Clinical trial NCT05930782
Conditions: Malaria
Keywords: Pharmacokinetics Malaria prevention Bioavailability Malaria Food effect Oral granule formulation
Sponsor: Medicines for Malaria Venture
Start date: 2023-08-14; Completion date: 2024-01-03
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial aims to characterise the pharmacokinetic (PK) profile and estimate drug exposure of a single oral dose of piperaquine (PQP) in a dispersible granule formulation compared to the PQP hard tablet formulation in the fasted state (Part 1), to advise the selection of dose when the PQP granule formulation is administered in a fed state in healthy adult participants. Part 2 will assess the effect on different types of meal composition on the PK of a single dose of PQP granule formulation in healthy adult participants.

Detailed description:
Adult participants who give written informed consent will be screened within 45 days to determine their eligibility before entering the trial on Day -1. The trial will initially establish the pharmacokinetic (PK) profile and estimated drug exposure of a single oral dose of PQP in a dispersible granule formulation compared to the PQP hard tablet formulation in the fasted state (Part 1). In the second study part, and based on the PK results of Part 1, it is intended to administer the same dose level of 320 mg PQP dispersible granules concomitant with different fed conditions. However, if from Part 1 of the study it is shown that PQP dispersible granules formulation provides a significant improvement in Cmax values in the fasted state, this dose level may be adjusted for Part 2, in order to take into account a potential 3-fold increase in exposure which is the observed food effect when film-coated tablets (Eurartesim®) are administered with a high fat/high calorie meal. Such dose adjustment will be based on the safety and preliminary PK interim results of the granule formulation in the fasted state. The PQP dose selected in Part 2 (as dispersible granules formulation) will take into account a 3-fold factor increase in exposure when administered with food (see above) with such predicted exposure in the presence of food being not higher than after the administration of 960 mg PQP in tablet of Eurartesim® in adult subjects dosed in fasting conditions. Furthermore, sufficient data will be available to address key questions on both, safety and PK parameters to enable the review and recommendation by the SRC for the optimal dose of the granule formulation to be administered in Part 2.

Arms: arm 1: Participants received a single oral dose of Piperaquine hard tablets 320mg (administered in fasting condition of at least 10 hours) (N=12)

Piperaquine: Piperaquine tetraphosphate hard tablets 320mg arm 2: Participants received a single oral dose of Piperaquine dispersible granule 320mg (administered in fasting condition of at least 10 hours) (N=12)

Piperaquine: Piperaquine tetraphosphate dispersible granules 320mg arm 3: Participants received a single oral dose of Piperaquine dispersible granule 320mg administered with a high-fat meal (N=12)

Piperaquine: Piperaquine tetraphosphate dispersible granules 320mg arm 4: Participants received a single oral dose of Piperaquine dispersible granule 320mg administered with a low-fat meal representative of African diet. (N=12)

Piperaquine: Piperaquine tetraphosphate dispersible granules 320mg arm 5: Participants received a single oral dose of Piperaquine dispersible granule 320mg administered with whole milk (250ml) (N=12)

Piperaquine: Piperaquine tetraphosphate dispersible granules 320mg
Interventions: intervention 1: Piperaquine Tetraphosphate uncoated tablets intervention 2: Piperaquine Tetraphosphate dispersible granules
Intervention descriptions: intervention 1: Piperaquine tetraphosphate hard tablet 320 mg; single dose (320 mg) given orally with 240 ml of water intervention 2: Piperaquine tetraphosphate dispersible granules 320 mg dose equivalent dispersed in 25 ml of water; single dose (320 mg) given orally

Protocol documents:
SAP_002.pdf: 
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STATISTICAL ANALYSIS PLAN 
 
Protocol title: A randomized, open label, two-part, parallel-group phase I study to 
evaluate the pharmacokinetics of Piperaquine oral dispersible granules formulation 
compared to Piperaquine hard tablets administered as a single dose in fasting 
condition (Part 1) and of Piperaquine oral dispersible granules formulation 
administered as a single dose in various fed states (Part 2) in healthy adult 
participants. 
Protocol number:  MMV_SMC_22_01 
Applicable Protocol Version: 3.0 
Author: 
Piyushkumar Jogani, Biostatistician 
Internal reviewer(s): 
Pramod Borgave,  
Associate Principal Biostatistician 
Sponsor representative(s): 
Myriam EL Gaaloul, Senior Clinical 
Scientist 
Anne Claire Marrast, Senior Medical 
Director 
Revision history: NA 
Date: NA 
 
The layout of this document is based on the Guidelines of the International Conference 
on Harmonization (ICH E9). 
 
 
 


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TABLE OF CONTENTS 
Signature page ........................................................................................................ 7 
Glossary of abbreviations ...................................................................................... 8 
1. 
Overview .......................................................................................................... 10 
1.1 
Introduction ............................................................................................... 10 
2. 
Trial objectives ................................................................................................. 11 
2.1 
Primary objective....................................................................................... 11 
2.2 
Secondary objectives ................................................................................ 11 
2.3 
Exploratory objectives ............................................................................... 11 
3. 
Endpoints ......................................................................................................... 12 
3.1 
Primary endpoint ....................................................................................... 12 
3.2 
Secondary endpoints ................................................................................ 12 
4. 
Trial design ...................................................................................................... 13 
4.1 
Design overview ........................................................................................ 13 
4.2 
Randomization .......................................................................................... 13 
4.3 
Determination of sample size .................................................................... 14 
4.4 
Schedule of Events ................................................................................... 14 
5. 
Changes/deviations from the planned analysis................................................. 15 
6. 
Analysis of populations ..................................................................................... 16 
6.1 
Enrolled Analysis Set (ENRL).................................................................... 16 
6.2 
Safety Analysis Set (SAF) ......................................................................... 16 
6.3 
PK Analysis Set (PK) ................................................................................ 16 
7. 
General considerations .................................................................................... 17 
7.1 
Baseline .................................................................................................... 17 
7.2 
Data consideration .................................................................................... 17 
7.3 
End of study .............................................................................................. 17 
7.4 
Stratifications ............................................................................................ 17 
7.5 
Statistical tests .......................................................................................... 17 
7.6 
Interim analysis ......................................................................................... 17 


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7.7 
Common calculations ................................................................................ 17 
7.8 
Software .................................................................................................... 17 
8. 
Statistical considerations .................................................................................. 18 
8.1 
Multicenter studies .................................................................................... 18 
8.2 
Missing data .............................................................................................. 18 
9. 
Output presentations ........................................................................................ 19 
10. 
Participant disposition and withdrawal .......................................................... 20 
10.1 
Variables and derivations .......................................................................... 20 
10.2 
Analysis .................................................................................................... 20 
11. 
Participant demographics and other baseline characteristics ........................ 21 
11.1 
Variables and derivations .......................................................................... 21 
11.2 
Analysis .................................................................................................... 21 
12. 
Exposure to IMP ........................................................................................... 22 
12.1 
Analysis .................................................................................................... 22 
13. 
Medical history summary .............................................................................. 23 
13.1 
Analysis .................................................................................................... 23 
14. 
Prior, concomitant, and other medications .................................................... 24 
14.1 
Variables and derivations .......................................................................... 24 
14.2 
Analysis .................................................................................................... 24 
15. 
Adverse events ............................................................................................. 25 
15.1 
Variables and derivations .......................................................................... 25 
15.2 
Analysis .................................................................................................... 26 
15.2.1 
Incidence of Pre-Treatment AEs ........................................................ 26 
15.2.2 
Incidence of TEAEs (all causalities) ................................................... 26 
15.2.3 
TEAEs by Toxicity Grade ................................................................... 26 
15.2.4 
TEAEs by Outcome ............................................................................ 26 
15.2.5 
TEAEs by Action Taken ..................................................................... 27 
15.2.6 
Drug-Related TEAEs .......................................................................... 27 


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15.2.7 
Drug-Related TEAEs by Severity ....................................................... 27 
15.2.8 
Serious AEs and Serious TEAEs ....................................................... 27 
15.2.9 
TEAEs and SAEs leading to withdrawal/discontinuation from the study
 
27 
15.2.10 
TEAEs leading to death .................................................................. 27 
16. 
Safety laboratory tests .................................................................................. 28 
16.1 
Variables and derivations .......................................................................... 28 
16.2 
Analysis .................................................................................................... 28 
17. 
12-Lead ECG & Vital signs ........................................................................... 30 
17.1 
Variables and derivations .......................................................................... 30 
17.2 
Analysis .................................................................................................... 30 
18. 
Primary Endpoint Analysis ............................................................................ 32 
18.1 
To determine the relative bioavailability of a single oral dose of PQP 
dispersible granule formulation (Test) as compared to PQP hard tablet formulation 
(Reference) in the fasted state. ............................................................................ 32 
18.1.1 
Variables and derivations ................................................................... 32 
18.1.2 
Analysis ............................................................................................. 32 
19. 
Secondary Endpoints .................................................................................... 34 
19.1 
To assess the effect of different types of meal composition on the PK of 
single doses of PQP dispersible granule formulation in healthy adult participants.34 
19.1.1 
Variables and derivations ................................................................... 34 
19.1.2 
Analysis ............................................................................................. 34 
19.2 
To further evaluate the PK of a single oral dose of PQP granule formulation 
in the fasted state and different fed states in healthy adult participants. ............... 36 
19.2.1 
Variables and derivations ................................................................... 36 
19.2.2 
Analysis ............................................................................................. 36 
19.3 
Physical examination ................................................................................ 38 
19.3.1 
Variables and derivations ................................................................... 38 
19.3.2 
Analysis ............................................................................................. 38 


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20. 
Exploratory endpoints ................................................................................... 39 
20.1 
PK profile and PK parameters for Piperaquine N-oxide metabolite ............. 39 
20.1.1 
Variables and derivations ................................................................... 39 
20.1.2 
Analysis ............................................................................................. 39 
20.2 
To evaluate the palatability of the new PQP granule formulation in healthy 
adult participants. ................................................................................................ 41 
20.2.1 
Variables and derivations ................................................................... 41 
20.2.2 
Analysis ............................................................................................. 41 
21. 
Revision history ............................................................................................ 42 
22. 
Appendix 1: Programming Conventions for Tables, Data Listings, and Figures 
(TLFs) 43 
22.1 
Paper Size, Orientation, and Margins ........................................................ 43 
22.2 
Fonts ......................................................................................................... 43 
22.3 
Header Information ................................................................................... 43 
22.4 
Table and Data Listing Table, Listing and Figure (TLF) Conventions ........ 44 
22.4.1 
General .............................................................................................. 44 
22.4.2 
Univariate statistics ............................................................................ 44 
22.4.3 
Frequencies and percentages [n, (m) and %] ..................................... 45 
22.4.4 
Confidence intervals (CIs) .................................................................. 45 
22.4.5 
P-values ............................................................................................. 46 
22.4.6 
Ratios................................................................................................. 46 
22.4.7 
Spacing .............................................................................................. 46 
22.4.8 
Missing values ................................................................................... 46 
22.5 
Figure output conventions ......................................................................... 46 
22.6 
Dates and times ........................................................................................ 46 
22.7 
Spelling format .......................................................................................... 46 
22.8 
Presentation of treatment groups .............................................................. 46 
22.9 
Presentation of visits ................................................................................. 46 
23. 
Appendix ...................................................................................................... 48 


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23.1 
Appendix 1: Partial date conventions for adverse events and prior and 
concomitant medication ....................................................................................... 48 
23.2 
Appendix 2: PLANNED LISTINGS ............................................................ 49 
23.3 
Appendix 3: PLANNED SUMMARY TABLES ............................................ 51 
23.4 
Appendix 4: PLANNED SUMMARY FIGURES .......................................... 53 
 
 
 


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Signature page
Authored by:
Piyushkumar Jogani
Biostatistician
Premier Research Pvt. Ltd.
                Signature and date
Internal reviewer(s):
Pramod Borgave
Associate Principal Biostatistician                             _______________________                                     
Premier Research. Pvt. Ltd.
   Signature and date
Sponsor representative(s):
Myriam EI Gaaloul                                                                
Senior Director, Clinical Sciences
                       _______________________                                     
MMV
    Signature and date
Anne Claire Marrast 
Sr Medical Director                                                  _______________________
                                    
MMV
Signature and date
                
______________________


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Glossary of abbreviations  
 
ABBREVIATION 
DESCRIPTION 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
AUC0-24h 
Area under the plasma concentration curve from time zero to 
24 hours 
AUC0-72h 
Area under the plasma concentration curve from time zero to 
72 hours 
AUC0-t 
Area under the plasma concentration curve from time zero up 
to the last quantifiable concentration 
AUC0-168h 
Area under the plasma concentration curve from time zero to 
168 hours 
AUC0-∞ 
Area under the plasma concentration-time curve from time 0 
extrapolated to infinite time 
%AUCextrap 
Percentage of AUC that is due to extrapolation from tlast to 
infinity 
BA/FE 
Bioavailability/Food Effect 
BPM 
Beats Per Minute 
CI 
Confidence Interval 
CV 
Coefficient of Variation 
𝐶𝐿
𝐹 
Apparent total plasma clearance 
Cmax 
Maximal plasma concentration 
DBL 
Database Lock 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
Frel 
Relative Bioavailability 
ICH 
International 
Council 
for 
Harmonisation 
of 
Technical 
Requirements for Pharmaceuticals for Human Use 
IMP 
Investigational Medicinal Product 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Sample size 
ODS 
Output Delivery System 
PK 
Pharmacokinetics 
PT 
Preferred Term 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SEM 
Standard Error of Mean 


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SOC 
System Organ Class 
TEAEs 
Treatment-Emergent Adverse Events 
TLFs 
Tables, data listings, and figures 
Tmax 
Time at which the maximum plasma concentration occurs 
𝑡1/2 
Terminal elimination half-life 
WHO 
World Health Organization 
WHO-DD 
WHO Drug Dictionary 
ENRL 
Enrolled Population Set 
SAF 
Safety Analysis Set 
PK 
PK Analysis Set 
PQP  
Piperaquine phosphate 
LOQ 
Limit of Quantification 
Vz/F 
Apparent volume of distribution during the terminal phase 
λz 
Terminal rate constant 
 
 
 


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1. 
Overview 
1.1 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within Protocol MMV_SMC_22_01 version 3.0 dated 
08 Nov 2023. The scope of this plan includes the final analysis, which will be executed 
by the Biostatistics department unless otherwise specified. 
The present pilot BA/FE study aims to assess the relative bioavailability and food effect 
on the systemic exposure of a new child-friendly, taste-masked dispersible granule 
formulation of PQP among healthy adults. In addition, PK and safety/tolerability profiles 
will be further evaluated and documented.  
 


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2. 
Trial objectives 
The following objectives are those stated in the protocol. 
2.1 
Primary objective 
 
To determine the relative bioavailability of a single oral dose of PQP dispersible 
granule formulation (Test) as compared to PQP hard tablet formulation 
(Reference) in the fasted state. 
2.2 
Secondary objectives 
 
To assess the effect of different types of meal composition on the PK of single 
doses of PQP dispersible granule formulation in healthy adult participants. 
 
To further evaluate the PK of a single oral dose of PQP granule formulation in 
the fasted state and different fed states in healthy adult participants. 
 
To further document the safety/tolerability of PQP in healthy adult participants. 
2.3 
Exploratory objectives 
 
To further document PQP metabolite profiling and PK depending on the results 
of a former study (optional objective) as well as the results of genetic testing of 
CYP450s polymorphism (optional). 
 
To evaluate the palatability of the new PQP granule formulation in healthy adult 
participants. 
 
 
 
 


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3. 
Endpoints 
3.1 
Primary endpoint 
 
Relative bioavailability (Frel) using the ratio of the geometric means for the 
dispersible granule (test) over the hard tablet (reference) in a fasted state for 
the area under the plasma concentration-time curve from time zero to 72 
hours (AUC0-72h), area under the plasma concentration-time curve from time 
zero to last detectable plasma concentration (AUC0-t), area under the plasma 
concentration-time curve from time zero to 168 hours (AUC0-168h), area under 
the plasma concentration-time curve from time zero extrapolated to infinity 
(AUC0-∞), and maximum plasma concentration (Cmax). 
3.2 
Secondary endpoints 
 
PK parameters for the hard tablet (fasted) and the dispersible granule 
formulations (fasted and fed); Cmax, AUC0-24h, AUC0-72h,  AUC0-t, AUC0-168h, 
AUC0-∞, time to maximum plasma concentration Tmax, terminal elimination 
rate constant (λz), terminal elimination half-life (t1/2), apparent volume of 
distribution during the terminal phase (Vz/F), apparent total plasma clearance 
(Cl/F), and percentage of AUC that is due to extrapolation from tlast to infinity 
(%AUCextrap). 
 
Occurrence of AEs including serious adverse events (SAEs) from the IMP 
administration throughout the entire study period (up to Day 30). 
 
Findings at different time points: 
o  Physical 
examination, 
vital 
signs, 
clinical 
laboratory 
safety 
parameters, 12-lead ECG parameters. 
 
 


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4. 
Trial design 
4.1 
Design overview 
This is a randomized, open-label, parallel-design study to evaluate the PK profile and 
relative bioavailability of a single dose of a PQP oral granule formulation dispersed in 
water (test) as compared to the PQP hard tablet formulation (reference) in fasting 
conditions (Part 1) and to assess the BA/FE of the PQP dispersible granules 
formulation when administered with different food restrictions (Part 2) among African 
participants residing in Tanzania, in Bagamoyo Town and surrounding areas. A total 
of sixty (60) healthy adult participants (male and female) will be enrolled in Part 1 and 
Part 2. 
 
