix 9. 
Routine Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte esterase] 
by dipstick 
• 
Microscopic examination (only if blood, protein, leucocyte esterase, or nitrite is positive) 
(only if dipstick is clinically significant as deemed by the investigator).  
Urine drug screen 
Cocaine 
Amphetamines 
Methamphetamines 
Opiates 
Barbiturates 
MDMA (ecstasy) 
Benzodiazepine 
Methadone 
THC (cannabinoids) 
Phencyclidine 
Tricyclic antidepressants 
 
Serology 
Hepatitis B surface antigen  
Hepatitis B core antibody 
Hepatitis C antibody 
Human immunodeficiency virus (HIV) I and II antibodies 
Pregnancy 
Serum hCG pregnancy test (at Screening) 
Urine pregnancy test (on Day -1) 
Other Screening 
Tests 
• 
Urine cotinine 
• 
Alcohol breath test 


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Appendix 8 
Package Inserts of Malarone and Riamet 
 


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Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model 
MS201618_0003 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
108/119 
 
 
 


M5717 
 
Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model 
MS201618_0003 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
109/119 
 
 
 
 


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M5717 
 
Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model 
MS201618_0003 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
112/119 
 
 
Section # and Name 
Description of Change 
Brief Rationale 
 
5.3 Lifestyle Considerations 
 
6.5.1 Rescue Medicine 
 
7.2 Participant Discontinuation/Withdrawal 
from the Study 
 
 
Appendix 1 Abbreviations 
Abbreviations added  
To clarify abbreviations used in 
this amendment. 
Appendix 11 COVID-19 Risk Assessment 
and Mitigation Strategies 
Added 
To describe risk assessment and 
mitigation strategies during 
COVID-19 pandemic. 
2.3 Benefit/Risk assessment 
Sentence removed 
Correction to protocol 
Throughout document 
‘Subject’ replaced with 
‘participant’, where 
applicable 
For consistency 
 
Protocol Version 2.0 (05 February 2020)  
This amendment is nonsubstantial based on the criteria in Article 10(a) of Directive 2001/20/EC 
of the European Parliament and the Council of the European Union because it neither significantly 
impacts the safety or physical/mental integrity of participants nor the scientific value of the study. 
Overall Rationale for the Amendment 
The original protocol had already been submitted and approved by the responsible independent 
ethics committee (IEC). However, during the implementation activities the site found a few 
administrative items that need to be adopted for logistical reasons, particularly allowing 
randomization to be performed also on Day -1 (instead of only pre-challenge Day 1), and widening 
the time window for PK and 12-Lead ECG at later time points to better accommodate qPCR sample 
analysis at the LUMC Laboratory on the same day. Also, there were a few incorrect entries in the 
tables due to reformatting that had to be corrected.  
 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis (Study Intervention Groups 
and Duration) 
 
1.3 Schedule of Activities (Tables 1 and 3) 
 
6.3.1 Study Intervention Assignment 
Added that randomization 
may occur on either Day  
-1 or Day 1. 
For logistical reasons in order to allow 
sufficient time for completion of 
randomization procedures. 
1.1 Synopsis (Study Intervention Groups 
and Duration) 
Clarified that participants 
will be hospitalized for 2 
nights. 
Wording revised for clarification 
purposes. 


M5717 
 
Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model 
MS201618_0003 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
113/119 
 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities (Tables 1 and 3) 
Incorrect entries due to 
reformatting corrected to 
be consistent with protocol 
text.  
Minor; therefore, have not been 
summarized. 
1.3 Schedule of Activities (Table 5) 
Allowed time windows for 
certain scheduled time 
points widened. 
Time windows for PK and 12-Lead 
ECG at later time points have been 
widened to better accommodate 
qPCR sample analysis at the LUMC 
Laboratory on the same day. 
8.2.4 Clinical Safety Laboratory 
Assessments 
 
Appendix 7 
Added that blood fasting 
state samples will be 
optional from Day 6 
onwards. 
Mandatory fasted status for lab 
assessments required only during 
Screening and Day 1 Predose visits to 
confirm eligibility. If needed for 
specific reasons it may be requested 
by the investigator from Days 6 to 33. 
Throughout 
Minor editorial and 
document formatting 
revisions. 
Minor; therefore, have not been 
summarized. 
 
 


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SAP_001.pdf: 