Part 1: PQP tablet / dispersible granule administered in fasting condition of at 
least 10 hours. 
o Group 1: PQP hard tablet, 320 mg (N=12)  
o Group 2: PQP dispersible granule, 320 mg (N=12) 
 
Transition to Part 2: 
o To minimize the risk to healthy participants, a decision on transitioning 
from Part 1 to Part 2, will be taken by the Safety Review Committee 
(SRC) see protocol section 13.7, based on the safety and preliminary 
PK interim report of the granule formulation, compared to the PQP hard 
tablet, with safety data obtained up to Day 15 and PK data obtained up 
to Day 8. If necessary, doses may be readjusted for Part 2 to assess 
the food effect. A description of the rationale and oversight related to 
the potential for dose adjustment is provided in protocol section 2.2. 
 
Part 2: PQP dispersible granule administered in fed conditions (planned as 320 
mg) 
o Group 3: High-fat meal (N=12) 
o Group 4: Low-fat meal representative of African diet (N=12) 
o Group 5: Whole milk 250 ml (N=12) 
Participants will be screened within a window of ≤ 45 days before in-house admission 
on Day -1. Each participant will be admitted to the trial unit on Day -1, and after a new 
eligibility check, will receive a single dose of PQP on Day 1 and will be discharged on 
Day 3 (a total of 4 in-house days). Participants will attend the trial unit clinic for 
outpatient visits on Days 8, 15, 22, and 30. 
4.2 
Randomization 
Healthy adult participants (male and female) will be randomly allocated to one of the 5 
following treatment groups, dosing will be carried out in the fasted or fed state: 
 
During the study part 1, participants for fasted conditions will be randomly 
allocated to either group 1 (n=12) or group 2 (n=12), in order to assess the 
relative bioavailability of the dispersible granules formulation as compared to 
the hard tablet formulation.  
o Randomization will occur in blocks of 2 (each block contains 1 
assignment from each of the groups 1 and 2). 
 
During study part 2, participants for fed conditions will be randomly allocated to 
either group 3 (n=12), 4 (n=12), or 5 (n=12), in order to assess the food effect 
after dosing of PQP dispersible granules formulation.  


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o Randomization will occur in blocks of 3 (each block contains 1 
assignment from each of the groups 3, 4, and 5). 
A computer-generated randomization schedule will be used and will be accessible only 
to the site-delegated study staff who will prepare the treatment for each participant 
according to the randomization allocation. 
4.3 
Determination of sample size 
This is an exploratory trial to evaluate the PK and safety of each treatment group and 
the sample size is not based on formal statistical power. The number assigned to each 
treatment arm (n=12) is considered adequate to assess the trial objectives. 
4.4 
Schedule of Events 
Refer to section 4.4 schedule of events of the protocol. 
 
 
 


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5. 
Changes/deviations from the planned analysis 
The statistical analysis/methods as described in the protocol were adopted. There 
are no changes to the planned analyses. Any deviation from the original statistical 
analysis plan will be described and justified in the SAP or final clinical study report. 
 
 
 
 


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6. 
Analysis of populations 
Protocol deviations will be reviewed, and exclusion of participants from each analysis 
sets will be decided during data review meeting prior to the final database hard lock. A 
list of all participants to be excluded from the relevant analysis populations, including 
the reason(s) for exclusion from the analysis populations will be provided. 
The following sets will be used for the statistical analyses: 
6.1 
Enrolled Analysis Set (ENRL)  
This population will include all participants who signed the informed consent form 
(ICF). 
6.2 
Safety Analysis Set (SAF) 
This population will include all randomized participants who received at least one dose 
of the IMP. 
6.3 
PK Analysis Set (PK) 
The PK analysis set will include those participants in the safety set who have sufficient 
blood samples taken for at least one of the PK variables to be calculated and 
experienced no protocol deviations with relevant impact on PK data. 
 
 


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7. 
General considerations 
7.1 
Baseline 
Baseline is defined as the last non-missing observation made before the study 
treatment administration. 
7.2 
Data consideration 
Not Applicable 
7.3 
End of study 
Day 30 is the end of study day. 
7.4 
Stratifications 
For analysis purposes, trial participants may be sub-classified into the following 
stratification levels, where applicable: 
 
Groups for Part-1 (Fasting): 
o Group 1 (PQP Hard Tablet) 
o Group 2 (PQP Dispersible Granules) 
 
Groups for Part-2 (PQP Dispersible Granules - Fed): 
o Group 3 (High-fat Meal) 
o Group 4 (Low-fat Meal) 
o Group 5 (Whole Milk 250ml) 
7.5 
Statistical tests 
No formal tests will be applicable for the safety analysis.  
7.6 
Interim analysis 
No formal interim analysis is planned for this study, other than the safety/PK report that 
will be performed for the SRC review during the transition from Part 1 to Part 2. 
7.7 
Common calculations 
For quantitative measurements, change from baseline will be calculated as: (Test 
value at Visit Day X – Baseline value), where the baseline value is defined as the last 
non-missing observation made before first study treatment administration. 
7.8 
Software 
All statistical analyses will be conducted using SAS® Version 9.4 or higher.  
 
 


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8. 
Statistical considerations 
8.1 
Multicenter studies 
Not applicable. 
8.2 
Missing data 
All data will be inspected for potential errors and a summary of missing data will be 
generated including the percentages of those with non-missing data, dropouts, and 
replacement of participants. Unrecorded values will be treated as missing. Missing 
values will not be imputed and will be reported in the listings as either “missing” or as 
the justification for the value being missing e.g., “ND” (not detected), where 
appropriate. 
For adverse event, prior and concomitant medication data, partial date imputations will 
be performed where at least the year is provided. 
 
 


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9. 
Output presentations 
The templates provided in the separate output templates document describe the 
format and content for the presentation of tables, listings, and figures (TLFs). 
For continuous measures, summary statistics will include the number of participants 
(n), number of missing values, mean, standard deviation (SD), median, minimum, and 
maximum for both the actual and the change from baseline measurements. For 
categorical measures, summary statistics will include the number of participants (n), 
number of missing values and percentages. 
All percentages (%) for a specific summary are calculated using the total number of 
participants included in the relevant analysis population as the denominator unless 
otherwise specified. 
 
 
 
 
 
 
 


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10. 
Participant disposition and withdrawal 
The following analysis will be applicable to both, part-1, and part-2 of the study. 
10.1 
Variables and derivations 
The following parameters will be summarized for the participant’s disposition table as 
per eCRF: 
 
Number of screened participants 
 
Number of screening failure participants 
 
Number of enrolled participants 
 
Number of participants screened but discontinued before randomization. 
 
Number of randomized participants* 
 
Number of study completed participants. 
 
Number of study discontinued participants. 
 
Reasons for study discontinuation 
 
Number of participants in the Safety analysis set. 
 
Number of participants in the PK analysis set. 
*Randomized: Participants who are screen positive and assigned to the treatment. 
Screening Failure: Participants who did not meet any Inclusion/ Exclusion Criteria or 
Are not eligible for the trial.  
10.2 
Analysis 
 
 
 
Population: 
ENRL 
Stratification: 
Table: By part and group 
Listing: By part, group and participant  
Statistics: 
All above mentioned participant’s disposition parameters, will be 
summarised (frequency & percentage) and participants listing for 
all participants by participant number will be provided. 
The reasons for study discontinuation will be summarized as per 
eCRF end of study form. 
The summary for safety and PK analysis set will be presented with 
their exclusion reason from respective analysis set and listing with 
population assignment and exclusion reason will be provided.  
Summary for protocol deviation will be presented by category (i.e., 
Major/Minor) and participant data listing will be provided by 
participant number. 


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11. 
Participant demographics and other baseline characteristics 
The following analysis will be applicable to both, part-1, and part-2 of the study. 
11.1 
Variables and derivations 
The following demographic and other baseline characteristics will be summarized: 
 
Age (Years) 
 
Sex 
 
Race 
 
Ethnicity 
 
Height 
 
Weight 
 
BMI 
11.2 
Analysis 
 
 
 
Population: 
Table: SAF and PK 
Listing: ENRL 
Stratification: 
Table: By part and group 
Listing: By part, group and participant 
Statistics: 
Baseline and Demographic variables will be summarized for each 
stratification factor and overall, also listed by participant number. 
The summaries will include descriptive statistics for continuous 
measures (number of participants, number of missing values, 
mean, SD, median, minimum & maximum) and for categorical 
measures (frequency, percentages, and number of missing 
values). 


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12. 
Exposure to IMP 
12.1 
Analysis 
 
 
 
 
Population: 
SAF 
Stratification: 
Table: By part and group 
Listing: By group and participant 
Statistics: 
Planned dose and actual dose will be summarized descriptively 
(number of participants, number of missing values, mean, SD, 
median, minimum & maximum). Study drug administration 
information will be listed by participant number. 


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13. 
Medical history summary 
The following analysis will be applicable to both, part-1, and part-2 of the study. 
13.1 
Analysis 
 
 
Population: 
SAF 
Stratification: 
Table: NA 
Listing: By group and participant 
Statistics: 
Medical history data will be listed by participant number. 


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14. 
Prior, concomitant, and other medications 
The following analysis will be applicable to both, part-1, and part-2 of the study. 
14.1 
Variables and derivations 
Concomitant medications will be coded using the WHO-DD, dated 1 March 2023, or 
higher. 
Prior medications are defined as any medication taken before the first administration 
of the study treatment. 
‘Concomitant medications’ are defined as any medication taken after the first 
administration of the study treatment.  
In section 23 of Appendix 1, the algorithm is given for the calculation of partial date 
imputation for prior and concomitant medications, and it will be used for partially 
missing prior and concomitant medications, start and end date imputation. 
The following parameters will be summarised for concomitant medications: 
 
Number of participants with at least one prior and concomitant medication 
 
Number of participants for each prior and concomitant medication by ATC 
and PT. 
14.2 
Analysis 
 
 
Population: 
Table: SAF 
Listing: ENRL 
Stratification: 
Table:  By part and group 
Listing: By part, group and participant 
Statistics: 
Prior and Concomitant medication will be summarized (frequency, 
percentages) by group and a listing will be presented. 


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15. 
Adverse events 
The following analysis will be applicable to both, part-1, and part-2 of the study. 
15.1 
Variables and derivations 
Adverse Events (AEs) will be coded using MedDRA central coding dictionary, version 
26.0 or higher. 
For the definition of Adverse events (AE) and Serious adverse events (SAE) refer to 
the protocol sections 8.1.2 & 8.4. 
Pre- treatment adverse-events are defined as AEs between informed consent and IMP 
administration. 
Treatment-emergent adverse events (TEAEs) are defined as an event that emerges 
during treatment, have been absent pre-treatment or worsens relative to the pre-
treatment state.  
The following parameters will be summarised for the participant’s adverse events as 
mentioned in eCRF: 
 
All Adverse Events 
 
Number of participants with at least one Pre-Treatment AE 
 
Number of participants with at least one TEAE 
 
Number of participants with at least one study drug-related TEAE 
 
Number of participants with at least one serious TEAE 
 
Number of participants with at least one study drug-related serious TEAE 
 
Ongoing AEs 
 
TEAEs by Toxicity Grade 
 
TEAEs by Outcome 
 
TEAEs by Action Taken with Study Treatment 
 
TEAEs by Relationship 
 
TEAEs leading to Death. 
 
TEAEs leading to withdrawn or discontinued the study. 
Derivations: 
 
The question on eCRF page Adverse Events “Relationship to investigational 
product” is answered “Related/Suspected”, then respective AEs will be 
considered as drug-related AEs. 
 
If The question on eCRF page Adverse Events “Was the adverse event 
serious” is answered as “YES” then the respective AE will be considered as 
serious AE. 
 
The question on eCRF page Adverse Events “Was the adverse event serious” 
is answered as “YES” and answered as “Related/Suspected” then respective 
AEs will be considered drug-related SAEs. 


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 
If the seriousness criteria are “RESULTS IN DEATH” then we will consider it 
as AE leading to death. 
 
participant’s primary reason for discontinuation is “ADVERSE EVENT” then we 
will consider it as AE leading to withdrawal/discontinued from the study. 
Imputations will only be performed where at least the year is provided. The imputations 
derived for partial dates will be as per appendix 1. 
15.2 
Analysis 
15.2.1 
Incidence of Pre-Treatment AEs 
The incidence of all AEs by SOC and PT will be presented. 
15.2.2 
Incidence of TEAEs (all causalities) 
The incidence of all TEAEs by SOC and PT will be presented. 
15.2.3 
TEAEs by Toxicity Grade 
The incidence of all AEs by SOC, PT, and toxicity grade will be presented. 
15.2.4 
TEAEs by Outcome 
The incidence of all AEs will be presented by SOC, PT, and outcome. 
Population: 
Table: SAF 
Listing: ENRL 
Stratification: 
Table: By part and group 
Listing: By part, group and participant 
Statistics: 
An overall summary will be presented as the number of 
participants within each of the event type categories described in 
the sub-sections below, including the incidence of AEs by system 
organ class (SOC) and preferred term (PT) sorted by decreasing 
frequency within the SOC and PT. The number of participants with 
AEs will be presented. Both number of participants, number of 
events (One participant may be counted more than once) and 
percentage will be provided.  
The Adverse Event will be summarized and presented in data 
listings with all AEs (including coding details SOC and PT) and 
participants with SAEs, death, and events resulting in study 
discontinuation will be listed separately by participant number.  
Treatment-emergent AEs (TEAE) will be summarized for all 
participants by SOC and PT. Each TEAE will be counted only once 
for a given participant. If the same TEAE occurs on multiple 
occasions, the highest severity and relationship will be assumed. 
A summary of serious TEAE will be presented separately. All other 
TEAEs will be summarized similarly. 
Note: If there are uncoded adverse events, then the uncoded 
category will be added to the AEs by SOC/PT summary tables. 


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15.2.5 
TEAEs by Action Taken 
The incidence of all TEAEs will be presented by SOC, PT, and action taken. 
15.2.6 
Drug-Related TEAEs  
The incidence of all drug-related TEAEs will be presented by SOC and PT. 
15.2.7 
Drug-Related TEAEs by Severity 
The incidence of all drug-related TEAEs will be presented by SOC, PT and severity. 
15.2.8 
Serious AEs and Serious TEAEs  
The incidence of all serious AEs and TEAEs will be presented by SOC and PT. 
15.2.9 
TEAEs and SAEs leading to withdrawal/discontinuation from the study 
The incidence of all TEAEs and SAEs leading to withdrawal/discontinuation will be 
presented by SOC and PT. A data listing of TEAEs and SAEs leading to 
withdrawal/discontinuation from the study will be presented. 
15.2.10 TEAEs leading to death 
The incidence of all TEAEs leading to death will be presented by SOC and PT. A data 
listing of all TEAEs for death participants will be presented. 
 
 


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16. 
Safety laboratory tests 
The following analysis will be applicable to both, part-1, and part-2 of the study. 
16.1 
Variables and derivations 
All the reported lab parameters will be presented for the below categories as per 
protocol: 
 
Biochemistry 
 
Hematology 
 
Thick blood smear – Malaria 
 
Urinalysis 
 
Urine for drugs of abuse 
 
Pregnancy test 
 
FSH 
 
Coagulation 
 
Serology 
 
Alcohol breath test 
Quantitative laboratory measurements reported as “< X”, i.e., below the limit of 
quantitation, or “> X”, i.e., above the upper limit of quantification, will be converted to 
X for quantitative summaries but will be presented as recorded, i.e., as “< X” or “> X” 
in the data listings. 
16.2 
Analysis 
Population: 
Table: SAF 
Listing: ENRL 
Stratification: 
Table: By part and group 
Listing: By part, group, participant, timepoint & parameter 
Statistics: 
Summaries of all the laboratory tests will include descriptive statistics 
at each assessment of the following: 
 
Actual and change from baseline (number of participants, mean, 
SD, 
median, 
minimum 
& 
maximum) 
(for 
quantitative 
measurements) for which baseline data is collected. i.e., 
Biochemistry, Hematology.  
 
Frequencies and percentages (n and %) (for qualitative 
measurements). i.e., Thick blood smear – Malaria, Pregnancy test, 
Urinalysis, Urine for drugs of abuse, Alcohol breath test.) 
Qualitative laboratory measurements will be compared with the 
relevant laboratory reference ranges and summarized as:  
 
Normal: Within the laboratory reference range (upper and lower 
limit included)  
 
Abnormal NCS: Abnormal not clinically significant 
 
Abnormal CS: Abnormal clinically significant 
 
High: Higher than the upper limit of the reference range 
 
Low: Lower than the lower limit of the reference range 


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Above categorizations and abnormal laboratory data will be flagged 
and presented in data listings. 
The qualitative urinalysis data will be listed only. Those above lab 
parameters that will only be done in screening will be listed only. 
 


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17. 
12-Lead ECG & Vital signs 
The following analysis will be applicable to both, part-1, and part-2 of the study. 
17.1 
Variables and derivations 
For ECG and vital signs, a baseline is defined as the last observation made before 
the first administration of study treatment. 
The following vital signs parameters will be reported for this study: 
 
Blood pressure (Systolic and Diastolic) 
 
Heart rate 
 
Axillary temperature 
 
respiratory rate 
All recorded in supine position. 
The following 12-lead ECG parameters will be reported for this study: 
 
PR 
 
QRS 
 
QT 
 
QTcB 
 
QTcF  
 
HR 
17.2 
Analysis 
Population: 
Table: SAF 
Listing: ENRL 
Stratification: 
Table: By part and group 
Listing: By part, group, participant, timepoint & parameter 
Statistics: 
Summaries of all 12-Lead ECG & vital parameters will include 
descriptive statistics at each assessment of the following: 
 
Actual and change from baseline (number of patients, mean, 
SD, 
median, 
minimum 
& 
maximum) 
(for 
quantitative 
measurements) 
 
Frequencies and percentages (n and %) (for qualitative 
measurements) 
"Any Clinically Significant Abnormality Found in Vital Signs" will be 
found as "Yes" on the eCRF page of Vital signs, it will be summarized 
as Frequencies and percentages (n and%). 
In ECG analysis, if triplicate ECG performed then the average of three 
repetitions will be calculated and used for the further evaluation. 
The qualitative measurements of ECG will be categorised as (Normal, 
Abnormal Clinically Significant and Abnormal Not Clinically Significant) 
Above categorizations and abnormal data will be flagged and 
presented in data listings. 


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Additionally, QTcF data will be summarized using frequencies & 
percentages (n and %) as follows: 
Absolute QTcF interval prolongation 
 
QTcF interval > 450 ms 
 
QTcF interval > 480 ms 
 
QTcF interval > 500 ms 
Change from baseline in QTcF interval  
 
QTcF interval increases from baseline > 30 ms  
 
QTcF interval increases from baseline > 60 ms 
The mean value of change from baseline QTcF parameters will be 
plotted by group and time point. 


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18. 
Primary Endpoint Analysis 
18.1 
To determine the relative bioavailability of a single oral dose of PQP 
dispersible granule formulation (Test) as compared to PQP hard tablet 
formulation (Reference) in the fasted state.  
18.1.1 
Variables and derivations 
 
AUC0-72h: Area under the plasma concentration curve from time zero to 72 
hours 
 
AUC0-168h: Area under the plasma concentration curve from time zero to 168 
hours 
 
AUC0-t: Area under the plasma concentration curve from time zero up to the 
last quantifiable concentration 
 
AUC0-∞: Area under the plasma concentration-time curve from time 0 
extrapolated to infinite time. 
 
Cmax: Maximal plasma concentration 
Comparisons of interest are as follows: 
 
Group 1: PQP hard tablet with Group 2: PQP dispersible granule 
 
18.1.2 
Analysis 
Population: 
Table: PK 
Listing: PK 
Stratification: 
Table: By part and group 
Listing: By group, participant, timepoint & parameter 
Statistics: 
The relative bioavailability will be assessed for PQP using the ratio of 
the geometric means for AUC(0-72h), AUC(0-168h), AUC(0-t), AUC(0-∞), and 
Cmax as follows: 
 
For Part 1 the comparisons will be Group 2 PQP dispersible 
granule (320 mg, fasted) [test] over the Group 1 PQP hard tablet 
(320 mg, fasted) [reference]. 
To determine bioequivalence between PQP dispersible granule (320 
mg) [test] and the PQP hard tablet (320 mg), ln-transformed PK 
parameters AUC0-72h,  AUC0-168h, AUC0-t, AUC0-∞, and Cmax will be 
analyzed using Type III sum of squares, with the fixed effect of treatment 
using General Linear Model (PROC GLM) in SAS software. 
Each analysis of variance will include calculation of least square means 
(LSM). Two 1-sided tests procedure at 5% level of significance will be 


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used to compare the geometric LSM values of PK parameters 
determined after administration of test and reference products. 
Point estimates of the ratio of geometric least squares means and its 
90% CI of PQP dispersible granule (320 mg) and PQP hard tablet (320 
mg) will be calculated and reported for ln-transformed PK parameters. 
Total subject variability for the PQP dispersible granule (320 mg) [test] 
and PQP hard tablet (320 mg) PK data will be calculated and reported. 
Summary statistics (i.e., mean, median, SD, CV%, minimum, maximum, 
n, geometric mean, geometric SD, and geometric CV%) will be 
calculated for blood concentrations for each time point and group. The 
same will be done for the PK parameters which will be listed for each 
individual and summarized by group. 


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19. 
Secondary Endpoints 
19.1 
To assess the effect of different types of meal composition on the PK 
of single doses of PQP dispersible granule formulation in healthy adult 
participants.  
19.1.1 
Variables and derivations 
 
AUC0-72h: Area under for the plasma concentration curve from time zero to 72 
hours 
 
AUC0-168h: Area under the plasma concentration curve from time zero to 168 
hours 
 
AUC0-t: Area under the plasma concentration curve from time zero up to the 
last quantifiable concentration 
 
AUC0-∞: Area under the plasma concentration-time curve from time 0 
extrapolated to infinite time. 
 
Cmax: Maximal plasma concentration 
 
Comparisons of the Interest are as follows: 
 
Group 3: High-fat meal with Group 2: PQP dispersible granule  
 
Group 4: Low-fat meal representative of African diet with Group 2: PQP 
dispersible granule 
 
Group 5: Whole milk 250 ml with Group 2: PQP dispersible granule 
 
19.1.2 
Analysis 
Population: 
Table: PK 
Listing: PK 
Stratification: 
Table: By part and group 
Listing: By part, group, participant, timepoint & parameter 
Statistics: 
The relative bioavailability will be assessed for PQP using the ratio of 
the geometric means for AUC(0-72),  AUC(0-168), AUC(0-t), AUC(0-∞), and Cmax 
as follows: 
For Part 2 the comparisons will be as follow. 
 
Group 3: High-fat meal (Fed) [test] over the Group 2 PQP 
dispersible granule (fasting) [reference] 
 
Group 4: Low-fat meal representative of African diet (Fed) [test] 
over the Group 2 PQP dispersible granule (fasting) [reference] 
 
Group 5: Whole milk 250 ml (Fed) [test] over the Group 2 PQP 
dispersible granule (fasting) [reference] 
 
 
To determine bioequivalence between PQP dispersible granule (320 
mg) [test] and each of different type of meal, ln-transformed PK 
parameters (AUC(0-72h), AUC(0-168), AUC(0-t), AUC(0-∞), and Cmax) will be 


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analyzed using Type III sum of squares, with the fixed effect of 
Treatment using General Linear Model (PROC GLM) of SAS software. 
Each analysis of variance will include calculation of least square mean 
(LSM). Two 1-sided tests procedure at 5% level of significance will be 
used to compare the geometric LSM values of PK parameters 
determined after administration of test (different type of meal) and 
reference products. 
Point estimates of the ratio of geometric least squares means of 
dispersible granules formulation between fed [high-fat meal, low-fat 
African meal, and milk] will be calculated and reported for ln-
transformed PK parameters. 
Total subject variability for the dispersible granules formulation between 
fed [high-fat meal, low-fat African meal, and milk] PK data will be 
calculated and reported. 
Summary statistics (i.e., mean, median, SD, CV%, minimum, maximum, 
n, geometric mean, geometric SD, and geometric CV%) will be 
calculated for blood concentrations for each time point and group. The 
same will be done for the PK parameters which will be listed for each 
individual and summarized by group. 


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19.2 
To further evaluate the PK of a single oral dose of PQP granule 
formulation in the fasted state and different fed states in healthy adult 
participants.  
19.2.1 
Variables and derivations  
The following pharmacokinetic parameters will be calculated for piperaquine: 
 
 
Cmax: Maximal plasma concentration 
 
Tmax: Time at which the maximum plasma concentration occurs 
 
t1/2: Terminal elimination half-life 
 
AUC0-∞: Area under the plasma concentration-time curve from time 0 
extrapolated to infinite time 
 
AUC0-t: Area under the plasma concentration curve from time zero up to the 
last quantifiable concentration 
 
AUC0-24h: Area under the plasma concentration curve from time zero to 24 
hours 
 
AUC0-72h: Area under the plasma concentration curve from time zero to 72 
hours 
 
AUC0-168h: Area under the plasma concentration curve from time zero to 168 
hours 
 
%AUCextrap: Percentage of AUC that is due to extrapolation from tlast to infinity 
 
CL/F: Apparent total plasma clearance 
 
Vz/F: Apparent volume of distribution during the terminal phase 
 
Λz: Terminal rate constant 
 
19.2.2 
Analysis 
Population: 
Table: PK 
Listing: PK 
Stratification: 
Table: By part and group 
Listing: By part, group, participant, timepoint & parameter 
Statistics: 
PK concentration 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) and maximum (Max). 
Graphical Presentation: Individual concentration versus time plots; 
linear and semi-log; using the actual time points by participants, and 
groups. Overlaying individual concentration time profiles will be 
displayed. 
Mean concentration time plots; linear with standard deviation and semi-
log; using scheduled (nominal) time points, and meal group. Error bars 
should be included only in the linear plots. 


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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) and maximum (Max), Geometric mean (Geo mean), 
Geometric  coefficient of variation (GCV%). 
Tmax will be summarized by treatment using Min, Max and Median. 
Plots for Individual PQP AUC0-t and Cmax by dose group will be provided. 


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19.3 
Physical examination 
19.3.1 
Variables and derivations 
Following physical examination parameters will be reported & applicable to both part 
1 & part 2 of the study: 
 
Skin 
 
Lymph Nodes 
 
Head 
 
Eyes 
 
Ear 
 
Nose 
 
Throat 
 
Respiratory 
 
Cardiovascular 
 
Abdomen 
 
Extremities 
 
Musculoskeletal 
 
Neurological 
19.3.2 
Analysis 
For the analyses of laboratory parameters, vital signs & ECG parameters refer to 
sections 16.2 & 17.2 respectively. 
 
Population: 
Table: NA 
Listing: ENRL 
Stratification: 
Table: NA 
Listing: By part, group, participant, timepoint & parameter 
Statistics: 
The physical examination assessment will be presented in data listings 
at all assessment time points. Physical examination data will be 
classified as normal, abnormal not clinically significant & abnormal 
clinically significant. 


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20. 
Exploratory endpoints 
20.1 
PK profile and PK parameters for Piperaquine N-oxide metabolite  
20.1.1 
Variables and derivations  
The following pharmacokinetic parameters will be calculated for N-oxide PQP 
(metabolite), whenever possible: 
 
 
Cmax: Maximal plasma concentration 
 
Tmax: Time at which the maximum plasma concentration occurs 
 
t1/2: Terminal elimination half-life 
 
AUC0-∞: Area under the plasma concentration-time curve from time 0 
extrapolated to infinite time 
 
AUC0-t: Area under the plasma concentration curve from time zero up to the 
last quantifiable concentration 
 
AUC0-24h: Area under the plasma concentration curve from time zero to 24 
hours 
 
AUC0-72h: Area under the plasma concentration curve from time zero to 72 
hours 
 
AUC0-168h: Area under the plasma concentration curve from time zero to 168 
hours 
 
%AUCextrap: Percentage of AUC that is due to extrapolation from tlast to infinity 
 
λz: Terminal rate constant 
 
20.1.2 
Analysis 
Population: 
Table: PK 
Listing: PK 
Stratification: 
Table: By part and group 
Listing: By part, group, participant, timepoint & parameter 
Statistics: 
PK concentration 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) and maximum (Max). 
Graphical Presentation: Individual concentration versus time plots; 
linear and semi-log; using the actual time points by participants, and 
groups. Overlaying individual concentration time profiles will be 
displayed. 
Mean concentration time plots; linear with standard deviation and semi-
log; using scheduled (nominal) time points, and meal group. Error bars 
should be included only in the linear plots. 


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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) and maximum (Max), Geometric mean (Geo mean), 
Geometric coefficient of variation (GCV%). 
Tmax will be summarized by treatment using Min, Max and Median. 
Plots for Individual PQP N-oxide (metabolite) AUC0-t and Cmax by dose 
group will be provided. 


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20.2 
To evaluate the palatability of the new PQP granule formulation in 
healthy adult participants. 
20.2.1 
Variables and derivations 
Variables: 
All the 3 questions (including sub-domains) and numerical answers (from 1 to 5) to 
these will be considered from the eCRF page of the Palatability Questionnaire 
[PALAQ]. 
20.2.2 
Analysis 
 
 
 
Population: 
Table: SAF 
Listing: ENRL 
Stratification: 
Table: By part and group 
Listing: By part, group and participant 
Statistics: 
The questionnaire data will be presented in data listings and 
summarised as frequency and percentages (n and %). 
 


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21. 
Revision history 
Version 
Date 
Change 
1.0 
19-DEC-2023 
Initial document 
 
 
 


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22. 
Appendix 1: Programming Conventions for Tables, Data Listings, and 
Figures (TLFs) 
22.1 
Paper Size, Orientation, and Margins 
The margin, page size, and line size specifications as stipulated in Table 22.1 will be 
used for the presentation of all TLFs. 
Table 22.1: Output margin, page size, and line size specifications 
 
Landscape 
Portrait 
Margins (Inches): 
Top  
Bottom 
Left 
Right 
 
1.25 
1 
1 
1 
 
1 
1 
1.25 
1 
Header (Inches) 
0.5 
0.5 
Footer (Inches) 
0.5 
0.5 
SAS® specifications: 
PAGES 
LINE SIZE 
 
46 
134 
 
67 
93 
22.2 
Fonts 
The font type “Courier New” should be used as a default for tables and data listings, 
with a font size of 8. The font color should be black. No bolding, underlining, or italics 
are permitted. 
Figures should have a default font of “Times Roman”, “Helvetica” or “Courier New”. 
22.3 
Header Information 
Headers should be defined as follows: 
 
The header should be placed at the top of the page (same place on each page). 
 
The sponsor’s name should appear in row 1, left-aligned. 
 
The word “CONFIDENTIAL” should appear in row 1, right aligned. 
 
The protocol number should appear in row 2, left-aligned. 
 
The page identification in the format Page X of Y (where Y is the total number of 
pages for the TLF) should appear in row 2, right aligned. 
 
The TLF identification number should appear in row 3, centered. 
 
The TLF title should start in row 4, centered. 


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 
The TLF population should appear in row 5, centered. The population should be 
spelled out in full, e.g., the Safety analysis population in preference to the Safety 
analysis population. 
 
Row 6 should be a continuous row of underscores (‘_’) (the number of underscores 
should equal the line size). 
 
Row 7 should be a blank line. 
 
Mixed cases should be used for titles. 
 
Titles should not contain quotation marks or footnote references. 
 
The column headings should be underlined with a row of underscores (‘_’). 
 
Column headings spanning more than one column should be underlined and have 
underscores on either side of the title and should be centered. 
 
Column headings containing numbers should be centered. 
 
Column headings should be in mixed case. 
 
In general, the analysis population count should appear in the column header in 
the form “(N=XX)”. 
22.4 
Table and Data Listing Table, Listing and Figure (TLF) Conventions 
22.4.1 
General 
 
The first row in the body of the table or data listing should be blank. 
 
The left-hand column should start in Column 1. No indenting or centering of the 
TLF should occur. 
 
Rounding should be done with the SAS® function ROUND. 
 
Numerical values in tables should be rounded, not truncated. 
 
Numerical values should be decimal point aligned. 
 
Text values should be left aligned. 
 
The first letter of a text entry should be capitalized. 
 
The study drug should appear first in tables with the treatment group as columns. 
 
All variables contained on the eCRF (which have data present) should appear in 
the data listings, along with all derived data appearing in the corresponding tables. 
 
The width of the TLF should match the line size. 
22.4.2 
Univariate statistics 
 
Statistics should be presented in the same order across tables (i.e., n, mean, SD, 
minimum, median, and maximum). 


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 
If the original data has N decimal places, then the summary statistics should have 
the following decimal places: 
o Minimum, maximum, and CV (%): N 
o Mean and median: N + 1. 
o SD: N + 2. 
22.4.3 
Frequencies and percentages [n, (m) and %] 
 
Mentions should be reported inside parentheses, with one space between the 
count and the left parenthesis of the mentions. An example is given below: 
o 124 (645) 
 
Percent values should be reported inside parentheses, with one space between 
the right parenthesis of the mention and the left parenthesis of the percentage. 
Parentheses should be justified to accept a maximum of 100.0 as a value and 
padded with blank space if the percent is less than 100.0. An example is given 
below: 
o 77 (156) (100.0) 
o 50 (56) ( 64.9) 
o 0 (0) (  0.0) 
 
Percentages will be reported to one decimal place, except percentages <100.0 but 
>99.9 will be presented as ‘>99.9’ (e.g., 99.99 is presented as >99.9); and 
percentages <0.1 will be presented as ‘<0.1’ (e.g., 0.08 is presented as <0.1). 
Rounding will be applied after the <0.1 and >99.9 rules. 
o (<0.1) 
o ( 6.8) 
o (>99.9) 
 
Percentages may be reported to 0 decimal places as appropriate (for example, 
where the denominator is relatively small). 
 
Where counts are zero, mentions of 0 and percentages of 0.0 should appear in the 
table. 
22.4.4 
Confidence intervals (CIs) 
 
CIs should be presented with one additional decimal place as that of the raw data, 
and SDs and standard errors (SEs) with two additional decimal places as that of 
the raw data. 
 
CIs should be justified so that parentheses are displayed on consecutive lines of a 
table “line up”. 


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22.4.5 
P-values 
 
P-values should be reported to four decimal places. 
22.4.6 
Ratios 
 
Ratios should be reported with one additional decimal place as that of the raw 
data. 
22.4.7 
Spacing 
 
There should be a minimum of 1 blank space between columns (preferably 2). 
22.4.8 
Missing values 
 
A “0” should be used to indicate a zero frequency. 
 