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1
Table of Contents
Approval Page……..............................................................................................................3
1
Table of Contents..................................................................................4
2
List of Abbreviations and Definition of Terms ....................................6
3
Modification History ............................................................................7
4
Purpose of the Integrated Analysis Plan...............................................7
5
Objectives and Endpoints .....................................................................8
6
Overview of Planned Analyses.............................................................9
7
Changes to the Planned Analyses in the Clinical Study Protocol ......10
8
Analysis Populations and Subgroups..................................................10
8.1
Definition of Analysis Populations.....................................................10
8.2
Subgroup Definition and Parameterization ........................................12
9
General Specifications for Data Analyses ..........................................12
9.1
Presentation of continuous and qualitative variables..........................13
9.2
Presentation of Study Visits................................................................14
9.3
Definition of Baseline and Change from Baseline .............................14
9.4
Definition of Duration and ‘time since’ Variables .............................14
9.5
Definition of End of the Study............................................................14
9.6
Imputation of Missing Data................................................................15
9.7
Software(s)..........................................................................................15
10
Study Participants ...............................................................................16
10.1
Disposition of Participants and Discontinuations...............................16
10.2
Protocol Deviations / Exclusion from Analysis Populations..............16
10.2.1
Important Protocol Deviations............................................................16
10.2.2
Reasons Leading to the Exclusion from an Analysis Population.......17
11
Demographics and Other Baseline Characteristics.............................18
11.1
Demographics.....................................................................................18
11.2
Medical History ..................................................................................18
12
Previous or Concomitant Medications/Procedures.............................18
13
Study Treatment: Compliance and Exposure .....................................19
14
Efficacy Analyses ...............................................................................19
14.1
Primary Analysis ...............................................................................19
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14.1.1
Exploratory Endpoint Analyses..........................................................22
15
Safety and Tolerability Analyses........................................................23
15.1
Adverse Events ...................................................................................23
15.1.1
All Adverse Events.............................................................................24
15.2
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...................................................................................25
15.2.1
Deaths .................................................................................................25
15.2.2
Serious Adverse Events ......................................................................25
15.3
Clinical Laboratory Evaluation...........................................................25
15.4
Vital Signs ..........................................................................................27
15.5
12 Lead Electrocardiogram (ECG).....................................................27
15.6
Physical Examination .........................................................................27
15.7
COVID-19 Impact ..............................................................................27
16
Analyses of Other Endpoints..............................................................27
16.1
Pharmacokinetics................................................................................27
16.1.1
Descriptive Statistics of PK Concentration Data................................28
16.1.2
Descriptive Statistics of PK Parameter Data ......................................28
16.1.3
General Specifications for PK Concentration and PK Parameter 
Data Handling.....................................................................................29
16.1.4
Estimation of Pharmacokinetic Parameters........................................29
16.1.5
Presentation of PK Concentration and PK Parameter Data................31
16.1.5.1
Listings and Tables.............................................................................31
16.1.5.2
Graphical Summaries and Individual plots (PK Analysis 
Population)..........................................................................................32
16.2
Pharmacokinetics (PK) and Pharmacodynamics (PD) 
Relationships.......................................................................................32
17
References...........................................................................................33
18
Appendices .........................................................................................33
18.1
Appendix 1 – Planned analyses for SMC meetings............................33
18.2
Appendix 2 – Vital Signs and 12-Lead ECG Reference Ranges........34
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2
List of Abbreviations and Definition of Terms
ADaM
Analysis Data Model
AE
Adverse Event
AUC
Area Under the Plasma Concentration-Time Curve
CI
Confidence Interval
CM
Concomitant Medication
Cmax
Maximum blood concentration observed
CRO
Contract Research Organization
CSR
Clinical Study Report
CV%
Percentage coefficient of variation
DMP
Data Management Plan
DVI
Direct Intravenous Inoculation
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
FU
Follow-up
GM/GeoMean
Geometric Mean
IAP
Integrated Analysis Plan
ICH
International Council for Harmonization
ICH
International Conference on Harmonization
ITT
Intention-To-Treat Analysis Population
KM
Kaplan-Meier
LCI
Lower Limit of the Confidence Interval
LLOQ
Lower Level of Quantification
MedDRA
Medical Dictionary for Regulatory Activities
MH
Medical History
ND
Not Determined
PD
Pharmacodynamics
PfSPZ
Plasmodium falciparum Sporozoite
PK
Pharmacokinetics
PKP
Pharmacokinetic Analysis Population
PP
Per Protocol Analysis Population
PR
Pulse Rate
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PT
Preferred Terms
Q1
First Quartile
Q3
Third Quartile
qPCR
Quantitative Polymerase Chain Reaction
SAE
Serious Adverse Event
SAF
Safety Analysis Population
SCR
Screening Analysis Population
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SMC
Safety Monitoring Committee
SoA
Schedule of Activities
SOC
System Organ Class
TEAEs
Treatment Emergent Adverse Events
TLF
Table, Listings and Figures
tmax
Time when Cmax is Observed
UCI
Upper Limit of the Confidence Interval
WHO-DD
World Health Organization Drug Dictionary
WONCBP
Women of Non-Childbearing Potential
3
Modification History
Unique
Identifier for
Version
Date of
IAP Version
Author
Changes from the Previous Version
1.0
12 March 2021
Initial document
4
Purpose of the Integrated Analysis Plan
The purpose of this IAP is to document technical and detailed specifications for the primary, 
secondary as well as exploratory analysis of data collected for protocol MS2001618-0003. Results 
of the analyses described in this IAP will be included in the Clinical Study Report (CSR). 
Additionally, the planned analyses identified in this IAP may be included in regulatory 
submissions or future manuscripts. Any post-hoc, or unplanned analyses performed to provide 
results for inclusion in the CSR but not identified in this prospective IAP will be clearly identified 
in the CSR.
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Objectives
Endpoints (Outcome Measures)
IAP section
To evaluate the safety and tolerability of 
single, oral doses of M5717 in healthy 
participants following infection with PfSPZ 
challenge
Nature, incidence, frequency, 
severity of adverse events (AEs)/ 
serious adverse events (SAEs), 
and relationship to the study 
intervention
Incidence of clinically significant 
changes and abnormalities in 
safety laboratory parameters 
(hematology, coagulation, 
biochemistry [specifically alanine 
aminotransferase (ALT) and 
aspartate aminotransferase 
(AST), alkaline phosphatase 
(ALP), bilirubin (total)], and 
urinalysis)
Incidence of clinically significant 
changes and abnormalities in vital 
signs and 12 lead 
electrocardiogram (ECG).
15
To investigate the PK of M5717 after 
administration of single, oral doses in healthy 
participants following infection with PfSPZ
Exposure endpoints:
Concentration-time curve for 
M5717 after single-dose 
administration
Pharmacokinetic parameters of 
M5717 such as AUC0-∞, AUC0-tlast, 
AUC0-24, AUC0-168, Cmax, C24, C168, 
tmax, t1/2, λZ, CL/f and Vz/f.
16.1
6
Overview of Planned Analyses
The SMC was established before enrollment of the first participant. The SMC will review the data 
after each cohort is completed, and decide on the dose, dose regimen, and number of participants 
for the next cohort as per protocol. Details of the procedure and analyses are provided in the SMC 
charter version 1.0, dated 31 October 2019 and SMC statistical analysis plan version 2.0, dated 05
Mar 2021.
All final, planned analyses identified in the Clinical Study Protocol and this Integrated Analysis 
Plan will be performed only after the last participant has completed the last visit, i.e., Follow 
Up/End of Study visit, with all study data inhouse, all data queries resolved, and the database 
locked.
Statistical analyses will be performed based on CDISC SDTM as well as ADaM data. 
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A data review meeting will be held prior to any database lock. In addition, no database can be 
locked, and no randomization code should be unblinded until this IAP has been approved, please 
refer to the latest version of unblinded plan for more details.
7
Changes to the Planned Analyses in the Clinical Study
Protocol
The definition of cured/not cured participants has been updated as follows:
Cured: Negative qPCR outcome throughout the study period are referred as cured. A participant
with a solitary (single) positive qPCR that is not confirmable in subsequent qPCR tests and 
remains < 100 /mL and not used rescue medication within 28 days of PfSPZ challenge is also 
to be classified as cured.
Not-cured: Participants with documented blood stage parasite growth defined as an increase of 
qPCR measured asexual parasites per mL compared to the first positive parasitemia 
measurement (equal or greater than 100 asexual parasites per mL of blood) within 28 days of 
PfSPZ challenge or if a participant receives rescue medication within 28 days of PfSPZ 
challenge are referred to as not-cured.
8
Analysis Populations and Subgroups
8.1
Definition of Analysis Populations
The final decision to exclude participants from any analysis population will be made during a 
blinded data review meeting prior to database lock and unblinding.
Screening Analysis Population (SCR)
All participants who provided informed consent, regardless of the participant’s randomization and 
study intervention status in the study.
Intention-To-Treat Analysis Population (ITT)
All participants, who were randomized to study intervention (M5717 or Placebo). Analyses 
performed on the ITT population will consider participants’ allocation to study intervention groups 
as randomized.
Safety Analysis Population (SAF)
All ITT participants, who have been inoculated using a DVI of PfSPZ and who were administered 
one dose of study intervention (M5717 or placebo).
All Safety analyses will be based on this analysis set. Analyses will consider participants as treated.
Per Protocol Analysis Population (PP)
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All SAF participants who comply with the protocol and meet no criteria that could impact the 
proper evaluation of key objectives of the study (as mentioned in this Integrated Analysis Plan 
section 5 and approved at the Blind Data Review Meeting). Participants who meet one of the 
following criteria will be excluded from the PP population:

Incorrect study intervention group allocation, different to assignment at randomization.
All Efficacy analyses will be based on this analysis set.
Pharmacokinetic Analysis Population (PK)
All participants, who receive one dose of M5717, have no clinically important protocol deviations 
or important events affecting PK, and provide at least one measurable postdose concentration. 
Participants will be analyzed per the actual study intervention they received. All PK analyses will 
be based on the PK analysis set.
Note: Important events which are affecting the PK will be identified on a case by case basis.
The following table summarizes the use of the analysis sets in the different analyses. 
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Analysis Population
Analyses
Screening 
Analysis 
Population 
(SCR)
Intention-To-
Treat Analysis 
Population
(ITT)
Safety 
Analysis 
Population
(SAF)
Per Protocol 
Analysis 
Population
(PP)
Pharmacokinetic
Analysis
Population
(PK)
Disposition of Participants 
and Discontinuations

Important Protocol 
Deviations

Demographics and Other 
Baseline Characteristics


Medical History

Previous or Concomitant 
Medications/Procedures

Study Treatment: Compliance 
and Exposure

Primary Efficacy Analysis 
(Positive Parasitemia, Time to 
Parasitemia, Documented 
blood stage parasite growth 
and Malaria Score)

Safety and Tolerability 
(Adverse Events, Clinical 
Laboratory Evaluation, Vital 
Signs, 12 Lead 
Electrocardiogram (ECG) and 
Physical Examination)

Pharmacokinetics (PK)

PK/PD-exposure-relationship
modelling

8.2
Subgroup Definition and Parameterization
Not Applicable.
9
General Specifications for Data Analyses
Unless otherwise indicated, all the analyses summary table will be presented by pooled placebo, 
M5717 dose groups and its total and overall total. Cohort 1-4 i.e. Early Liver Stage will be 
combinedly presented and analyzed. Cohort 5 i.e.  Late Liver Stage will be presented and analyzed 
separately. 
The Treatment will be labeled as mentioned below:

Pooled Placebo

M5717 200 mg
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
M5717 100 mg

M5717 60 mg

M5717 30 mg

M5717 xxx mg

All M5717 Doses

Overall= Pooled Placebo + All M5717
The listings will be presented by treatment and participants. All participants will be included in 
individual participant data listings. All derived data will also be listed.
No formal statistical hypothesis testing will be performed. Missing data will not be imputed. A
participant who withdraws prior to the last planned observation in a study period will be included
in the analyses up to the time of discontinuation.
Study intervention groups are defined and labelled as M5717 xxx mg and Placebo.
9.1
Presentation of continuous and qualitative variables
Unless otherwise specified, the below mentioned continuous variables will be summarized using
descriptive statistics, i.e.

number of non-missing observations,

mean, standard deviation,

median, 25th percentile, 75th percentile (Q1, Q3),

minimum and maximum.
Unless otherwise specified, the qualitative variables will be summarized by frequencies and
percentages.
Unless otherwise stated, the calculation of proportions will be based on the number of participants
of the analysis population of interest. Therefore, counts of missing observations will be included
in the denominator and presented as a separate category.
For reporting the descriptive statistics “Merck BOA-General Output Specification” guideline will 
be followed.
For the creating the mock-shells “Merck BOA TLFs Template” will be followed 
Descriptive statistics by nominal visit or time point, e.g. for laboratory measurements, will include
only data from scheduled visits. Unscheduled visits will be presented in listings.
The compiled final file will be presented which include overall analysis in PDF format with TOC 
for listing and table/figures. The single output files of Table, Listing and Figures will be
provided for overall final analysis in RTF and PDF files using the SAS® Output Delivery 
System (ODS).
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9.2
Presentation of Study Visits
The study analysis visits for early and late liver stage, i.e., cohort 1-5 will be presented as 
mentioned below:

For analyses, for all participants: Study Day = Study Intervention Day = Day 1 for both 
scenarios Screening (Early Liver Stage: Study Day -28 to -2; Late Liver stage: Study Day 
-33 to -6

Analysis visits will be presented in table/listings/figures for baseline visit as “Baseline” 
and for remaining visits as “Study Day X” format.

End of the Study visit will be presented as “End of the Study
For the PK Data analysis, schedule and actual timepoints will be presented in table/listings/figures
as mentioned below,

Pre-dose

x  
Here, Pre-dose means 0-hour timepoint before administration of study intervention (M5717 or 
Placebo) and for remaining timepoints, X represents the time in hours. For example: 0.5.
9.3
Definition of Baseline and Change from Baseline
The last non-missing measurement prior to the study intervention (M5717 or Placebo). 
administration, including scheduled and unscheduled results (if necessary, Example, for laboratory 
data when the re-test is needed, etc.) will serve as the baseline measurement.
Change from baseline = visit value – baseline value
Note: If baseline observation is missing then respective participant’s change from baseline will not 
be calculated.
9.4
Definition of Duration and ‘time since’ Variables
Durations in days will be calculated by the difference of start and stop date + 1 (e.g. time to 
parasitemia (days) = date of first qPCR outcome equal or greater than 100 asexual parasites per 
mL of blood – date of PfSPZ DVI + 1) if not otherwise specified.
The time since an event (e.g. time since first diagnosis) will be calculated as reference date minus 
date of event.
9.5
Definition of End of the Study
A participant has completed the study if he/she has completed all study parts, including the last 
study visit (End of Study visit).
The end of the study is defined as the date of the last visit of the last participant.
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9.6
Imputation of Missing Data
Unless otherwise specified all data will be evaluated as observed, and no imputation method for 
missing values will be used.
In all participant data listings, imputed values will be presented, and imputed information will be 
flagged.
Missing statistics, e.g. when they cannot be calculated, should be presented as not determined. 
“nd”. For example, if n=1, the measure of variability (SD) cannot be computed and should be 
presented as “nd” and if n=0 then all the summary statistics left blank.
If required for an analysis, incomplete start and stop date (as appropriate) fields will be imputed. 
The whole missing date will not be imputed for this study and only partial date imputation will be 
performed. Conventions pertaining to partial dates are presented below:
Adverse events
Partial AE start and stop dates will be imputed as follows:
Imputation for AE start date:

If AE start day is missing and AE start month = Treatment start month 
and AE start year = treatment start year, then AE start day= minimum 
of (treatment start day and AE end day) Otherwise AE start day=01

If AE start day and month is missing and AE start year = treatment start 
year, then AE start day and month = minimum of (treatment start day 
and month or AE stop day and month) Otherwise AE start day and 
month = “01 Jan”

For missing AE start day, month, and year no imputation will be 
performed.
Imputation for AE stop date:

If AE stop day is missing and AE stop month = study conclusion month 
and AE stop year =study conclusion year, then AE stop day =study 
conclusion day Otherwise AE stop Day = last day of respective month

If AE stop day and month is missing and AE stop year =study 
conclusion year, then AE stop day and month= study conclusion day 
and month Otherwise AE stop day = last day of respective month and 
AE stop month = last month of the year

For missing stop day, month, and year no imputation will be performed.
9.7
Software(s)

Non-compartmental computation of PK parameters will be performed using the computer 
program Phoenix® WinNonlin® version 6.4, or higher (Certara, L.P., 1699 S Hanley Road, St 
Louis, MO 63144, USA).
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
The statistical software to be used is SAS® (Statistical Analysis System, SAS-Institute, Cary,
NC, USA, windows version 9.1 or higher).