A blank will be used to indicate missing data in data listings. 
22.5 
Figure output conventions 
Figures should be provided in RTF files using the SAS® Output Delivery System (ODS). 
22.6 
Dates and times 
Depending on the data available, dates and times will take the form ddMMMyyyy and 
hh: mm. 
22.7 
Spelling format 
The spelling format to be used is English US.  
22.8 
Presentation of treatment groups 
 
Part 1 
o Group 1 (PQP Hard Tablet - Fasted) 
o Group 2 (PQP Dispersible Granules - Fasted) 
 
Part 2 
o Group 3 (PQP Dispersible Granules - High-fat Meal) 
o Group 4 (PQP Dispersible Granules - Low-fat Meal) 
o Group 5 (PQP Dispersible Granules - Whole Milk 250ml) 
22.9 
Presentation of visits 
 
Screening  


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 
Day -1 (Admission) 
 
Day 1 
 
Day 2 
 
Day 3 
 
Day 5 
 
Day 8 
 
Day 15 
 
Day 22 
 
Day 30 
 
 


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23. 
Appendix 
23.1 
Appendix 1: Partial date conventions for adverse events and prior and 
concomitant medication 
Event 
Missing 
Imputation 
Start Date 
Day 
If event start Month = Treatment start 
month and event start Year = Treatment 
start Year, then event start Day= minimum 
of (Treatment Start Day or event end Day). 
Otherwise, event start day = “01”.  
 
  
Day and Month 
If event start Year = Treatment start Year, 
then event start Day and Month = minimum 
of (Treatment Start Day and Month or event 
end Day and Month). Otherwise, event start 
Day and Month = “01 Jan”.  
 
  
Day, Month and 
Year 
No Imputation will be performed. 
 
End Date 
Day 
If event End Month = Study conclusion 
Month and event End Year= Study 
conclusion Year, Then event End Day= 
Study Conclusion Day. Otherwise, event 
End Day = last day of respective month.  
 
Day and Month 
If event End Year = Study Conclusion Year, 
then event End Day and Month = Study 
Conclusion Day and Month. Otherwise, 
event End Day and Month = “31 Dec”.  
 
Day, Month and 
Year 
No Imputation will be performed. 
 
 
 


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23.2 
Appendix 2: PLANNED LISTINGS 
The following listings are planned to be generated for the study (note: Numbering is 
indicative only and may be updated based on CSR requirements): 
 
Listing Number 
Listing Title 
Population 
16.2.1 Participants Discontinuation/Completion 
 
 
Listing16.2.1.1 
Screening Status 
Enrolled 
 
Listing16.2.1.2 
Participants Disposition Status 
Enrolled 
 
Listing 16.2.1.3 
Visit Dates 
Enrolled 
 
Listing 16.2.1.4 
Treatment Assignment 
Enrolled 
16.2.2 Protocol Deviations 
 
 
Listing16.2.2.1 
Protocol Deviations 
Enrolled 
16.2.3 Subject Excluded from Analyses 
 
 
Listing16.2.3.1 
Patients Excluded from the Analysis Sets 
Enrolled 
16.2.4 Demographic and Other Baseline Data 
 
 
Listing16.2.4.1 
Informed Consent 
Enrolled 
 
Listing16.2.4.2 
Participant Demographics 
Enrolled 
 
Listing16.2.4.3 
Inclusion and Exclusion Criteria 
All Participants 
 
Listing16.2.4.4 
Medical History 
Enrolled 
 
Listing16.2.4.5 
Participants Substance Use - Drugs 
Enrolled 
 
Listing16.2.4.6 
Participants Substance Use - Tobacco 
Enrolled 
 
Listing16.2.4.7 
Participants Substance Use - Alcohol 
Enrolled 
 
Listing 16.2.4.8 
Prior Medication 
Enrolled 
 
Listing 16.2.4.9 
Concomitant Medication 
Enrolled 
16.2.5 Compliance and Drug Concentration Data 
 
Listing16.2.5.1 
Study drug administration 
Safety 
 
Listing16.2.5.2 
Blood Collection for PK Assessments 
Enrolled 
 
Listing16.2.5.3 
PK Concentrations  
Enrolled 
 
Listing16.2.5.4 
PK Parameters for PQP 
PK 
 
Listing16.2.5.5 
PK Parameters for PQP N-oxide (metabolite) 
PK 
16.2.6 Individual response data 
 
16.2.6.1 
Palatability Questionnaire 
Safety 
16.2.7 Adverse Event listings 
 
Listing16.2.7.1 
All Adverse Events  
Enrolled 
 
Listing16.2.7.2 
Study discontinuation of participants due to 
Serious Adverse Event and Death 
Enrolled 
 
Listing16.2.7.3 
Participant Deaths 
Enrolled 
16.2.8 Laboratory Assessment and other safety assessment 
 
Listing16.2.8.1 
Listing of Laboratory Results - Haematology 
Enrolled 
 
Listing16.2.8.2 
Listing of Laboratory Results - Biochemistry 
Enrolled 
 
Listing16.2.8.3 
Listing of Laboratory Results - Coagulation 
Enrolled 
 
Listing16.2.8.4 
Listing of Laboratory Results - Thick Blood 
Smear - Malaria 
Enrolled 
 
Listing16.2.8.5 
Listing of Laboratory Results - Urinalysis 
Enrolled 
 
Listing16.2.8.6 
Vital Signs 
Enrolled 
 
Listing16.2.8.7 
Pregnancy Test 
Enrolled 
 
Listing16.2.8.8 
Follicle-stimulating hormone 
Enrolled 
 
Listing16.2.8.9 
Serology and Special Tests 
Enrolled 
 
Listing16.2.8.10 
Urine Drug Screen and Alcohol Breath Test 
Enrolled 


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Listing Number 
Listing Title 
Population 
 
Listing16.2.8.11 
12- Lead ECG 
Enrolled 
 
Listing16.2.8.12 
Physical Examination 
Enrolled 
 
 


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23.3 
Appendix 3: PLANNED SUMMARY TABLES 
The following tables are planned to be generated for the study (note: Numbering is 
indicative only and may be updated based on CSR requirements): 
 
Table Number 
Table Title 
Population 
14.1 Demographic Data 
 
 
Table14.1.1.1 
Participant Disposition at Screening 
Enrolled 
 
Table14.1.1.2 
Participant Disposition Status by Parts 
Randomized 
Participants 
 
Table14.1.1.3 
Summary of Analysis Set by Parts 
Randomized 
Participants 
 
Table14.1.1.4 
Summary of Protocol Deviation by Parts 
Safety 
14.1.2 Participants Baseline Characteristics 
 
 
Table14.1.2.1.1 
Summary of Demographics by Parts 
Safety 
 
Table14.1.2.1.2 
Summary of Demographics by Parts 
PK 
 
Table14.1.2.2 
Study drug administration by Parts 
Safety 
 
Table14.1.2.3 
Summary of Prior Medications by Parts 
Safety 
 
Table14.1.2.4 
Summary of Concomitant Medications by Parts 
Safety 
14.2.1 Primary and Secondary Endpoint Analysis 
 
 
Table14.2.1.1 
Summary of PQP pasma concentrations by Parts 
PK 
 
Table14.2.1.2 
Summary of PQP PK parameters by Parts 
PK 
 
Table14.2.1.3 
Assessment of bioequivalence between PQP 
dispersible granule and PQP hard tablet 
PK 
 
Table14.2.1.4 
Assessment of Bioequivalence between PQP 
dispersible granule (Fasted) and High-fat meal, 
Low-fat African meal, and Milk 
PK 
14.2.2 Exploratory Endpoint Analysis 
 
 
Table14.2.2.1 
Summary of PQP N-oxide (metabolite) plasma 
concentrations by Parts 
PK 
 
Table14.2.2.2 
Summary of PQP N-oxide (metabolite) PK 
Parameters by Parts 
PK 
 
Table14.2.2.3 
Summary of Palatability questionnaire by Parts 
Safety 
14.3.1 Adverse Events- Safety Analysis 
 
Table14.3.1.1 
Overall Adverse Events by Parts 
Safety 
 
Table14.3.1.2 
Summary of Pre-Treatment Adverse Events by 
System Organ Class and Preferred Term and by 
Parts 
Safety 
 
Table14.3.1.3 
Summary of TEAEs by System Organ Class and 
Preferred Term and by Parts 
Safety 
 
Table14.3.1.4 
Summary of Serious TEAEs by System Organ 
Class and Preferred Term and by Parts 
Safety 
 
Table14.3.1.5 
Summary of TEAEs and SAEs leading to 
withdrawal/discontinuation from the study by 
Parts 
Safety 
 
Table14.3.1.6 
Summary of TEAEs leading to death by Parts 
Safety 
 
Table14.3.1.7 
Summary of TEAEs by Relationship, System 
Organ Class, and Preferred Term and by Parts 
Safety 


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Table Number 
Table Title 
Population 
 
Table14.3.1.8 
Summary of TEAEs by Outcome, System Organ 
Class, and Preferred Term and by Parts 
Safety 
 
Table14.3.1.9 
Summary of TEAEs by Action taken, System 
Organ Class, and Preferred Term and by Parts 
Safety 
 
Table14.3.1.10 
Summary of TEAEs by Toxicity Grade, System 
Organ Class, and Preferred Term and by Parts 
Safety 
 
Table14.3.1.11 
Summary of Drug related TEAEs by Severity and 
by Parts 
Safety 
 
Table14.3.2.1 
Listing of Deaths 
Safety 
 
Table14.3.2.2 
Participant Listing of Serious Adverse Events 
Safety 
14.3.4 Laboratory Assessment 
 
 
Table14.3.4.1 
Summary of Abnormal Clinical Laboratory Values 
Safety 
 
Table14.3.4.2 
Summary of Clinical Laboratory tests by Parts 
Safety 
 
Table14.3.4.3 
Cross-Tabulation of Laboratory Abnormalities 
Versus Baseline by Parts and Groups 
Safety 
14.3.5 Other Safety Assessment 
 
 
Table14.3.5.1 
Descriptive Statistics of Vital Signs by Parts 
Safety 
 
Table14.3.5.2 
Overall Abnormal Vital Signs Results by Parts 
Safety 
 
Table14.3.5.3 
Descriptive Statistics of 12-Lead ECG by Parts 
Safety 
 
Table14.3.5.4 
Abnormal ECG Results by Parts 
Safety 
 
Table14.3.5.5 
Summary of 12-Lead Electrocardiograms 
Interpretation Categories by Parts 
Safety 
 
Table14.3.5.6 
Summary of QTcF by Parts 
Safety 
 
 


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23.4 
Appendix 4: PLANNED SUMMARY FIGURES 
The following figures are planned to be generated for the study (note: Numbering is 
indicative only and may be updated based on CSR requirements): 
 
Figure Number 
Figure Title 
Population 
14.2.1 Primary and Secondary Endpoint Analysis 
 
 
Figure14.2.1.1 
Arithmetic mean (SD) of PQP plasma 
concentration-time profiles by dose group 
PK 
 
Figure14.2.1.2 
Geometric mean (SD) of PQP concentration time-
profiles by dose group 
PK 
 
Figure14.2.1.3 
Overlaying individual PQP plasma concentration-
time profiles by dose group 
PK 
 
Figure14.2.1.4 
Individual PQP plasma concentration-time 
profiles by dose group 
PK 
 
Figure14.2.1.5 
Individual PQP AUC/Cmax by Dose Group 
PK 
14.2.2 Exploratory Endpoint Analysis 
 
 
Figure14.2.2.1 
Arithmetic mean (SD) of PQP N-oxide 
(metabolite) plasma concentration-time profiles 
by dose group 
PK 
 
Figure14.2.2.2 
Geometric mean (SD) of PQP N-oxide 
(metabolite) plasma concentration-time profiles 
by dose group 
PK 
 
Figure14.2.2.3 
Overlaying individual PQP N-oxide (metabolite) 
plasma concentration-time profiles by dose group 
PK 
 
Figure14.2.2.4 
Individual PQP N-oxide (metabolite) plasma 
concentration-time profiles by dose group 
PK 
 
Figure14.2.2.5 
Individual PQP N-oxide (metabolite) AUC/Cmax by 
Dose Group 
PK 
14.3.5 Other Safety Assessment 
 
 
Figure 14.3.5.1 
Mean value of change from baseline QTcF 
Safety 
 
 

ICF_003.pdf: 
COVER PAGE 
 
 
 
                                                                                        Participant ID: MMV_SMC_22_01_01_-I__I__I__I 
 
Participant Information Sheet 
Clinical Study title: 
 
 
A randomized, open label, two-part, parallel-group, phase I study to evaluate the 
pharmacokinetics of Piperaquine oral dispersible Granules Formulation compared to 
Piperaquine hard Tablets administered as a single dose in fasting condition (Part 1) and of 
Piperaquine oral dispersible Granules Formulation administered as single dose in various 
fed states (Part 2) in healthy adult participants. 
 
 
 
Short title: Piperaquine granule formulation relative bioavailability and food effect study in 
healthy volunteers. 
 
 
This clinical study is organized by MMV Medicines for Malaria Venture, Geneva, Switzerland, in 
collaboration with Ifakara Health Institute of Tanzania. 
 
Protocol Number 
MMV_SMC_22_01 
Version Number 
 2.0  
Document Date 
14.02.2023 
Study Registration 
ClinicalTrials.gov: NCT05930782 
 
Responsible 
Institution 
Isabelle Borghini-or Stephan Chalon 
Medicines for Malaria Venture 
ICC – Block G, 3rd floor 
20 route de Pré-Bois 
P.O. Box 1826 
1215 Geneva 15, Switzerland 
Principal Investigator 
Dr. Florence Aphida Milando, MD, MPH 
Ifakara Health Institute  
P.O. Box 74, Bagamoyo, Tanzania 
Investigational 
Medicinal Product 
Piperaquine (PQP) 
 
 
 
 
 
 
 
 


 
 
 
 
                                                                                        Participant ID: MMV_SMC_22_01_01_-I__I__I__I 
Informed Consent Form_ Ped-PQP BA/FE_ EN_Version 2.0; 14 February 2023  
 
 
 
 
 
Page 1/22 
 
Participant Information Sheet 
Clinical Study title: 
 
 
A randomized, open label, two-part, parallel-group, phase I study to evaluate the 
pharmacokinetics of Piperaquine oral dispersible Granules Formulation compared to 
Piperaquine hard Tablets administered as a single dose in fasting condition (Part 1) and of 
Piperaquine oral dispersible Granules Formulation administered as single dose in various 
fed states (Part 2) in healthy adult participants. 
 
 
 
Short title: Piperaquine granule formulation relative bioavailability and food effect study in 
healthy volunteers. 
 
 
This clinical study is organized by MMV Medicines for Malaria Venture, Geneva, Switzerland, in 
collaboration with Ifakara Health Institute of Tanzania. 
 
Protocol Number 
MMV_SMC_22_01 
Version Number 
 2.0  
Document Date 
14.02.2023 
Study Registration 
Intended registries: 
ClinicalTrials.gov, Tanzania Clinical Trial Register (TzCTR) - 
imis2.tmda.go.tz/ 
Responsible 
Institution 
Isabelle Borghini-or Stephan Chalon 
Medicines for Malaria Venture 
ICC – Block G, 3rd floor 
20 route de Pré-Bois 
P.O. Box 1826 
1215 Geneva 15, Switzerland 
Principal Investigator 
Dr. Florence Aphida Milando, MD, MPH 
Ifakara Health Institute  
P.O. Box 74, Bagamoyo, Tanzania 
Investigational 
Medicinal Product 
Piperaquine (PQP) 
 
 
 
 
 
 
 
 


 
 
 
 
                                                                                        Participant ID: MMV_SMC_22_01_01_-I__I__I__I 
Informed Consent Form_ Ped-PQP BA/FE_ EN_Version 2.0; 14 February 2023  
 
 
 
 
 
Page 2/22 
 
Dear Sir or Madam, 
We would like to invite you to take part in our clinical study investigating a new child-friendly, taste-
masked dispersible granule formulation of PQP for the future potential prevention of malaria. PQP 
is a well-known antimalarial drug and already available for oral treatment under another 
formulation. 
Your participation is entirely voluntary. Before you decide whether to participate, it is important that 
you understand why the study is being conducted and what is involved. In this participant 
information sheet, we explain what the study is about and what is involved in both a short version 
(summary) and a longer version with more details. Please take the time to read the following 
information carefully. If anything is not clear, or if you would like more information, please do not 
hesitate to ask us questions. 
Thank you for your consideration and taking the time to read this information.  
Summary: 
1. 
Why is this clinical study needed? Aim and Selection 
Malaria is still a major problem in the African Region, and about 80% of malaria 
deaths occur in children under five years of age. The WHO strongly recommends the 
use of medicines to prevent malaria infection and its effects (malaria 
chemoprevention) in infants, children under five years and pregnant women.  Safe and 
well tolerated compounds are needed for these preventative medicines and new 
combinations need to be tested as malaria parasites become resistant to existing 
drugs.  
Piperaquine phosphate (PQP) combined with another antimalarial already in use is a 
potential option for malaria prevention as it has been in use for over 50 years. 
As the people to benefit from malaria prevention are mostly children, a child-friendly 
way of giving the medicine is needed.  A new granule version of PQP has been 
developed which can be mixed with water and should have acceptable taste.  To find 
out how well and how fast the new child-friendly PQP oral granule formulation is  
absorbed and eliminated in the human body when administered with different food 
conditions, we need to test it first in 60 healthy adult participants (male and female). 
The total study duration is 4 to 6 months. Each participant will be in the study for 37 to 
75 days. 
 