PK/PD modeling will be performed using NONMEM 7. (version 7.3.0 or higher) and/or R 
3.5.1 or higher.
10
Study Participants
The subsections in this section include specifications for reporting participant disposition and 
study treatment/study discontinuations. Additionally, procedures for reporting protocol deviations 
are provided.
10.1
Disposition of Participants and Discontinuations
Total number of screened participants (i.e., participants who gave informed consent).
Number of participants who discontinued from the study prior to randomization (as applicable), 
with reason of discontinuation (including COVID-19-related and COVID-19-non-related).
Number of randomized participants (use as denominator for percentages calculation for the 
categories below)
Number of participants who received DVI
Number of randomized participants who did not receive dose (as applicable)
Number of treated participants
Number of treated participants who completed the study
Number of treated participants who discontinued the study with the reason of discontinuation
(including COVID-19-related and COVID-19-non-related)
Number of participants in the SCR, ITT, SAF, PP and PK analysis population.
The number and percentage of participants in each of the above disposition categories will be
presented in table and corresponding individual listings for the study termination status, study 
entry (including screening failure), randomization and discontinued participants with their reason 
for withdrawal will be presented.
10.2
Protocol Deviations / Exclusion from Analysis Populations
10.2.1
Important Protocol Deviations
Important protocol deviations are protocol deviations that might significantly affect the
completeness, accuracy, and/or reliability of the study data or that might significantly affect a
participant's rights, safety, or well-being.
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Important protocol deviations included but not limited:
Participants that are dosed on the study despite not satisfying the inclusion or meeting the
exclusion criteria, i.e. any inclusion/exclusion criteria violations.
Participants that develop withdrawal criteria whilst on the study but are not withdrawn
Participants that receive an excluded concomitant medication
Deviation from Good Clinical Practice (GCP)
PK Samples and assessments obtained outside the allowed time window (see Table 5 in
protocol) from dosing will be captured as a minor protocol deviation, if the exact time of the
assessment/sample collection is noted on the source document and data collection tool (e.g.,
eCRF).
Important protocol deviations documented in the SDTM DV dataset whether identified through 
sites monitoring, medical review or programming.
The listing of important protocol deviations by treatment, participant and date of deviation, will 
be provided based on the ITT analysis population.
Specific to PK:
Clinically important protocol deviations or important events that might have an effect on PK 
include, but may not be limited to and will be identified on case-by case basis, the following:
Adverse events, diarrhea etc. (these instances will be discussed on a case-by case basis)
Vomiting after administration following oral dosing (these instances will be discussed in 
alignment with applicable regulatory guidelines on a case-by case basis)
Sample processing errors that may lead to inaccurate bioanalytical results
Inaccurate dosing or dosing errors (e.g. dose administration delayed, dose change or missed 
doses)
Pre-dose sample collected after the actual start of dosing
Concomitant medication violations
Should one or more of these events be available at the Data Review Meeting, its implication for 
PK evaluation will be discussed and agreed amongst relevant study team members (e.g. Sponsor 
Clinical Pharmacology/Biostatistics/Clinical Pharmacokinetics & Pharmacodynamics team 
representative).
10.2.2
Reasons Leading to the Exclusion from an Analysis 
Population
For participants excluded from the PP, PK analysis population, the reasons for exclusion will be
listed by the SAF analysis population:
Listing of reasons of exclusion from analysis population and which contain the participants 
included in respective analysis population (yes/no) and respective analysis population exclusion 
reason.
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11
Demographics and Other Baseline Characteristics
11.1
Demographics
The below mentioned demographic characteristics will be summarized and listed as appropriate
from the Screening/Baseline Visit eCRF pages.
Sex: male, female, undifferentiated
Race: white, black or African American, Asian, American Indian or Alaska Native, native
hawaiian or pacific islander, not collected at site, other
Note: “Multiple” Category will also be added for race variable in the table.
Ethnicity: hispanic or latino, not hispanic or latino
Year of birth
Age (in years) at screening
Weight (kg) at screening
Height (cm) at screening
BMI (kg/m2) at screening
Serum Pregnancy test
The demographic characteristics table will be presented, and listings will be presented for ITT and 
SAF analysis population.
11.2
Medical History
The medical history will be captured from the “Medical History” eCRF page, using the MedDRA, 
version as mentioned in the Data Management Plan (DMP).
The listings will be presented by treatment, participant, start date of medical history and 
alphabetically for primary System organ class and preferred term within each primary system 
organ class for SAF analysis population.
12
Previous or Concomitant Medications/Procedures
Previous medications defined as, any medication discontinued prior to the IMP administration (i.e. 
start and end date less than the IMP administration date.
Concomitant medications defined as, any medication taken duration the course of the study, with 
a starting date greater than or equal to the IMP administration date, or with a starting date prior to 
the IMP administration and ongoing at the time of IMP administration.
All the previous and concomitant medication will be listed by treatment, participants and 
alphabetically Anatomical Therapeutic Chemical (ATC) term 2nd level and preferred term using 
SAF analysis population.
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Analysis
(Analysis 
Population)
Derivation
Statistical Analysis Methods
Missing data 
handling
The qPCR results 
(aPf/mL) will be taken 
from the eCRF 
“Parasitemia by qPCR” 
page.
PROC LIFETEST (SAS® Version 9.4 or above) 
will be used to analyze the response rates (cured
vs. not cured). With the CENSOR variable, 1 is 
for censored observations (i.e. negative 
parasitemia); and 0 indicates the event occurred
(positive parasitemia). For censored observations 
(CENSOR=1), the time variable value is the 
number of days from PfSPZ DVI to censoring, 
i.e., the minimum of the latest negative parasite 
measurement date and Day 28; for observations 
with CENSOR=0, the time variable value is the
number of days from PfSPZ DVI to first positive 
parasitemia within Day 28.
Kaplan-Meier curves and median estimates
calculated using log-rank test (with 95% CI) of the 
time from DVI PfSPZ to positive parasitemia will 
be presented and compared by each M5717 
doses versus Pooled Placebo.
Spaghetti plots will be created based on qPCR 
data for each M5717 dose versus Pooled 
Placebo.
Primary endpoint: Number of participants with documented blood stage parasite growth, defined as an 
increase of qPCR measured asexual parasites per mL compared to the first parasitemia measurement,
within 28 days of PfSPZ DVI
Analysis 
Population: PP
Documented blood stage 
parasite growth is defined 
as increase of qPCR 
measured asexual 
parasites per mL 
compared to the first 
parasitemia 
measurement (i.e. Date 
of DVI PfSPZ).
The qPCR results 
(aPf/mL) will be taken 
from the eCRF 
“Parasitemia by qPCR” 
page.
No hypothesis testing will be performed. 
The response is binary: Response= 1: if Increase 
of qPCR measured asexual parasites per mL 
compared to the first parasitemia measurement
within 28 days of PfSPZ DVI. Othewise, 
Response = 0
The number and proportion (%) of participants 
with documented blood stage parasite growth
and the exact 95 % confidence interval of the 
proportion (%) based on Clopper Pearson 
Method will be presented by each M5717 doses 
and Pooled Placebo.
The PROC FREQ procedure in SAS will be used 
with the appropriate BINOMIAL and EXACT 
statements for the proportion and corresponding 
95% CIs.
No imputation 
will be done
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Analysis
(Analysis 
Population)
Derivation
Statistical Analysis Methods
Missing data 
handling
Primary endpoint: Overall Cured/Not Cured Status:
Analysis 
Population: PP
The qPCR results 
(aPf/mL) will be taken 
from the eCRF 
“Parasitemia by qPCR” 
page.
The response is binary: 
Cured= 1: Negative qPCR outcome throughout 
the study period are referred as cured. A 
participant with a solitary (single) positive qPCR 
that is not confirmable in subsequent qPCR tests 
and remains < 100 /mL and not used rescue 
medication within 28 days of PfSPZ challenge is 
also to be classified as cured.
Not Cured = 0: Participants with documented 
blood stage parasite growth defined as an 
increase of qPCR measured asexual parasites 
per mL compared to the first positive parasitemia 
measurement (equal or greater than 100 asexual 
parasites per mL of blood) within 28 days of 
PfSPZ challenge or if a participant receives 
rescue medication within 28 days of PfSPZ 
challenge are referred to as not-cured.
The number (%) of participants with cured/ not 
cured status and the exact 95 % confidence 
interval of the proportion (%) of cured participants 
based on Clopper Pearson Method will be 
presented by each M5717 doses and Pooled 
Placebo.
The PROC FREQ procedure in SAS will be used 
with the appropriate BINOMIAL and EXACT 
statements for the proportion and corresponding 
95% CIs.
No imputation 
will be done
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Analysis
(Analysis 
Population)
Derivation
Statistical Analysis Methods
Missing data 
handling
Primary endpoint: Clinical symptoms of malaria using the Malaria Clinical Score.
Analysis 
Population: PP
The list of malaria 
symptoms for calculating 
the malaria clinical score 
is provided (Refer to the 
protocol Appendix 6).
Each observed clinical 
symptom of malaria will 
have below four 
categories:

Absent (0)

Mild (1)

Moderate (2)

Severe (3)
The malaria clinical score 
will be calculated using 
the sum of all observed 
symptoms clinical 
categories and the 
maximum malaria clinical 
score is 42.
The Malaria Clinical score 
will be taken from the 
“Malaria Clinical Score 
Assessment” eCRF page.
The below mentioned summary will be presented 
for the malaria clinical score:

By symptoms (i.e., for each symptoms): 
number and percentage of participants 
within each category (absent, mild, 
moderate, severe) by visit.

Total Score: Descriptive statistics by 
visit.
The listing will be presented.
No imputation 
will be done
Primary endpoint: Dose-exposure-response relationship of a single oral dose of M5717 administered after 
DVI of PfSPZ challenge, selected pharmacokinetic (PK) endpoints/ concentrations (e.g. AUC0-24, AUC0-
168, C24, C168) and pharmacodynamic (PD) endpoints (cured/not-cured) will be used for PK/PD modeling
approaches.
Analysis 
Population:
SAF
Refer to the section 16.2
Refer to the section 16.2
No imputation 
will be done
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15
Safety and Tolerability Analyses
The safety assessment is as follows,
Adverse events (AEs)
Safety laboratory parameters
Vital signs
12-lead safety ECGs
Physical Examination
Safety analyses will be done on the SAF analysis population.
15.1
Adverse Events
Adverse Events (AEs) will be coded using MedDRA central coding dictionary, Version (refer the
DMP for dictionary version). Details on AEs will be recorded on eCRF page “Adverse Events”.
The AEs and SAEs reporting period for safety surveillance begins when the participant is initially 
included in the study (date of first signature of informed consent/date of first signature of first 
informed consent) and continues until the End of Study Visit.
Treatment-emergent adverse events (TEAE) are those events with onset date and time occurring 
on or after the treatment administration date or events that worsen after treatment administration
date and time. Any AE occurring before the IMP administration and resolved before IMP 
administration or not worsening after IMP administration will be included in the AE listings, but 
will not be included in the summary tables (unless otherwise stated). These will be referred to as 
“pre-treatment” AEs.
Adverse events related to study treatment are those events with relationship to the investigations 
medicinal product is related based on the adverse event eCRF page.
The pre-treatment AEs, TEAEs and Serious TEAEs will be provided in the listing separately and 
sorted by treatment, participant, start date of adverse event and alphabetically for primary system 
organ class and preferred term within each primary system organ class.
Each participant will be counted only once within each SOC or PT. If a participant experiences 
more than one AE within a SOC or PT for the same summary period, only the AE with the strongest 
relationship or the worst severity, as appropriate, will be included in the summaries of relationship 
and severity. 
For the analysis if required the incomplete date or date/time fields for the adverse events will be 
imputed as mentioned in the section 9.6 in this IAP.
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15.1.1
All Adverse Events
The below overall summary of TEAEs table will include the number and percentage of participants 
with each of the following:
TEAEs
TEAEs, [by severity (Mild (Grade 1), Moderate (Grade 2) and Severe (Grade 3)]
TEAEs related to study intervention (M5717 or Placebo)
TEAEs related to study intervention (M5717 or Placebo), [by severity (Mild (Grade 1), 
Moderate (Grade 2) and Severe (Grade 3)]
Serious TEAEs
Non-Serious TEAEs
Serious TEAEs related to study intervention (M5717 or Placebo)
TEAEs leading to death
TEAEs related to study intervention (M5717 or Placebo) leading to death
TEAEs leading to study discontinuation
The below overall summary of AEs related to DVI table will include the number and percentage 
of participants with each of the following:

AEs related to DVI

AEs related to DVI, [by severity (Mild (Grade 1), Moderate (Grade 2) and Severe (Grade 3)]