 
2. 
General information about the study 
● PQP is already available as part of a combination products e.g. an antimalarial 
known as D-ARTEPP® in Tanzania, for treatment of uncomplicated malaria. 
● We would like to test a child-friendly PQP oral granule in adults to get 
preliminary information. 
● Child-friendly PQP oral granules have not been tested in humans before. 
● We would like to find out how the human body absorption is affected, when 
administered with different food conditions. The study doctor will let you know 
the type of food that you will be given. You can be given either  high fat meal, 
low fat meal or milk or no food (fasting). You will not choose the type of food. 
● We would like to find out how well tolerated the new child-friendly PQP oral 
granule is. 
3.  
What are the procedures? 


 
 
 
 
                                                                                        Participant ID: MMV_SMC_22_01_01_-I__I__I__I 
Informed Consent Form_ Ped-PQP BA/FE_ EN_Version 2.0; 14 February 2023  
 
 
 
 
 
Page 3/22 
 
Taking part in the study will involve: 
● Attending several hospital appointments to check that you are healthy and can 
participate in the study. 
● After an overnight fast, taking the study medicine with or without food (see 
above), and staying in the hospital for three days, where we will closely follow 
you and do several tests to check your heart, your blood and vital signs. 
● Samples of your blood will be checked to see how much of the study drug is in 
it at regular time points (Pharmacokinetics). 
● Optional genetic testing of a liver enzyme (CYP450) from a blood sample.  
● Attending follow-up checks for 30 days after you have taken the drug.   
4. 
What are the benefits of participation? 
There will be no direct benefit to you if you decide to participate. However, you may 
profit from a comprehensive health check and aid future malaria control efforts if the 
new PQP child-friendly formulation is shown to improve the amount of study drug in the 
body at a given time point (bioavailability) and this isn’t affected by the type of food 
eaten. 
5.  
Is it mandatory to participate in this study? 
No, it is completely up to you. If you decide to take part you will be asked to sign a 
consent form.  
What are my duties? 
You will be asked to adhere to a certain lifestyle during the study and for women to 
follow contraception requirements.  
6.  
What are the risks and burdens? 
a) Risk of taking Piperaquine (PQP) 
PQP has been used extensively in many African and South East Asian countries. 
It’s known to be well tolerated in children and adults in the treatment of 
uncomplicated malaria, when combined with another medicine for malaria called 
Dihydroartemisinin (DHA).  
Common side effects (that affect more than 1 in 100 people, but fewer than 1 in 10 
people, who take the medicine) are: 
• a change in the heart’s electrical system (called prolonged QTc interval), and 
increased heart rate (tachycardia), anaemia (reduced haemoglobin), fever, 
headache and feeling weak. 
 
Uncommon side effects (that affect more than 1 in 1000 people, but fewer than 1 in 
100 people, who take the medicine) are: a slowing of heart rate (bradycardia), 
increases in the liver function enzymes (proteins that speed up chemical reactions 
in the body), dizziness, nausea and vomiting, abdominal pain, diarrhoea, skin 
changes such as inflammation, itchiness, rash or redness/dryness, muscle aches 
and joint pain, reduced appetite, cough, fever. 
 
Rare/ Very rare side effect (that affect fewer than 1 in 1000 people who take the 
medicine):  convulsion (similar to an epileptic fit/seizure). 
 
PQP as a dispersible granule formulation has not been administered to human 
subjects yet. PQP in tablets form has been given to healthy participants in a Phase 
1 study. The study participants were reported to have had temporary mild abnormal 
laboratory liver test results without being accompanied by clinical symptoms. These 
abnormal liver test results were considered rare. 


 
 
 
 
                                                                                        Participant ID: MMV_SMC_22_01_01_-I__I__I__I 
Informed Consent Form_ Ped-PQP BA/FE_ EN_Version 2.0; 14 February 2023  
 
 
 
 
 
Page 4/22 
 
There is also a risk of increased in absorption of PQP (and QTc effect) by the body 
in case it is taken together with some medications (antibiotics and herbal 
medication), that are strong 3A4 inhibitors. 
PQP is known to induce abnormal electrical conduction within the heart, which can 
lead to a change in the heart’s electrical system (QTc prolongation) in human 
participants and possibly abnormal beats of the heart with a risk of loss of 
consciousness. Therefore, during this study, healthy participants with risk factors for 
abnormal electrical conduction within the heart will be excluded and enrolled 
participants will be monitored for the effects of PQP on electrical conduction within 
the heart through Electrocardiogram recording. 
b) Risk associated with blood sampling and examinations  
There may be a risk of infection, bruising or pain from the procedures. 
c) Allergic reactions 
Everyone reacts differently to different medicines. There are very rare cases of skin 
irritation after taking PQP.  
d) Pregnancy risk and risk to foetus development  
Current data are not sufficient to exclude any potential risk to unborn babies if you 
become pregnant during the study. Therefore, we ask you to follow strict 
contraception requirements.  
e) Study burden 
Attending all appointments and staying in the hospital for parts of the study period 
will require your time and dedication. 
7.  
Will I know the results? 
All information learned during the study and relevant to your health and decision to 
continue taking part in the study will be communicated to you in a timely manner. At the 
end of the study, we will share the study results with you. 
8.  
Will my data and samples be kept confidential? 
During this clinical study, certain data will be collected, such as your name, date of birth, 
gender, address, phone number, medical condition and history, medical images, 
biological samples, genetic sequence, race and ethnicity, etc. We call this “Personal 
Data” as this allows to identify you.   
Your Personal Data is collected and kept confidential by the clinical site. All persons 
involved in the collection of your Personal Data at the clinical site are subject to 
professional secrecy. The clinical site will replace your Personal Data with a code. We 
call this the “Personal Coded Data”. The Sponsor will only receive the Personal Coded 
Data and will not be able to identify you.  
Only some of the Sponsor’s employees, vendors or health agencies will be able to see 
the Personal Data when they check the quality and progress of the Study (monitoring).   
 
Since the objective of clinical studies is to advance science for obtaining new 
treatments, the Sponsor is required to combine your Personal Coded Data collected 
from the study with other participants´ Personal Coded Data. This is done in order to (i) 
assess the safety and efficacy of the study drug, (ii) submit the study drug to the 
competent health agencies for approval and generally (iii) support scientific research.   
In order to meet this objective, the following persons and organizations need to have 
access to your Personal Coded Data:   


 
 
 
 
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 
Sponsor’s employees, collaborators or vendors (such as clinical research 
organizations);  
 
 
Worldwide health agencies’ employees and officers (i.e. Federal Drug Agency, 
European Medicine Agency, etc.);  
 
Regulatory authority, Ethics Committees or Investigational Review Boards, as 
applicable;  
 
Editors of scientific journals;  
 
Insurers, as the case may be. 
 
They may be located in other countries but during the transfer, the Sponsor will ensure 
protection of the Personal Coded Data as required by law.    
The Sponsor and the clinical site have to keep all study data by law for several years in 
accordance with applicable law.   
If the results of the trial are published, you will not be named. 
You understand that it is not possible to erase the Personal Data as the study data 
needs to be complete, precise and available for regulatory purposes.  
 
What will happen to my Samples?  
You consent to the collection, processing and storage of your biological samples. The 
samples will be destroyed after completion of the clinical safety report or at the discretion 
of the sponsor and your study doctor.  
 
Should a regulatory authority request further testing, the Sponsor will proceed with such 
testing. 
9. 
Can I withdraw from the study? 
You are free to withdraw at any time, without giving a reason and this will not affect 
your right to receive any medical attention you require, but you might need to attend a 
follow-up control check for your own safety. Your Personal Data and samples provided 
until then in the study will still be analyzed and used in accordance with the section 
above. 
10. 
Will I receive compensation? 
Your participation is entirely free, and you will be compensated for your time by 
receiving TSH 25,000 per study visit.  
Who owns the results of the study?  
The Sponsor is the owner of the Study results and any intellectual property rights 
derived from the Study results.  
By signing this form, I agree to the use of the Personal Coded Data for the research 
as described above.  
11. 
Is the study insured? 
All participants will be insured for any harm caused by participation and in connection 
with the study. 
12. 
How is the study funded? 
This study is financed by the Sponsor, MMV Medicines for Malaria Venture (MMV).  


 
 
 
 
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13. 
Who do I contact if I have any concerns? 
If you have any concerns or complaints about anything to do with the study, please 
contact: 
Principal Investigator: 
Dr Florence Aphida Milando, Tel: +255 712 935292 
Email: fmilando@ihi.or.tz 
 
Lead Physician: 
Dr. Hussein Mbarak Tel: +255623397766 Email: hmbarak@ihi.or.tz 
 
Community engagement personnel : 
Bakari Mwalimu  
Tel: +255655680551 
Email : bmwalimu@ihi.or.tz 
For data privacy concerns :  
Sylvie Fonteilles Drabek, General Counsel & EVP at MMV Medicines for Malaria 
Venture (E-mail: privacy@mmv.org) 
 
 
 
 


 
 
 
 
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What would taking part involve and detailed information? 
 
1. Why is this clinical study needed?  
Aim 
Malaria is still a major problem in the world, with most of malaria deaths in children under five 
years of age in WHO (World Health Organization) Africa Region. There is strong benefit from 
using malaria medication to protect children by clearing existing infections and preventing malaria 
infections during the season of greatest risk (chemoprevention). Only two malaria medications,SP 
(Sulfadoxine-Pyrimethamine) and SPAQ (Sulfadoxine-Pyrimethamine and Amodiaquine) are 
currently recommended by WHO for chemoprevention, The efficacy of these medicine is currently 
threatened by increasing resistance to SP. 
 
PQP is available as a fixed dose in combinations such as an antimalarial called 
Dihydroartemisinin (DHA) as D-ARTEPP in Tanzania, for treatment of uncomplicated malaria. 
The combination has been used extensively in many African and South East Asian countries. It is 
known to be well tolerated for the treatment of uncomplicated malaria in children and adults.  
A new dispersible child-friendly granule formulation is being developed to improve the amount of 
PQP in the body at a given time point (bioavailability) and prevent it from being affected by the 
food eaten (food effect). 
 
The aim of this pilot bioavailability/food effect study is to perform preliminary assessments on sixty 
(60) healthy adult participants (male and female) to evaluate the effects of different type of food 
regimen, including fasting condition, during the administration of a new child-friendly PQP oral 
granule formulation, as compared to a reference tablet formulation of PQP, on how well and how 
fast it is absorbed in the human body. 
Selection  
To participate in this study, we will check that:  
● You have consented to participate in the study 
● You are healthy 
● You are between 18 years and 55 years of age at the time of consent 
● You have a normal body weight 
● You understand and agree to comply with the study visits and requirements  
● You are willing to follow contraception  
● You are willing to not donate sperm or ova. 
 
In order to take part, you also must not: 
● Be pregnant or breastfeeding (for female participants) 
● Have a female partner(s) who is (are) pregnant or lactating (for male participants) 
● Have milk intolerance 
● Be unable or unwilling to follow the food requirement 
● Currently use tobacco in any form 
● Have donated blood or blood products (excluding plasma) within 90 days prior to the first 
day of dosing 
● Have received or plan to receive a COVID-19 vaccination two weeks prior to dosing or one 
week after trial last visit.    
 
● Have received PQP containing medication within 90 days or any other medications from 14 
days prior to first planned dosing of investigational medicine. If a doctor has prescribed any 
medication for you or if you took herbal therapies, you must tell the Research Physician.  


 
 
 
 
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● Be unable to swallow tablets 
● Have had any drug or alcohol abuse within the two years 
● Have used any dietary supplements or herbal medicines within 30 days prior to the first day 
of dosing. 
● Have ingested any poppy seeds within the 24 hours prior to screening or admission. 
 
The medical doctors will ask questions about your health and your current medication. They will 
ask you about any previous diseases you might have suffered from, potential allergies, and 
conditions that may prevent you from taking part in the study. 
They will also perform different examinations and several laboratory tests. You will be asked to 
give blood samples, urine to detect any potential infections such as malaria, HIV and hepatitis B or 
C. There may also be other reasons why you might not be suitable to take part in the study for your 
own safety. The doctor will discuss the test results with you.  
 
2. General information about the study 
This clinical trial is called “A randomized, open label, two-part, parallel-group, phase I study to 
evaluate the pharmacokinetics of Piperaquine oral dispersible Granules Formulation compared to 
Piperaquine hard Tablets administered as a single dose in fasting condition (Part 1) and of 
Piperaquine oral dispersible Granules Formulation administered as single dose in various fed 
states (Part 2) in healthy adult participants” 
What do these terms mean in more details?  
a) Randomization means that participants are allocated to a treatment group at random, by 
chance. Therefore, it is a matter of chance whether a participant is assigned to five different 
treatment groups. By comparing these treatments groups, we can really see if the amount 
of drug in the blood after administration is the same or increased by chance or not.  
b) Open label means that both the participant and the medical team will know which treatment 
has been assigned to whom.  
c) A phase I is a study which determines if a test substance does not induce any important 
medical reaction in healthy participants. Phase 1 study usually also evaluate 
Pharmacokinetic (see below).  
d) Pharmacokinetic tells how much there is test substance in your body over a period of time 
and how it is absorbed and then eliminated from your body. To know this, we need to take 
several blood samples at different times.  
Where will the study be conducted? 
The study will be conducted at Bagamoyo Clinical Trial Facility (BCTF) of Ifakara Health Institute 
located at Kingani Estate in Bagamoyo, which is part of the Ifakara Health Institute in the Bagamoyo 
district. 
Who is responsible for the study? 
The institution responsible for the conduct of the study is MMV Medicines for Malaria Venture 
(MMV). They are called the Sponsor.  We are conducting this study in accordance with Tanzania’s 
laws and internationally recognized guidelines. The Ifakara Health Institute Independent Review 
Board and the National Institute for Medical Research, the competent and independent ethics 
committees in Tanzania, have reviewed and approved this study. As well, Tanzanian Medicines 
and Medical Devices Authority has also reviewed the study and information about this medicine 
and has approved the study to take place.  
How does the study work? 


 
 
 
 
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A total of sixty (60) healthy adult participants (male and female) will be enrolled: 24 in part 1 and 
36 in part 2. 
Healthy adult participants (male and female) will be randomly allocated (one after the other) to one 
of the 5 treatment groups as follows: 
 
Part of the 
study 
Treatment 
Groups 
Number of 
Participants 
Conditions for treatment 
administration. 
Treatment /dosage  
Part 1  
  
1 
12  
Fasting for at 10 hours 
before treatment 
PQP hard tablet (320 
mg) 
 
2 
12  
Fasting for at 10 hours 
before Treatment 
PQP dispersible 
granule (320 mg)  
  
Part 2  
 
3 
12  
Fast for at least 10 hours 
before feeding with a 
high-fat meal (feeding will 
happen at least 30 
minutes before 
treatment). 
PQP dispersible 
granule (320 mg) 
4 
12  
Fast for at least 10 hours 
before feeding with a 
Low-fat meal 
representative of the 
African diet (feeding will 
happen at least 30 
minutes before 
treatment). 
  
PQP dispersible 
granule (320 mg) 
5 
12  
Fast for at least 10 hours 
before feeding with 250 
ml of whole milk (feeding 
will happen at least 30 
minutes before 
treatment). 
  
PQP dispersible 
granule (320 mg) 
 
The study doctor will let you know the fasting conditions required and the type of food that you will 
be given. You can be given either high fat meal, low fat meal or milk, or being dosed in fasting 
condition. You will not choose the type of food. 
3. What are the procedures?  
Participating in the study involves coming to the clinical trial facility for several appointments. The 
total study duration is 4 to 6 months; each participant will be in the study for 37 to 75 days. 
 
 
 


 
 
 
 
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Screening period (D-45 to D-2) 
You will come to the facility and you will be screened. First, we will explain the study to you. After 
you have signed the informed consent and agreed to take part in the study, we will ask you 
questions about your health, recent illnesses, and medications. If you seem suitable, we will: 
● Give you a medical examination. This includes taking your vital signs, an electrocardiogram 
(a painless test that records the rhythm of the heart) to check that you are healthy.  
● Measure your height, and weight. 
● Do a blood pregnancy test on women of childbearing potential.  
● Discuss and consult you on contraception requirements 
● Test your urine and blood for different health conditions and infections. 
● Test your blood for malaria 
● Test your blood for the hepatitis viruses B and C (viruses that can damage the liver) and HIV 
(the AIDS virus). 
 
If any of the tests are positive, we will treat you on site or refer you to the National Health System 
or the clinic at the Bagamoyo District Hospital. This will be for counselling, follow-up and referral if 
needed. A positive HIV or hepatitis test means that you are at risk of developing a serious disease 
in the future, and you might need to take medications to prevent it. 
During this first visit, we will take your passport size picture to make a study identification card, so 
that we can easily identify you when you come for subsequent study visits. You must keep this card 
with you all the time, so that you have contact numbers for the study team available in case of a 
medical emergency in case you are enrolled into the study. 
If any of the screening tests need repeating, or if we cannot do all the tests at your first visit, we will 
ask you to come back for a repeat tests or do the remaining tests. 
 