Serious AEs related to DVI
Note: For AEs related to DVI tables, all AEs related to DVI occurring before/after study 
intervention administration (M5717 or Placebo) will be considered.
The following summary tables will be provided for TEAEs and sorted by alphabetically for 
primary system organ class and preferred term within each primary system organ class along with 
statistics: number of participants, percentage, and number of events:
TEAEs
TEAEs related to study intervention (M5717 or Placebo)
TEAEs by severity
TEAEs related to study intervention (M5717 or Placebo) by severity
TEAEs leading to subject withdrawal
TEAEs leading to death
TEAEs related to study intervention (M5717 or Placebo) leading to death
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The following summary tables will be provided for AEs related to DVI and sorted by 
alphabetically for primary system organ class and preferred term within each primary system organ 
class along with statistics: number of participants, percentage, and number of events:
AEs related to DVI
15.2
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events
15.2.1
Deaths
The below mentioned deaths information will be tabulated from the “Death” page of CRFs and 
provided in the summary table.
Number of Deaths
Primary Reason of Death (Progressive disease and/or disease related condition, Event unrelated 
to study treatment, Unknown)
15.2.2
Serious Adverse Events
The following overall frequency tables will be prepared for serious treatment emergent serious 
adverse events (serious TEAEs) and sorted by alphabetically for primary system organ class and 
preferred term within each primary system organ class: 
Serious TEAEs
Serious TEAEs by severity
Serious TEAEs related to study intervention (M5717 or Placebo)
Serious TEAEs related to study intervention (M5717 or Placebo) by severity
The listings of SAEs will also be provided.
15.3
Clinical Laboratory Evaluation
Clinical laboratory data will be taken from the Hematology, Biochemistry, Urinalysis and 
Coagulation) eCRF pages. The Safety laboratory data (including Hematology, Biochemistry, 
Urinalysis, Coagulation) will be summarized in table as absolute values and changes from baseline 
to each visit over time for quantitative data and for qualitative data as frequency and percentages
as appropriate. Coagulation data will be captured on screening (Day -28 to -2/-6) visit only. 
Box-and-whisker plots for the absolute change from baseline by visit, treatment M5717 doses and 
pooled placebo.
Listings and summary statistics at each assessment time will be presented using the Système 
International (SI) units. Normal ranges will be provided by the central laboratory, and out of range 
flags will be calculated based on the normal ranges.
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All the clinical laboratory data will be provided in the listing and sorted by treatment, laboratory 
test, date of test and visits of each participants. the abnormal laboratory values outsides the normal 
ranges will be flagged in the data listings along with corresponding normal ranges Any out-of-
range values that are identified by the investigator as being clinically significant will be shown in 
a data listing. Listings of abnormal test results (low and high) will be provided. For the allowed 
time windows for scheduled time points for the laboratory parameter see the protocol section 1.3 
(Table 5).
The below mentioned clinical laboratory (Hematology, Coagulation, Biochemistry, Urinalysis) 
parameters will be used for analysis:
Hematology: 
[Hemoglobin (mmol/L), Hematocrit (L/L), Erythrocytes (RBC) count (10^12/L), 
Reticulocytes (10^9/L), Platelet count (10^9/L), Mean Corpuscular Volume (MCV) (fL), 
Mean Corpuscular Hemoglobin (MCH) (fL), Mean Corpuscular Hemoglobin 
Concentration (MCHC) (mmol/L), Neutrophils (10^9/L), Lymphocytes (10^9/L), 
Monocytes (10^9/L), Eosinophils (10^9/L), Basophils (10^9/L)]