Admission to the facility (Day -1) 
You will be admitted to the ward of the Bagamoyo Clinical Trial Unit on the day before receiving 
the treatment.  
Please do not bring any food or drink from home as well as any recreational drugs, cigarettes, 
alcohol and medicines. This is for your safety and ensures you are at the best health. 
At the ward we will: 
● ask you about your health since your last visit and do an examination 
● check your vital signs and heart  
● take some blood to check you are healthy 
● do a blood pregnancy test on women of childbearing potential . 
 
We will ask you to fast for at least 10 hours before receiving the trial medication.  
Study procedures (Day 1 to Day 3) 
You will stay on the ward for two (2) days and three (3) nights in a row. We will ask you to come 
back after discharge for the follow-up visits on days 5,8,15,22 and 30.  
 
The following procedures and assessment will be done on the day when you receive your 
treatment, during the observation days and at the follow-up visit. 


 
 
 
 
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Study Day 
Procedures and assessments 
Treatment day 
Day 1 in the ward 
Early in the morning, we will review your medical history and 
medications and ask if you are still willing to participate in the study. 
You will be allocated at random, by chance to the treatment group. 
Neither you nor the Doctor will know in advance to which treatment 
group you will be allocated. 
Before and after your treatment we will do the following: 
● check your vital signs 
● take blood at 7 different time points (this will correspond to a total of 
21 ml = 4 teaspoons of blood) 
● Do electrocardiogram at 5 different time points 
● Within 10 minutes after receiving the study compound, you will be 
asked to complete a questionnaire on the taste of the compound.  
● No food will be allowed for 4 hours after having received the study 
compound. After that period, you will receive standardized meals at 
regular times during your stay in the ward. 
● Water will not be permitted 1 hour before and 1 hour after dosing. 
Otherwise, you may drink water at your own convenience.  
Observation days 
Day 2   
On day 2, we will do the following: 
● check your vital signs and examine you in case of any symptoms 
● take blood samples (3 ml = less than a teaspoon of blood) 
● do Electrocardiogram once 
Observation days 
Day 3   
On 3 days, we will do the following: 
● check your vital signs and examine you in case of any symptoms 
● take blood samples (6 ml = a teaspoon of blood) 
● do Electrocardiogram once 
In the afternoon of day 3, you will be discharged. 
Follow-up visits 
Days 5,8,15,22 
and 30 
On days 5,8,15,22 and 30 you will come back to the facility for a 
medical examination.  
We will do the following: 
● check your vital signs 
● take blood samples (3 ml = less than a teaspoon on day 5 and 22; 6 
ml = a teaspoon of blood on days 8 and 15; and 5 ml = a teaspoon 
of blood on day 30).  
● examine you in case of any unusual symptoms  
● do a blood pregnancy test on women of childbearing potential  on 
Day 30 
● check for malaria on day 30 
● do Electrocardiograms 
During the whole study, you will be asked to give a total of 67 ml (about 14 teaspoons) of blood.  
CYP450 is an enzymatic system (proteins) involved in causing chemical changes of a drug in your 
body and that occurs differently from one individual to the others. It causes each individual to handle 
PQP differently. In this study, to find out how different forms of CYP450 influence the 
biotransformation of PQP we would like to do a genetic testing of CYP450 from a single sample of 


 
 
 
 
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your blood.  You can opt out of this genetic test if you wish, without any effect on your participation 
in the study. 
 
4. What are the benefits? 
You will not have a direct benefit if you participate in this study.  
You may benefit from a comprehensive health check. The screening tests might be of benefit to 
you if we find an important medical problem. If any of the tests are positive, we will treat you on site 
or refer you to the National Health System or the clinic at the Bagamoyo District Hospital. This will 
be for counselling, follow-up and referral if needed.  
You will be closely monitored and you will receive free medical attention for illness or injury related 
to study participation during the entire study period. Routine medical or dental care and illness or 
injury not related to the study will not be compensated. 
If you participate, you may be helping malaria control efforts in the future if a new PQP formulation 
improves the amount of study drug in the body at a given time point (bioavailability) and is minimally 
affected by the food eaten. 
 
5. Do I have to participate?  
Your participation is voluntary. If you do not want to take part or later change your mind, you do not 
have to justify this.  
Duties if you decide to participate in the study: 
You must: 
● Not use tobacco in any form (e.g. smoking or chewing) or other nicotine-containing products 
in any form (e.g. gum, patch, electronic cigarettes)  
● Not consume or drink products containing cranberry, pomegranate, star fruit, grapefruit, 
pomelos, exotic citrus fruits or Seville oranges (including marmalade and juices made from 
these fruits) within 30 days before the first planned trial drug administration. 
● Not exercise very hard (anything that might make your muscles ache – for example, manual 
work, running, cycling, gym workouts, weightlifting), 48 hours before screening, admission 
and outpatient / follow-up visit. 
● Not have any food or drinks containing xanthine (e.g. chocolate, tea, coffee or cola drinks), 
48 hours before the planned first trial drug administration and each out-patient/ follow-up 
visit. 
● Not drink energy drinks or drinks containing taurine, glucuronolactone (e.g. Red Bull and 
Mo energy) 48 hours before the planned first trial drug administration and each out-
patient/ follow-up visit. 
● Not consume alcohol 48 hours before the first planned trial drug administration and each 
outpatient / follow-up visit. On other days: less than 14 units a week and less than three 
units in one day is permitted. 
 
● Remain in a semi-supine position for the first four hours after dosing each day, except to 
use the bathroom. 
 
● Fast overnight (no food or drink, except water) for at least 10 hours each time before getting 
treatment and to remain fasting for four hours afterwards if you are in treatment groups 1 
and 2.  


 
 
 
 
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● Not take any other medicines (prescribed, non-prescribed, dietary supplements, herbal 
remedies) from now until the end of the study. If another doctor advises you in the meantime 
to take a medicine, please let us know as soon as possible and inform your doctor that you 
are taking part in this study. 
● Not donate blood and plasma 90 days before the planned first trial drug administration. 
● Notify the medical team of any new symptoms or any concerns or injuries to your person 
during the study 
● Not take COVID-19 vaccination two weeks before the planned drug administration or one 
week after trial last visit.    
● Be willing to follow the contraception requirements of the study, which are detailed below; 
Contraception and risks 
If you are a woman of childbearing potential, you have to use a highly effective contraception.  
Personnel qualified in family planning (e.g., a nurse or a doctor) will counsel you on the options 
and what is best in your case. 
1) Options of highly effective contraceptives: 
● Hormones (taking tablets by mouth, injected or implanted under the skin) 
● Intrauterine device (T-shaped device that is placed inside the womb) to prevent 
pregnancy either by releasing hormones or not 
● Vasectomized partner (surgical procedure for male sterilization or permanent 
contraception) 
● Bilateral tubal occlusion (a long-life form of birth control, sterilization) 
● Abstinence from having sex. 
 
 
Contraceptives must be started at least 30 days prior to the first dose and need to be continued up 
to 16 weeks after the last dosage of PQP. If you become pregnant within 4 months after receiving 
the trial medication, you must inform the study doctor at Ifakara Health Institute as soon as possible. 
 
6. What are the risks and burdens? 
In any clinical study, there is a risk of an unexpected and serious reaction to the test substance, 
which could be life-threatening.  
 
a) Risk of taking the test substance (PQP) 
PQP as a dispersible granule formulation is a new formulation which has not been administered 
yet. PQP as tablets have been administered to healthy subject in phase 1 clinical study, participants 
(who were given PQP in tablets) were reported to have had temporary mild abnormal laboratory 
liver test results without being accompanied by clinical symptoms. These abnormal liver test results 
were considered rare (less than 1 in 1000 people). 
Side effects of piperaquine in (PQP); The following side effects (called adverse events) have been 
experienced after people took PQP in combination with another antimalarial substance called 
Dihydroartemisinin ( DHA) in the past. You may or may not experience any of these side effects: 
Common side effects (that affect more than 1 in 100 people, but fewer than 1 in 10 people, who 
take the medicine): 
• a change in the heart’s electrical system (called prolonged QTc interval), and increased 
heart rate (tachycardia) 
• anaemia (reduced haemoglobin) 


 
 
 
 
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• fever 
• headache 
• feeling weak 
Uncommon side effects (that affect more than 1 in 1000 people, but fewer than 1 in 100 people, 
who take the medicine): 
• a slowing of heart rate (bradycardia) 
• increases in the liver function enzymes (proteins that speed up chemical reactions in your 
body) 
• dizziness 
• nausea and vomiting 
• abdominal pain 
• diarrhoea 
• skin changes such as inflammation, itchiness, rash or redness/dryness 
• muscle aches and joint pain 
• reduced appetite 
• cough 
• fever 
Rare/ Very rare side effect (that affect fewer than 1 in 1000 people who take the medicine): 
• convulsion (similar to an epileptic fit/seizure). 
During this study, healthy participants with risk factors for abnormal electrical conduction within the 
heart will be excluded and enrolled participants will be monitored for the effects of PQP on electrical 
conduction within the heart through ECG recording (simple or triplicate ECGs recording depending 
on the time point). Also, biochemistry and hematology measurements (from blood samples) will be 
done periodically as part of clinical monitoring. 
You will remain in the facility under medical supervision until 48 hours following the drug 
administration and will be followed up to Day 30 (+/-1 day). 
The medical team will check you frequently for symptoms or side effects and provide treatment 
accordingly, if necessary. 
 
b) Risk associated with blood sampling and examinations  
All medical procedures involve some risk of injury such as a risk of infection, bruising, or pain from 
the procedures. Blood will need to be taken from you. This will be done with a cannula (a small 
tube inserted into your vein) or a needle.  
The pads we stick to your chest to monitor your heart may irritate your skin and cause itching and 
redness. We may have to shave you to make sure they stick correctly.  
All reasonable precautions will be taken to avoid these associated risks.  
 
c) Allergic reactions 
Everyone reacts differently to different medicines. There are very rare cases of skin irritation after 
taking PQP.  


 
 
 
 
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d) Pregnancy risk and risk to foetus development  
There is a potential risk to unborn babies if you become pregnant during the study. Therefore, it is 
necessary to avoid getting pregnant during the study or within 4 months after receiving the trial 
medication and follow strict safety and contraception requirements. If you or your partner (for male 
participants), becomes pregnant during this time period, you must inform the study doctor 
immediately and you will be asked to provide information on the course and outcome of the 
pregnancy. The study doctor will discuss these steps with you.  
In addition, three pregnancy tests are carried out in all women participating in the study of 
childbearing potential : one at the screening, one on the day of admission and one at the last follow-
up visit. 
e) Study burden 
Attending all appointments and staying in the hospital for parts of the study period will require your 
time and dedication.  
 
7. Results 
During the study, the study doctors will inform you orally and in writing of any new results and 
findings that are important to you personally and to decide whether you want to continue 
participating in the study.  
"Incidental findings", for example, results that were not specifically researched for, but found by 
chance during a test (such as blood sample for example), will be communicated to you if these 
findings are relevant to your health and well-being. This means that you may also be informed 
about an unknown disease if this is detected by chance. If you do not want to be informed about 
this, please inform your study doctor. 
At the end of the study, your study doctor will receive the study results and will share them with 
you. 
 
8. Will my data and samples be kept confidential? 
The steps taken to ensure your confidentiality are detailed below: 
a) Identifier- anonymity 
If you agree to participate in the study, certain data will be collected, such as name, date of birth 
gender, address, phone number, medical condition and history, images, biological samples, 
genetic sequence, race and ethnicity, etc. We call this “Personal Data” as this allows to identify 
you..   
Your samples and other medical data will not include any personal identification details. Your data 
will be stored using a unique patient identification number. This process is called coded data. The 
study doctors are responsible for maintaining the code list that links your assigned participant 
identification number to your name. This code list will be kept in a safe place at the Ifakara Health 
Institute and will allow you to be identified and contacted in case of emergency. 
b) Access to your information by Sponsor’s employees and external people 
The information that we collect may be reviewed by study sponsor’s employees and sponsor’s  
representatives (collaborators or vendors, such as clinical research organizations), authorized 
members from the government or regulatory health authorities, worldwide health agencies’ 
employees and officers (i.e. Federal Drug Agency, European Medicine Agency, etc.), independent 
ethics committees or institutional review boards’ members as part of their responsibility with 


 
 
 
 
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regards to the supervision of this study, editors of scientific journals, insurers, as the case may be. 
All of these must also maintain confidentiality of your records within the limits of the law. They may 
be located in other countries but during the transfer, the Sponsor will ensure protection of the 
Personal Coded Data as required by law.    
If the results of the trial are published, your identity will remain confidential. 
c) Transfer and storage of data and blood samples 
Your coded data will be transferred to Switzerland, the UK and the European Union; therefore, your 
data will be protected and follow applicable laws. 
Several blood samples collected for specific analysis, which cannot be done in Tanzania will be 
coded and shipped to Switzerland and the UK. They will be destroyed after the clinical safety report 
has been completed or at the discretion of the sponsor and PI.  
 
The Personal Data will be stored for a period of time in accordance with applicable laws.  
The code list and your medical data will be kept in a safe place at the Ifakara Health Institute for a 
period of 20 years after the end of the study.  
 
9.  Can I withdraw from the study? 
You are free to stop and withdraw from the study at any time without giving a reason. Your 
withdrawal from the study will not affect your general medical care. If you decide to stop 
participating in the research study, we might ask you to do a final safety follow-up assessment. 
Your data and samples collected until then will still be evaluated in coded form.  
Please note that the medical team can remove you from the study by the medical team for any of 
the following reasons: 
● If you experience a significant reaction to the test substance 
● If you develop a medical condition for which continuing would pose a risk to you or interfere 
with the analysis of the study result 
● If you cannot comply with visits or assessments 
● If the study is terminated for any reason 
● If the investigator believes that it is in your best interest to remove you from the study, 
 
10. Will I receive compensation? 
If you participate in this study, you will not be paid for your participation. However, we will 
compensate for your time lost during the period of clinic visits and admission only. This amount is 
25,000 TSH per study visit. For outpatient visits, you will be paid at the end of the visit before 
returning home. For the stay on the ward, you will be paid on the day of discharge for the number 
of days you stayed on the ward. In addition, meals and beverages will be provided during your 
admission to the hospital and the transportation fare incurred when returning to the hospital will be 
reimbursed.  
 
11. Is the study insured? 
MMV Medicines for Malaria Venture is responsible and liable for any damages you may incur in 
connection with the study product or the research procedures (e.g. examinations). MMV Medicines 
for Malaria Venture has taken out insurance for this purpose. The conditions and procedure are 
regulated by law.  


 
 
 
 
                                                                                        Participant ID: MMV_SMC_22_01_01_-I__I__I__I 
Informed Consent Form_ Ped-PQP BA/FE_ EN_Version 2.0; 14 February 2023  
 
 
 
 
 
Page 17/22 
 
 
12. How is the study funded? 
All of the costs of the study are financed by MMV Medicines for Malaria Venture, Geneva, 
Switzerland. 
 
13. Who do I contact if I have any concerns? 
The Ifakara Health Institute Institutional Review Board (IRB) secretary and the MRCC (Medical 
Research Coordinating Committee) chair and Tanzania Medicines and Medical Devices Authority 
(TMDA) representative may be contacted in case of any question or need of clarification related to 
this study or to your participation at any time before signing the consent form and during the study 
period. You can also contact these individuals in the event of an injury resulting from your 
participation in this study: 
Secretary of Ifakara Health Institute IRB: 
Dr. Mwifadhi Mrisho 
Ifakara Health Institute, Plot 463, Kiko Avenue Mikocheni, P.O. Box 78 373 - Dar es Salaam 
Tel: +255 222 774 756 or +255 655 766 675 
Email: enquiries@Ifakara Health Institute.or.tz 
 
Chair of the MRCC (NIMR). 
Medical Research Coordinating Committee (MRCC), National Health Research Ethics Review 
Committee, National Institute for Medical Research (NIMR), 2448 Ocean Road, P.O.Box 9653, Dar 
es Salaam, Tanzania  
Tel +255 22 2121400  
Email: info@nimr.or.tz 
 
TMDA Representative: 
Tanzania Medicines and Medical Devices Authority (TMDA), P. O. Box 77150, Dar es Salaam, 
Tanzania 
Tel +255 22 2450512, 
Email: info@tmda.or.tz  
 
Principal Investigator (Medical team): 
Dr. Florence Aphida Milando 
Ifakara Health Institute  
P.O. Box 74, Bagamoyo, Tanzania 
Tel: +255 712 935292 
Email: fmilando@ihi.or.tz 
 
Co-Investigators (Medical team): 
Dr. Hussein Mbarak 
Tel: +255623 397766 
Email: hmbarak@ihi.or.tz 


 
 
 
 
                                                                                        Participant ID: MMV_SMC_22_01_01_-I__I__I__I 
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Page 18/22 
 
Dr. Mohammed Ally Rashid  
Tel: +255673837063           
Email: mrashid@ihi.or.tz 
 
Community engagement personnel: 
Dr. Bakari Mwalimu 
Tel: +255655680551 
Email: bmwalimu@ihi.or.tz 
 
 
The Sponsor, directly or through insurance coverage, will only pay for study related injuries in 
accordance with applicable laws. 
You have the right to contact the sponsor MMV Medicines for Malaria Venture to obtain information 
about your stored personal data. 
Contact person for any questions relating to data privacy/personal data of MMV Medicines 
for Malaria Venture:  
 
MMV Medicines for Malaria Venture, ICC – Block G, 3rd floor, 20 route de Pré-Bois, P O Box 1826, 
1215 Geneva 15, Switzerland  
Sylvie Fonteilles Drabek, General Counsel & EVP 
E-mail: privacy@mmv.org 
 
 
 
 


 
 
 
 
                                                                                        Participant ID: MMV_SMC_22_01_01_-I__I__I__I 
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Page 19/22 
 
 
Informed Consent Form 
Please read this form carefully.  
Please ask if you do not understand or want to know something. 
Your written consent is required for participation in the study. 
Study Information: 
 
Study title: 
 
A randomized, open label, two-part, parallel-group, phase I 
study to evaluate the pharmacokinetics of Piperaquine oral 
dispersible Granules Formulation compared to Piperaquine 
hard Tablets administered as a single dose in fasting 
condition (Part 1) and of Piperaquine oral dispersible 
Granules Formulation administered as single dose in various 
fed states (Part 2) in healthy adult participants” 
Responsible institution: 
MMV Medicines for Malaria Venture 
ICC – Block G, 3rd floor, 20 route de Pré-Bois 
P O Box 1826, 1215 Geneva 15, Switzerland 
Site of study conduct: 
Ifakara Health Institute  
P.O. Box 74, Bagamoyo, Tanzania 
Principal Investigator: 
Dr. Florence Milando 
P.O. Box 74, Bagamoyo, Tanzania 
 
Participant Information: 
 
First name, middle name and 
last name (in capital letters) 
 
Date of birth (dd.mm.yyyy) 
 
Sex 
󠄸 Female                                            󠄸 Male 
 
 
● I was informed verbally and in writing by the undersigned study doctor/ clinician/nurse about 
the purpose, the course of the project, possible advantages and disadvantages and 
possible risks. 
● I voluntarily participate in this study and accept the content of the written information 
provided. I had enough time to make my decision. 
● My questions regarding participation in this study have been answered. I retain the written 
information and receive a copy of my signed informed consent. 


 
 
 
 
                                                                                        Participant ID: MMV_SMC_22_01_01_-I__I__I__I 
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Page 20/22 
 
● I agree that the responsible experts of the sponsor, the responsible ethics committees and 
the drug regulatory agencies may inspect my uncoded data for review and control purposes, 
but with strict maintenance of confidentiality. 
● I will be informed of the results of the study and incidental findings that directly affect my 
health. If I do not wish this, I will inform the study doctor/ clinician. 
● I know that my health-related and personal data (and samples) can only be passed on in 
coded form for research purposes for this study abroad. The sponsor is responsible for 
ensuring that the same standards as in Switzerland/Europe/Tanzania laws are respected.  
● I can withdraw from the study at any time and without giving reasons. The data and samples 
collected up to the time of withdrawal will be used for the evaluation of the study. 
● I am informed that an insurance policy covers damages that are attributable to the study  
● I am aware that the obligations stated in the participant information must be complied with. 
In the interest of my health, the study doctor may exclude me from the study at any time. 
 
 
Date (dd.mm.yyyy) and time (hh: mm) 
Participant’s signature: 
 
 
Confirmation of the person taking the consent: 
I hereby confirm that I have explained the nature, meaning and scope of the study to this participant. 
I assure that I will fulfil all my obligations in connection with this study in accordance with applicable 
law. If, at any time during the conduct of the study, I become aware of any aspect that may affect 
the participant's willingness to participate in the study, I will inform the participant immediately.  
 
First name, middle name 
and last name of the 
person taking the 
consent: 
(in capital letters) 
 
Role in the study: 
(in capital letters) 
 
Date (dd.mm.yyyy) and time (hh: mm) 
 
 
 
Signature 
of 
the 
person 
taking the consent: 
 
 
 


 
 
 
 
                                                                                        Participant ID: MMV_SMC_22_01_01_-I__I__I__I 
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Page 21/22 
 
ONLY FOR THOSE WHO CONSENT 
 
Do you agree your blood to be used for genetic testing of CYP450 system?        
Yes   
No  
 
Date (dd.mm.yyyy) and time (hh: mm) 
Participant’s signature: 
 
 
 
First name, middle name 
and last name of the 
person 
taking 
the 
consent: 
(in capital letters) 
 
Role in the study: 
(in capital letters) 
 
Date (dd.mm.yyyy) and time (hh: mm) 
Signature 
of 
the 
person 
taking the consent: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
                                                                                        Participant ID: MMV_SMC_22_01_01_-I__I__I__I 
Informed Consent Form_ Ped-PQP BA/FE_ EN_Version 2.0; 14 February 2023  
 
 
 
 
 
Page 22/22 
 
APPENDIX: Optional Consent for Future Research 
 
During or after the clinical study, the Sponsor (MMV) may want to use the Personal Coded Data 
for additional research projects. The Personal Coded Data includes your year of birth, gender, a 
special code that identifies you, study information, and biological samples as explained in the 
Section 8 “Will my data and samples be kept confidential?”. 
 
Wherever permitted by law or requested by the authorities, this additional research may include 
studies to get more information on (Malaria or other diseases with similar mechanism of action). It 
may be used to design or improve methods for analyzing, comparing, or combining your study data 
with data from subjects treated with other drugs. It may involve new approaches or biological 
markers of Malaria and other aspects of Malaria. Researchers may study the benefits and risks of 
(paediatric) PQP and compare the data from (paediatric) PQP with other drugs. This will allow MMV 
and other researchers to better understand Malaria, how (paediatric) PQP works and to be able to 
find the best way to treat subjects with Malaria (or other diseases with a similar mechanism of 
action).  
 
The information under section 8 “Will my data and samples be kept confidential?” is applicable to 
this optional consent.   
 
You will not own any data and discoveries generated from the additional research studies. The 
data will not become part of your medical record.  
 
If you choose to give consent for additional research, you can change your mind at any time. If you 
decide you no longer want MMV to use the Personal Coded Data for additional research, this is 
possible. You can continue to be in the main study. Please notify the study doctor if this is the case.  
 
By signing below, I agree to the use of the Personal Coded Data for additional research as 
described above.   
 
This consent is valid unless and until I withdraw it. 
 
Participant Name 
(First name, middle name and 
last name). 
 
Date (dd.mm.yyyy)  
 
 
Participant signature: 
 
 
 
Name 
of 
presenter who 
presented/explained 
the 
document. (First name, middle 
name and last name). 
 
Date (dd.mm.yyyy)  
 
 
Signature of presenter who 
presented/explained 
the 
document: 
 

Prot_000.pdf: 
Ped-PQP BA/FE 
MMV_SMC_22_01 Version 3.0; 8 November 2023 
 
1 of 64 
Clinical Study Protocol 
A randomized, open label, two-part, parallel-group, phase I study to evaluate the 
pharmacokinetics of Piperaquine oral dispersible Granules Formulation compared to 
Piperaquine hard Tablets administered as a single dose in fasting condition (Part 1) 
and of Piperaquine oral dispersible Granules Formulation administered as single dose 
in various fed states (Part 2) in healthy adult participants. 
Study ID 
MMV_SMC_22_01 
Protocol Version; Date 
Version 3.0; 8 November 2023 
Study Registration 
Intended registries: 
ClinicalTrials.gov, Tanzania Clinical Trial Register (TzCTR) - 
imis2.tmda.go.tz/ 
Sponsor  
MMV Medicines for Malaria Venture 
ICC – Block G, 3rd floor 
20 route de Pré-Bois 
P O Box 1826 
1215 Geneva 15, Switzerland 
Principal Investigator 
Dr Florence Aphida Milando, MD, MPH 
Ifakara Health Institute (IHI) 
P.O. Box 74, Bagamoyo, Tanzania 
Email: fmilando@ihi.or.tz 
Tel: +255 712 935 292 
Investigational Medicinal 
Product 
Piperaquine (PQP) 
The information contained in this document is confidential. It is intended solely for the Investigators, 
potential Investigators, consultants, or applicable Independent Ethics Committees and Regulatory 
Authorities. It is understood that this information will not be disclosed to others without prior written 
authorisation from the Sponsor, except where required by applicable local laws. 
 
 


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1 GENERAL INFORMATION 
1.1 
List of Trial Personnel 
Names 
Institution 
Position 
Dr. Florence Aphida Milando, 
IHI 
Principal Investigator 
Dr. Salim Abdulla 
IHI 
Project Director 
Dr. Said Jongo 
IHI 
IHI Project Clinical Sciences and Medical Operations 
Gloria Nyaulingo 
IHI 
Study Coordinator 
Anneth-Mwasi Tumbo 
IHI 
Laboratory Scientist 
Juliether Tiago 
IHI 
Lead Study Nurse 
Beatus Simon Bongole 
IHI 
Pharmacist 
Kamaka Kassimu 
IHI 
Senior Study Coordinator 
Dr. Hussein Mbarak 
IHI 
Lead Clinician 
Dr. Mohamed Ally Rashid 
IHI 
Study Clinician 
Bakari Mwalimu 
IHI 
Study Clinician 
Thabit Athuman 
IHI 
Site Clinical Data Manager 
Ali Ali 
IHI 
Site Statistician 
 
 


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1.2 
List of Facilities and Providers 
Central/Local Safety 
Laboratory 
Laboratory of Ifakara Health Institute (IHI), Tanzania 
Bagamoyo Research and Training Centre (BRTC) 
P.O. Box 74, Bagamoyo 
Pharmacovigilance 
Prime Vigilance  
The Surrey Research Park  
1 Occam Court, Occam Road,  
Guilford, Surrey, GU2 7HJ, UK  
Tel: +44 (0) 1483 307 920 email: MMV@primevigilance.com  
Bioanalytical Laboratory 
Swiss BioQuant AG  
Kägenstrasse 18  
4153 Reinach, Switzerland  
Tel: +41(0) 617 1698 12 : email: anita.kress@swissbioquant.com 
ECG Analyses 
Banook  
84 Avenue du XXème Corps  
5400 Nancy, France  
Tel : 33(0) 3 83 39 10 10 : email: noemie.maignan@banookgroup.com 
Project Management,  
Clinical Monitoring,   
Data Management,  
Biostatistics,   
Medical Writing 
IQVIA  
3 Forbury Place, 23 Forbury Road  
Reading, RG1 3JH  
United Kingdom  
Tel: +447501 617 422 : email: liam.livingstone@iqvia.com 
Pharmacokinetic 
Parameters  
PharmaKinetic Ltd 
BioCity, Pennyfoot Street, Nottingham NG1 1GF, United Kingdom 
Tel: +44 (0) 7712 897 059 : email: helen.walker@clinpharm.co.uk 
Medical Monitoring 
Dr. med. Michael Marx MD PhD 
Medical Director 
ICON Clinical Research Service 
Heinrich-Hertz Str.26 
63225 Langen 
Germany 
Tel: +49 6103 1950 
eTMF 
Phlexglobal Ltd. 
Chesham House, Deansway,  
Chesham, Bucks, HP5 2FW, UK M: +44 (0)7718705137 
Genotyping 
The Doctors Laboratory  
The Halo Building, 1 Mabledon Place 
London, WC1H 9AX, United Kingdom 
Tel: +44 (0)20 7307 7373  
Email: tdl@tdlpathology.com 
   
 
 
 


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1.3 
Signatures (Sponsor and Investigator) 
This clinical trial protocol has been reviewed and approved by the Sponsor. 
Sponsor’s Medical Director 
Signature 
 
 
Name  
Anne Claire Marrast, MD 
Date of Signature (dd.mm.yyyy) 
Title 
Senior Medical Director  
Institution 
Medicines for Malaria Venture 
ICC – Block G, 3rd floor 
20 route de Pré-Bois 
P O Box 1826 
1215 Geneva 15, Switzerland 
 
Sponsor’s Director Clinical Sciences  
Signature 
 
 
Name  
Myriam el Gaaloul, PhD 
Date of Signature (dd.mm.yyyy) 
Title 
Senior Clinical Scientist  
Institution 
Medicines for Malaria Venture  
ICC – Block G, 3rd floor  
20 route de Pré-Bois  
P O Box 1826  
1215 Geneva 15, Switzerland 
 
 


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Principal Investigator’s Agreement: 
• 
I have read this protocol MMV_SMC_22_01 “A randomized, open label, two-part, parallel-group, 
phase I study to evaluate the pharmacokinetics of Piperaquine oral dispersible Granules 
Formulation compared to Piperaquine hard Tablets administered as a single dose in fasting 
condition (Part 1) and of Piperaquine oral dispersible Granules Formulation administered as single 
dose in various fed states (Part 2) in healthy adult participants.” and agree that it contains all 
necessary details for carrying out this study. I will conduct the study as outlined herein and will 
complete the study within the time designated. 
• 
I will ensure that all individuals and parties contributing to this study are qualified and I will implement 
procedures to ensure integrity of study tasks and data. 
• 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me 
who assist in the conduct of this study. I will discuss this material with them to ensure they are fully 
informed regarding the drug and the conduct of the study. 
• 
I will use only the informed consent forms approved by the Sponsor or its representative and will 
fulfil all responsibilities for submitting pertinent information to the Independent Ethics Committees 
responsible for this study. 
• 
I agree that the Sponsor or its representatives shall have access to any source documents from 
which Case Report Form information may have been generated. 
• 
I agree to conduct the study in compliance with the current version of the Declaration of Helsinki, 
ICH-GCP E6(R2) as well as all the national legal and regulatory requirements.  
Principal Investigator 
Signature 
 
 
Name  
Dr. Florence Aphida Milando, MD, MPH 
Date of Signature (dd/mm/yy) 
Title 
Principal Investigator 
Institution 
Ifakara Health Institute 
Address 
P.O. Box 74, Bagamoyo, Tanzania 
Phone 
+255 712 935 292 
Site Project Clinical Sciences and Medical Operations 
Signature 
 
 
Name  
Said Abdallah Jongo, MD, MMed (Internal 
Medicine), PhD 
Date of Signature (dd/mm/yy) 
Title 
IHI Project Clinical Sciences and Medical Operations 
Institution 
Ifakara Health Institute 
Address 
P.O. Box 74, Bagamoyo, Tanzania 
Phone 
+255 714 939 831 
 
 


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1.4 
Table of contents 
1 
GENERAL INFORMATION .......................................................................................................................................... 2 
1.1 
LIST OF TRIAL PERSONNEL .............................................................................................................................................. 2 
1.2 
LIST OF FACILITIES AND PROVIDERS .................................................................................................................................. 3 
1.3 
SIGNATURES (SPONSOR AND INVESTIGATOR) ..................................................................................................................... 4 
1.4 
TABLE OF CONTENTS ..................................................................................................................................................... 6 
1.5 
ABBREVIATIONS ........................................................................................................................................................... 9 
1.6 
SYNOPSIS .................................................................................................................................................................. 11 
2 
BACKGROUND INFORMATION ............................................................................................................................... 18 
2.1 
INTRODUCTION .......................................................................................................................................................... 18 
2.1.1 
General treatment / Administration ................................................................................................................. 19 
2.1.2 
Efficacy .............................................................................................................................................................. 19 
2.1.3 
Mechanism of action, clearance and pharmacokinetics ................................................................................... 19 
2.1.4 
Safety and tolerability ....................................................................................................................................... 19 
2.1.5 
Safety profile and potential risks ...................................................................................................................... 20 
2.2 
JUSTIFICATION FOR THE DOSAGE AND DOSAGE PLAN .......................................................................................................... 20 
3 
OBJECTIVES AND PURPOSE .................................................................................................................................... 22 
3.1 
STUDY RATIONALE AND OBJECTIVES ................................................................................................................................ 22 
3.1.1 
Study rationale .................................................................................................................................................. 22 
3.1.2 
Primary objective .............................................................................................................................................. 22 
3.1.3 
Secondary objectives ......................................................................................................................................... 22 
3.1.4 
Exploratory objectives ....................................................................................................................................... 23 
3.2 
SCIENTIFIC JUSTIFICATION AND RATIONALE OF STUDY POPULATION ....................................................................................... 23 
4 
STUDY DESIGN ....................................................................................................................................................... 24 
4.1 
PRIMARY AND SECONDARY ENDPOINT ............................................................................................................................. 24 
4.1.1 
Primary endpoint .............................................................................................................................................. 24 
4.1.2 
Secondary endpoints ......................................................................................................................................... 24 
4.2 
MEASURES TO MINIMIZE BIAS ....................................................................................................................................... 25 
4.2.1 
Randomization .................................................................................................................................................. 25 
4.2.2 
Blinding ............................................................................................................................................................. 25 
4.3 
STUDY DURATION AND DURATION OF PARTICIPANT’S PARTICIPATION .................................................................................... 25 
4.4 
SCHEDULE OF EVENTS .................................................................................................................................................. 26 
4.5 
SAFETY HOLD AND EARLY TERMINATION OF THE STUDY ....................................................................................................... 27 
5 
SELECTION OF THE STUDY PARTICIPANTS ............................................................................................................... 28 
5.1 
STUDY SETTING .......................................................................................................................................................... 28 
5.2 
RECRUITMENT ........................................................................................................................................................... 28 
5.2.1 
Inclusion criteria ................................................................................................................................................ 29 
5.2.2 
Exclusion criteria ............................................................................................................................................... 29 
5.3 
DISCONTINUATION OF INDIVIDUAL PARTICIPANTS .............................................................................................................. 32 
5.4 
REPLACEMENT OF INDIVIDUAL PARTICIPANTS ................................................................................................................... 32 
6 
TREATMENT OF PARTICIPANTS .............................................................................................................................. 33 
6.1 
IDENTITY OF INVESTIGATIONAL PRODUCTS (TREATMENT / MEDICAL DEVICE) ........................................................................... 33 
6.1.1 
Experimental intervention (Piperaquine tetraphosphate dispersible granules) ............................................... 33 
6.1.2 
Comparator (Piperaquine tetraphosphate tablets) .......................................................................................... 33 
6.2 
ADMINISTRATION OF EXPERIMENTAL AND CONTROL INTERVENTIONS .................................................................................... 33 