Biochemistry:
[Aspartate Aminotransferase (AST)  (U/L), Alanine Aminotransferase (ALT)  (U/L), 
Alkaline phosphatase  (U/L), Gamma-glutamyl-transferase (GGT)  (U/L),  Lactate 
dehydrogenase (U/L), Creatine phosphokinase (CPK)  (U/L), Total Protein (g/L), 
Albumin (g/L), Bilirubin (total) (µmol/L), hs Troponin T (ng/L), Amylase (U/L), Lipase 
(U/L), Uric acid (mmol/L), Blood Urea Nitrogen (mmol/L), Blood Urea Nitrogen 
(mmol/L), Creatinine (umol/L), Glucose (fasting) (mmol/L), Sodium (mmol/L), 
Potassium (mmol/L), Chloride (mmol/L), Calcium (mmol/L), Magnesium (mmol/L), 
Bicarbonate (mmol/L), Phosphate (mmol/L)]
Urinalysis:
[Urine Glucose (mmol/L), Urine Bilirubin, Urine Ketone (mmol/L), Urine Specific gravity, 
Urine Blood (ery/ul), Urine pH, Urine Protein (g/L), Urine Urobilinogen (umol/L), Urine 
nitrite, Urine leucocytes (leuco/ul), Urine - Erythrocytes (RBC), Urine - Leukocytes (WBC), 
Urine - Epithelial Cells, Urine – Bacteria, Urine – Crystals, Urine - Casts]
Coagulation:
[Prothrombin time (sec), Activated partial thromboplastin time (sec), International 
Normalized Ratio (INR) (Ratio)]
All the above laboratory parameters having lab original units as per eCRF and these units will be 
converted into Système International (SI) units at the time of programming. Both original units 
and SI units will be provided in the SDTM domain.
For all the safety laboratory results in case if we have < or > symbol with result value then < or > 
symbol will be removed and will use only the numeric result values. Example: If Hemoglobin 
(mmol/L): < 20 then in worse case scenario it will be considered as 20.
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15.4
Vital Signs
Vital signs including Systolic blood pressure (mmHg), Diastolic blood pressure (mmHg), Pulse 
(beats/min), Respiratory rate (breaths/min) and Temperature (in C) will be assessed according to 
the trial schedule and taken from “Vital Signs” eCRF pages.
Vital signs parameters will be summarized absolute values and changes from baseline to each visit 
over time. The listing will be provided by treatment, vital signs parameter, date of test and visits 
of each participants and abnormal values will be flagged in the listing (Please use the section 18.2
(Appendix 2) reference ranges to identify the abnormal vital signs values).
For the allowed time windows for scheduled time points for the vital sign parameters see the 
protocol section 1.3 (Table 5).
15.5
12 Lead Electrocardiogram (ECG)
12-lead ECG including Heart rate (bpm), PR duration (msec), QRS duration (msec), QT duration 
(msec) and the results of ECG (i.e., normal, abnormal not clinically significant and abnormal 
clinically significant) will be assessed according to the trial schedule and taken from “12-lead 
ECG” eCRF page.
12-lead ECG parameters will be summarized absolute values and changes from baseline to each 
visit over time. The listing will be provided by treatment, 12-lead ECG parameter, date of test and 
visits of each participants and abnormal values will be flagged in the listing (Please use the section 
18.2 Appendix 2 reference ranges to identify the abnormal 12-lead ECG values).
For the allowed time windows for scheduled time points for the 12-lead ECG parameters see the 
protocol section 1.3 (Table 5).
15.6
Physical Examination
The abnormal physical examination will be recorded as medical history and adverse event. For the
physical examination data, no separate listing/table will be presented.
15.7
COVID-19 Impact
The listing will be presented COVID-19 related protocol deviations separately.
16
Analyses of Other Endpoints
16.1
Pharmacokinetics
Blood samples for measurement of M5717 concentrations in whole blood will be collected at the 
assigned time points as per protocol. Metabolite concentrations, as applicable, may also be 
measured in blood samples. Remaining samples collected for measurement of M5717 may also be 
used to evaluate metabolites or used for testing of bioanalytical standards.
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Actual date and time of the PK sampling, as well as date/time of drug administration, will be 
recorded in the eCRF. Samples and assessments obtained outside the allowed time window See 
the protocol section 1.3 (Table 5) from dosing will be captured as a minor protocol deviation, if 
the exact time of the assessment/sample collection is noted on the source document and data 
collection tool (e.g., eCRF). If sample collection within or outside the allowed time window, then 
scheduled timepoints will be used at the time of analysis. For participants randomized to placebo 
treatment, no PK samples will be analyzed unless deemed necessary by the Investigator and/or 
Sponsor. Details on blood sample collection, preparation for processing, and shipment was
specified in a separate Laboratory Manual (Latest version).
All the pharmacokinetic analysis will be based on the PK analysis population.
16.1.1
Descriptive Statistics of PK Concentration Data
PK measurements will be descriptively summarized using: number of non-missing observations 
(n), number of missing observations, arithmetic mean (Mean), standard deviation (SD), median 
(Median), minimum (Min), maximum (Max) and coefficient of variation (CV%).
Descriptive statistics will only be calculated for n>2 in which a measurement of <LLOQ represents 
a valid measurement and Values below the lower level of quantification (LLOQ) will be taken as 
zero for descriptive statistics of PK concentrations.
Descriptive statistics of PK concentration data will be calculated using values with the same 
precision as the source data and rounded for reporting purposes only.
The following conventions will be applied when reporting descriptive statistics of PK 
concentration data:
Mean, Min, Median, Max: 
3 significant digits
SD
4 significant digits
CV%:
2 decimal places
16.1.2
Descriptive Statistics of PK Parameter Data
PK parameter data will be descriptively summarized using: number of non-missing observations 
(n), arithmetic mean (Mean), standard deviation (SD), coefficient of variation (CV%), minimum 
(Min), median (Median), maximum (Max), geometric mean (GeoMean), the geometric coefficient 
of variation (GeoCV) and the 95% confidence interval for the GeoMean (LCI 95% GM, UCI 95% 
GM). For time to reach maximum observed concentration (tmax), only n, Min, Median, and Max 
will be reported.
Descriptive statistics will only be calculated for a PK parameter when n>2.
PK parameters read directly from the measurements (i.e., Cmax) will be reported with the same 
precision as the source data. All other PK parameters will be reported to 3 significant figures. In 
export datasets, as well as in the Derived PP dataset for SMC, PK parameters will be provided
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with full precision and will not be rounded. Descriptive statistics of PK parameter data will be 
calculated using full precision values and rounded for reporting purposes only.
The following conventions will be applied when reporting descriptive statistics of PK parameter 
data:
Mean, Min, Median, Max, GeoMean, 95% CI: 
3 significant digits
SD:
4 significant digits
CV%, GeoCV%:
2 decimal places
16.1.3
General Specifications for PK Concentration and PK 
Parameter Data Handling
Pre-dose samples which have been taken after the subsequent dosing with M5717 will be reported 
as protocol deviation. The resulting concentrations will be included in concentration listings but 
excluded from descriptive statistics of concentrations and from PK parameter estimation of the 
previous PK profile. This concentration could be included in the subsequent PK profile decided 
on a case-by case decision.
Values below the lower limit of quantification of the assay (LLOQ) will be taken as zero for 
summary statistics of PK concentration data, PK parameter estimation (e.g., AUC etc.) and for 
graphical presentations.
Missing concentrations (e.g., no sample, insufficient sample volume for analysis, no result or result 
not valid) will be reported and used generally as “N.R.”. A participant who withdraws prior to the 
last planned observation will be included in the analyses up to the time of discontinuation.
Any PK concentrations or PK parameters excluded from summary statistics will be included in 
participant listings and flagged.
PK concentrations and PK parameters excluded from summary statistics will not be included in 
individual and mean figures. Mean plots will only contain averages when n>2.
16.1.4
Estimation of Pharmacokinetic Parameters
Plasma concentrations will be tabulated and summarized using descriptive statistics. PK 
parameters will be calculated if possible, as appropriate for the respective sampling schemes. All 
PK parameters will be calculated using standard non compartmental methods and the actual 
administered dose. Calculations will be performed using a validated software tool as described 
below.
The following PK parameters will be calculated, when appropriate:
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Table 2
PK parameters
Symbol
Definition
AUC0-tlast
Area under the blood concentration-time curve (AUC) from time 
zero to the last sampling time at which the concentration is at or 
above LLOQ, calculated according to the mixed log linear 
trapezoidal rule (i.e., linear up, log down)
AUC0-∞
The AUC from time zero (dosing time) extrapolated to infinity, 
based on the predicted value for the concentration at tlast, as 
estimated using the linear regression from λz determination. 
AUC0-∞= AUC0-tlast +Clast pred/ λz
AUC0-24
The AUC from time zero (= dosing time) to 24 hours post dose. 
Calculated using the mixed log linear trapezoidal rule (linear up, 
log down) using the nominal dosing interval. The actual dosing 
interval calculated from CRF time data should not be used.
AUC0-168
The AUC from time zero (= dosing time) to 168 hours post dose. 
Calculated using the mixed log linear trapezoidal rule (linear up, 
log down) using the nominal dosing interval. The actual dosing 
interval calculated from CRF time data should not be used.
Cmax
Maximum blood concentration observed
C24
Blood concentration at 24 hours
C168
Blood concentration at 168 hours
tmax
Time to reach the maximum blood concentration (1st occurrence 
in case of multiple/identical Cmax values)
t1/2
Apparent terminal half-life, calculated as ln2/λz
λz
Terminal first order (elimination) rate constant. Determined 
from the terminal slope of the log-transformed concentration 
curve using linear regression on terminal data points of the curve
CL/f
Total body clearance of drug from blood following oral 
administration, calculated as Dose/ AUC0-∞
The predicted AUC0-∞should be used.
Vz/f
Apparent volume of distribution during the terminal phase 
following extravascular administration. The predicted AUC0-∞
should be used.
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AUCextra%
The AUC from time tlast extrapolated to infinity given as 
percentage of AUC0-∞.
AUC0-tlast/ Dose
The Dose normalized AUC from time zero to the last sampling 
time (tlast) at which the concentration is at or above the lower 
limit of quantification. Normalized using the actual dose, using 
the formula AUC0-tlast /Dose.
AUC0-∞/Dose
The Dose normalized AUC from time zero extrapolated to 
infinity. Normalized using actual dose and AUC0-∞using the 
formula AUC0-∞/Dose.
Cmax/Dose
Dose-normalized Cmax
LLOQ=lower limit of quantification, CRF=case report form.
PK parameters will be evaluated and listed for all participants who provide sufficient concentration 
time data.
Estimation of Individual PK Parameters:
Pharmacokinetic parameters will be calculated by TCD and overseen by the Clinical PK/PD 
Group of Quantitative Pharmacology, Merck Healthcare KGaA, Darmstadt, Germany, using 
standard non-compartmental methods and the actual administered dose. PK parameters will be 
calculated using the actual timepoint since dosing, given with a precision of 14 significant digits
or the SAS format Best12. When the actual sampling time is missing, calculations will be 
performed using the scheduled time. Otherwise, there will be no further imputation of missing 
data.
Non-compartmental computation of PK parameters will be performed using the computer 
program Phoenix® WinNonlin® version 6.4, or higher (Certara, L.P., 1699 S Hanley Road, St 
Louis, MO 63144, USA).
The statistical software to be used is SAS® (Statistical Analysis System, SAS-Institute, Cary, 
NC, USA, windows version 9.1 or higher) may be used to produce tables, listings and figures, 
if appropriate.
16.1.5
Presentation of PK Concentration and PK Parameter Data 
Listing of all the PK concentrations data and the PK parameter data by cohort/dose/participants 
will be provided using subject IDs.
Individual concentration versus time plots will be provided.
16.1.5.1
Listings and Tables
The following PK tables will be produced:
Document No. 
Object No. 
Global Version ID: 
CCI
CCI
CCI


M5717
Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model
MS201618-0003
Version 1.0
C O N F I D E N T I A L
I N F O R M A T I O N
32/34
Individual PK concentrations with descriptive statistics by time points and each cohort/dose
and Overall (Sum of all cohort participants).
Individual estimated PK parameters with descriptive statistics by PK parameters and each 
cohort/dose (treatment M5717) and Overall (Sum of all cohort participants).
Individual dose normalized PK parameters with descriptive statistics by dose normalized PK 
parameters and each dose cohort (treatment M5717) and Overall (Sum of all cohort participants)
The PK concentration estimated PK parameters and dose normalized PK parameters will be 
presented.
The Phoenix WinNonlin NCA Core Output will be provided in a separate listing.
16.1.5.2
Graphical Summaries and Individual plots (PK Analysis 
Population)
Individual concentration versus time plots; linear and semi-log; using the time points on x axis and 
concentration on y axis by participants and cohort.
Overlaid individual concentration versus time plots; linear and semi-log; using the time points on 
x axis and concentration on y axis by cohort.
Mean concentration time plots i.e. (Mean±SD concentration-time curves); linear and semi-log ; 
using the time on x axis and mean response ± SD for linear and only mean response for semi-log
on y axis using scheduled (nominal) time points by cohort. Error bars should be included only in 
the linear plots.
Scatter Plots using subject IDs: For PK parameters: Cmax, C24, C168, AUC0-tlast, AUC0-inf, AUC0-
24, AUC0-168 and dose normalized PK parameters (AUC/Dose and Cmax/Dose) (including 
regression line not forced through 0), using the respective PK and dose-normalized PK parameter 
data on y axis and dose on x axis and with group by dose levels.
Boxplots for PK parameters (Cmax, C24, C168, AUC0-tlast, AUC0-inf, AUC0-24, AUC0-168) and dose-
normalized PK parameters (AUC0-tlast/Dose, AUC0-inf/Dose and Cmax/Dose), Using the respective 
PK and dose-normalized PK parameter data on y axis and dose on x axis with group by dose level.
16.2
Pharmacokinetics 
(PK) 
and 
Pharmacodynamics 
(PD) 
Relationships
The PK/PD modeling is a part of primary endpoint and will be used to explore the dose-exposure-
response relationship of a single oral dose of M5717 administered after DVI of PfSPZ challenge 
in healthy participants. The analysis will be performed by OCCAMS and overseen by the Merck 
Pharmacometrician based on the SAF analysis population.
The influence of PK exposure metrics on response will be assessed using logistic regression.
The logistic regression model is as follows:
Document No. 
Object No. 
Global Version ID: 
CCI
CCI
CCI


M5717
Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model
MS201618-0003
Version 1.0
C O N F I D E N T I A L
I N F O R M A T I O N
33/34
Logit(p) = log ( 

 ) = β0 + β1*PK exposure + β2*X2+ β3*X3+…+ βn*Xn
Where,
P is the probability of response
β0 is the intercept, β1…βn are the regression coefficients for the n covariates (Xn)
PK exposure refers to different exposure metrics that will be assessed. The exposure metrics may 
also be parametrized as emax model, if allowed by the data.
The response here is binary, i.e., 1 (cured) or 0 (not cured) which will be identified as follows:
Cured (response= 1): Negative qPCR outcome throughout the study period are referred as 
cured. A participant with a solitary (single) positive qPCR that is not confirmable in subsequent 
qPCR tests and remains < 100 /mL and not used rescue medication within 28 days of PfSPZ 
challenge is also to be classified as cured.
Not-cured (response= 0): Participants with documented blood stage parasite growth defined as 
an increase of qPCR measured asexual parasites per mL compared to the first positive 
parasitemia measurement (defined as equal or greater than 100 asexual parasites per mL of 
blood) within 28 days of PfSPZ challenge or if a participant receives rescue medication within 
28 days of PfSPZ challenge, are referred to as not-cured.
The PK/PD analysis will be performed utilizing logistic regression to model cured, i.e. response 
on PK exposure metrics AUC0-24, AUC0-168, C24, C168 etc. Additional details will be 
mentioned in a separate analysis plan. The results of these analysis will be reported in a separate 
report outside of clinical trial report.
17
References
Clinical Protocol Number: MS201618-0003, Version: 03 December 2020/4.0
Electronic case report form (eCRF): Version: 08 September 2020/4.0
ICH E9 Statistical Principles for Clinical Trials (September 1998)
COVID-19 Guidance on Statistical Methods: Version: 28 August 2020/2.0
18
Appendices
18.1
Appendix 1 – Planned analyses for SMC meetings
Refer to the SMC charter.
Document No. 
Object No. 
Global Version ID: 
CCI
CCI
CCI




ELECTRONIC SIGNATURES
Document: iap-ms201618-0003
Signed By
Event Name
Meaning of Signature
Server Date
(dd-MMM-yyyy
HH:mm ‘GMT’Z)
Task Completed (Approval
eSign): Approved
Technical Approval
15-Mar-2021 14:01
Task Completed (Approval
eSign): Approved
Technical Approval
16-Mar-2021 13:20
Task Completed (Approval
eSign): Approved
Technical Approval
17-Mar-2021 08:31
Task Completed (Approval
eSign): Approved
Technical Approval
19-Mar-2021 07:58
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Object No. 
Global Version ID: 
CCI
CCI
CCI
PPD
PPD
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