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6.2.1 
Administration under fasted conditions: Part 1 (Groups 1 and 2) .................................................................... 33 
6.2.2 
Administration under fed conditions: Part 2 (Groups 3, 4 and 5) ..................................................................... 33 
6.3 
GENERAL APPROACH FOR PREPARING MEALS FOR ADMINISTRATION UNDER FED CONDITIONS ..................................................... 33 
6.3.1 
Standard meals at regular intervals throughout the in-house stay. ................................................................. 34 
6.4 
PACKAGING, LABELLING AND STORAGE CONDITIONS .......................................................................................................... 34 
6.5 
DOSE MODIFICATIONS ................................................................................................................................................. 34 
6.6 
COMPLIANCE WITH STUDY INTERVENTION ....................................................................................................................... 34 
6.7 
CONCOMITANT INTERVENTIONS (TREATMENTS) ................................................................................................................ 35 
6.8 
STUDY DRUG ACCOUNTABILITY ...................................................................................................................................... 35 
6.9 
RETURN OR DESTRUCTION OF STUDY DRUG / MEDICAL DEVICE ............................................................................................. 35 
7 
STUDY ASSESSMENTS AND VISITS .......................................................................................................................... 36 
7.1 
CLINICAL ASSESSMENT PARAMETERS............................................................................................................................... 36 
7.1.1 
Vital signs .......................................................................................................................................................... 36 
7.1.2 
Medical history and review of systems ............................................................................................................. 36 
7.1.3 
Physical Examination ........................................................................................................................................ 36 
7.1.4 
12-lead ECG safety recording ............................................................................................................................ 36 
7.2 
LABORATORY ASSESSMENT PARAMETERS ......................................................................................................................... 37 
7.2.1 
PK assessment ................................................................................................................................................... 37 
7.2.2 
Exploratory assay .............................................................................................................................................. 38 
7.2.3 
Total blood volume ........................................................................................................................................... 38 
7.2.4 
Exploratory questionnaire: Palatability ............................................................................................................ 38 
7.3 
STUDY VISITS ......................................................................................................................................................... 38 
7.3.1 
Screening period (Day-45 to Day-2) .................................................................................................................. 38 
7.3.2 
In-house visit procedures .................................................................................................................................. 39 
7.3.3 
Clinic follow-up visits ......................................................................................................................................... 40 
7.3.4 
Unscheduled visits ............................................................................................................................................. 41 
8 
ASSESSMENT OF SAFETY ........................................................................................................................................ 42 
8.1 
SAFETY PARAMETERS................................................................................................................................................... 42 
8.1.1 
Collection and reporting of adverse events....................................................................................................... 42 
8.1.2 
Definition of adverse events .............................................................................................................................. 42 
8.1.3 
Types and recording of adverse events ............................................................................................................. 43 
8.2 
GRADING OF ADVERSE EVENTS ...................................................................................................................................... 43 
8.2.1 
Standard Toxicity Grading ................................................................................................................................. 43 
8.2.2 
Grading of abnormal values for safety laboratory assessments ....................................................................... 44 
8.2.3 
Abnormal assessments to be considered as adverse events ............................................................................. 44 
8.3 
ASSOCIATION OF ADVERSE EVENTS – RELATEDNESS TO THE MEDICINAL (INVESTIGATIONAL) PRODUCT .......................................... 44 
8.4 
SERIOUS ADVERSE EVENTS ............................................................................................................................................ 45 
8.5 
EXPECTEDNESS OF ADVERSE REACTIONS .......................................................................................................................... 45 
8.6 
ADVERSE EVENTS REPORTING OBLIGATIONS ..................................................................................................................... 45 
8.7 
RECORDING OF ADVERSE EVENTS ................................................................................................................................... 46 
8.7.1 
Adverse Event Reporting in eCRF ...................................................................................................................... 46 
8.7.2 
Reporting mechanism to sponsor, Ethics Committees and Regulatory Authorities .......................................... 46 
8.8 
FOLLOW-UP OBSERVATION FOR STUDY PARTICIPANTS WITH ADVERSE REACTIONS .................................................................... 47 
8.8.1 
Pregnancy follow-up ......................................................................................................................................... 48 
9 
DESCRIPTION OF DATA MANAGEMENT .................................................................................................................. 49 
9.1 
SPECIFICATION OF SOURCE DOCUMENTS ......................................................................................................................... 49 
9.2 
DATA MANAGEMENT SYSTEM ....................................................................................................................................... 49 
9.3 
DATA SECURITY, ACCESS, ARCHIVING AND BACK UP ........................................................................................................... 49 


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10 
STATISTICS ............................................................................................................................................................. 50 
10.1 
HYPOTHESIS .............................................................................................................................................................. 50 
10.2 
DETERMINATION OF SAMPLE SIZE .................................................................................................................................. 50 
10.3 
DESCRIPTION OF STATISTICAL METHODS .......................................................................................................................... 50 
10.4 
STATISTICAL ANALYSIS PLAN ......................................................................................................................................... 50 
10.5 
ANALYSIS SETS ........................................................................................................................................................... 50 
10.6 
SAFETY ANALYSES ....................................................................................................................................................... 50 
10.7 
PK ANALYSES ............................................................................................................................................................ 51 
10.8 
PRIMARY ANALYSIS ..................................................................................................................................................... 52 
10.9 
SECONDARY ANALYSES ................................................................................................................................................ 52 
10.10 INTERIM ANALYSES ..................................................................................................................................................... 52 
10.11 DEVIATION(S) FROM THE ORIGINAL STATISTICAL PLAN ........................................................................................................ 52 
10.12 HANDLING OF DATA .................................................................................................................................................... 52 
11 
DUTIES OF THE INVESTIGATOR ............................................................................................................................... 53 
11.1 
INVESTIGATOR’S CONFIRMATION ................................................................................................................................... 53 
11.2 
SAFETY REPORTING ..................................................................................................................................................... 53 
11.2.1 Serious adverse event reporting ....................................................................................................................... 53 
11.2.2 Project facilities and subcontracts .................................................................................................................... 53 
12 
ETHICAL CONSIDERATIONS ..................................................................................................................................... 54 
12.1 
INDEPENDENT ETHICS COMMITTEE (IEC) ........................................................................................................................ 54 
12.2 
EVALUATION OF THE RISK-BENEFIT RATIO ........................................................................................................................ 54 
12.3 
PARTICIPANT INFORMATION AND CONSENT ..................................................................................................................... 54 
12.4 
REGISTRATION OF CLINICAL TRIAL................................................................................................................................... 55 
12.5 
PARTICIPANT CONFIDENTIALITY ..................................................................................................................................... 55 
12.6 
PARTICIPANTS REQUIRING PARTICULAR PROTECTION .......................................................................................................... 55 
12.7 
INSURANCE ............................................................................................................................................................... 55 
12.8 
PARTICIPANT REIMBURSEMENT ..................................................................................................................................... 56 
12.9 
PROTOCOL AMENDMENTS ............................................................................................................................................ 56 
13 
QUALITY CONTROL AND QUALITY ASSURANCE: DESCRIPTION OF MEASURES ........................................................ 57 
13.1 
RISK MANAGEMENT .................................................................................................................................................... 57 
13.2 
RISK IDENTIFICATION, ASSESSMENT AND MITIGATION......................................................................................................... 57 
13.2.1 Study-specific preventive measures .................................................................................................................. 57 
13.2.2 Birth control and pregnancy testing ................................................................................................................. 57 
13.2.3 Participant restrictions ...................................................................................................................................... 58 
13.3 
MONITORING ............................................................................................................................................................ 59 
13.4 
AUDITS AND INSPECTIONS ............................................................................................................................................ 60 
13.5 
CONFIDENTIALITY, DATA PROTECTION ............................................................................................................................. 60 
13.6 
STORAGE OF BIOLOGICAL MATERIAL AND RELATED HEALTH DATA .......................................................................................... 60 
13.7 
SAFETY REVIEW COMMITTEE (SRC) ............................................................................................................................... 61 
14 
FUNDING ................................................................................................................................................................ 62 
15 
DISSEMINATION OF RESULTS AND PUBLICATION POLICY ....................................................................................... 62 
15.1 
DISSEMINATION TO SCIENTIFIC COMMUNITY; INCL. LEAD IN PUBLICATIONS ............................................................................. 62 
15.2 
INFORMATION OF COMMUNITY AND POLICY MAKERS ......................................................................................................... 62 
16 
REFERENCES ........................................................................................................................................................... 63 
 


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1.5 
Abbreviations 
%AUCextrap  
Percentage of AUC that is due to extrapolation from tlast to infinity 
ADR 
Adverse drug reaction 
AR 
Adverse reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
aPTT 
activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
AUC0-24h 
Area under the plasma concentration curve from time zero to 24 hours 
AUC0-168 
Area under the plasma concentration curve from time zero to 168 hours 
AUC0-72 
Area under the plasma concentration curve from time zero to 72 hours 
AUC0-∞ 
Area under the plasma concentration curve from time zero to infinity with 
extrapolation of the terminal phase 
AUC0-t 
Area under the plasma concentration curve from time zero to the last quantifiable 
concentration at time t 
BA/FE 
Bioavailability/food effect 
BCTF 
Bagamoyo Clinical Trial Facility 
BCTU 
Bagamoyo Clinical Trial Unit 
BRTC 
Bagamoyo Research and Training Center 
CL/F 
Apparent total plasma clearance 
Cmax 
Observed maximum plasma concentration 
CRF 
Case report form 
DHA 
Dihydroartemisinin 
DOT 
Directly Observed Treatment 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
FE 
Food effect 
Frel 
Relative bioavailability 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IHI 
Ifakara Health Institute 
IHI-IRB 
Ifakara Health Institute Institutional Review Board 
IMP 
Investigational medicinal product 


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IPTi 
Intermittent preventative treatment in infants 
iPTp 
Intermittent preventative treatment in pregnancy 
IRB 
Institutional Review Board 
LLN 
Lower limit of normal 
LLOQ 
Lower Limit of Quantification  
LOQ 
Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMV 
Medicines for Malaria Venture 
NatHREC 
National Health Research Ethics Sub-Committee 
PI 
Principal investigator 
PIS 
Participant Information Sheet 
PK 
Pharmacokinetics 
PQP 
Piperaquine phosphate 
PT 
Prothrombin time 
SAE 
Serious adverse event 
SMC 
Seasonal malaria chemoprevention 
SmPC 
Summary of product characteristics 
SOP 
Standard Operating Procedure 
SP 
Sulfadoxine-pyrimethamine 
SPAQ 
Sulfadoxine-pyrimethamine plus amodiaquine 
SRC 
Safety Review Committee 
SUSAR 
Suspected unexpected serious adverse reaction 
T1/2 
Elimination half-life 
TdP 
Torsade de pointes 
Tmax 
Time to reach Cmax 
TMDA 
Tanzania Medicines and Medical Devices Authority 
TzCTR 
Tanzania Clinical Trial Register 
TZS 
Tanzanian Shilling 
ULN 
Upper limit of normal 
USD 
United States Dollar 
Vz/F 
Apparent volume of distribution during the terminal phase 
WBC 
White blood cell count 
WHO 
World Health Organization 
WOCBP 
Women of child bearing potential 
WONCBP 
Women of non-child bearing potential 
λz 
Terminal elimination rate constant 


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1.6 
Synopsis  
Sponsor 
Medicines for Malaria Venture, Geneva, Switzerland. 
Study Title 
A randomized, open label, two-part, parallel-group phase I study to evaluate the 
pharmacokinetics of Piperaquine oral dispersible Granules Formulation compared to 
Piperaquine hard Tablets administered as a single dose in fasting condition  
(Part 1) and of Piperaquine oral dispersible Granules Formulation administered as 
single dose in various fed states (Part 2) in healthy adult participants. 
Study ID 
MMV_SMC_22_01 
Protocol 
Version; 
Date 
Version 3.0; 8 November 2023 
Intended 
Trial 
Registration 
ClinicalTrials.gov 
Tanzania Clinical Trial Register (TzCTR) - imis2.tmda.go.tz/ 
Study 
Category 
with 
Rationale 
Investigational Medicinal Product molecule is registered in Tanzania under the 
classification of Human Medicinal Product in combination with Dihydroartemisinin or 
Artemisinin in several brand names 
Clinical 
Phase 
Phase I 
Background 
and 
Rationale 
Malaria is still a major problem with an estimated 241 million cases of malaria that 
have occurred worldwide in 2020, with more than 90% occurring in the World Health 
Organization (WHO) African Region, leading to 627 000 deaths, of which 77% were 
in children under five years of age. In addition, 34 % (11.6 million) of pregnant women 
in the moderate to high transmission countries of the WHO African Region, were 
exposed to malaria infection (1). 
WHO strongly recommends with high-certainty evidence the following malaria chemo 
preventive therapies: seasonal malaria chemoprevention (SMC), intermittent 
preventive treatment in infants (IPTi), and intermittent preventive treatment of malaria 
in pregnancy (IPTp) (1). Despite the strong public health evidence of 
chemoprevention, only SP (sulfadoxine-pyrimethamine) and SPAQ (sulfadoxine-
pyrimethamine plus amodiaquine) are currently recommended by WHO for 
chemoprevention, which use is currently threatened by increasing resistance to SP 
(1, 2).  
Medicines for Malaria Venture’s (MMV) strategy is to re-combine existing and 
approved antimalarials used in combination with other antimalarials for the treatment 
of malaria, for the purpose of malaria chemoprevention. As part of this strategy, a 
review of the potential efficacy and duration of protection, the safety and tolerability, 
as well as the risk of emergence of resistance of currently approved compounds has 
been conducted, with a view to identify a new combination of two registered 
compounds that may be suitable for malaria chemoprevention. 
Piperaquine phosphate (PQP), as the partner drug for such a new combination, was 
considered to have potential for this purpose. PQP is currently marketed in a fixed 
dose combination with the short acting antimalarial dihydroartemisinin (DHA) as 
Eurartesim® in Europe (4) and as several brands in combination with DHA or 


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artemisinin in Tanzania, for treatment of acute uncomplicated malaria. Based on 
efficacy data provided to support registration for malaria treatment, PQP is a long 
acting antimalarial, whose extended half-life (about 22 days) confers a protection for 
one month with the standard 3-day regimen with a protective effect of over 75% (3). 
It is therefore assumed that a monthly based treatment, for 3 to 4 consecutive months 
during the malaria season, shall achieve adequate efficacy. 
Malaria chemoprevention therapies must be highly safe and well tolerated, 
considering use in otherwise healthy, parasite-free or asymptomatic infants, children, 
and pregnant women. With no evidence of teratogenic liabilities, PQP is a potential 
safe option for malaria prevention in pregnant women and women of child-bearing 
potential (WOCBP) which is a key asset towards malaria eradication. Through their 
extensive use in many African and South-East Asian countries, the safety and 
tolerability of PQP for the treatment of uncomplicated malaria when combined to 
DHA, is well established. Safety data from a European registry have also been 
recently published for DHA-PQP (4). 
In healthy adult participants, PQP exposure from the currently approved hard tablet 
increased approximately 3-fold with high fat/high calorie meals (10). However, no 
significant impact on PQP exposure was observed with local low-fat meals in South-
East Asia (5, 6, 7). For SMC (and other use cases), no food restrictions are ideal, as 
food intake of young children before and after drug administration varies and cannot 
be controlled. A new child-friendly, taste-masked dispersible granule formulation of 
PQP is being developed to increase bioavailability and minimize the food effect. The 
paediatric formulation for this study has been selected based on in vitro dissolution 
in biorelevant media.  
The aim of this pilot bioavailability/food effect (BA/FE) study is to evaluate in healthy 
adults, the PK profile of a PQP dispersible granules formulation when administered 
with different food restrictions. 
Objective(s) 
Primary objective: To determine the relative bioavailability of a single oral dose of 
PQP dispersible granule formulation (Test) as compared to PQP hard tablet 
formulation (Reference) in the fasted state. 
Secondary objectives: 
• 
To assess the effect of different types of meal composition on the PK of single 
doses of PQP dispersible granule formulation in healthy adult participants. 
• 
To further evaluate the PK of a single oral dose of PQP granule formulation 
in the fasted state and different fed states in healthy adult participants. 
• 
To further document safety/tolerability of PQP in healthy adult participants. 
Exploratory objectives: 
• 
To further document PQP metabolite profiling and PK depending on results 
of former study (optional objective) as well as the results of genetic testing of 
CYP450s polymorphism (optional). 
• 
To evaluate the palatability of the new PQP granule formulation in healthy 
adult participants. 
Outcome (s) 
Relative bioavailability: 
Using the ratio of the geometric means for the dispersible granules [test] over the 
hard tablet [reference] in fasted state for AUC0-72h, AUC0-t, AUC0-168h, AUC0-∞, and 
Cmax. 


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Using the ratio of the geometric means for the dispersible granules between fed [high-
fat 
meal, 
low-fat 
African 
meal, 
and 
milk] 
and 
fasted 
for 
AUC0-72h,  
AUC0-t, AUC0-168h, AUC0-∞, and Cmax. 
Safety: 
Occurrence of adverse events (AE) including serious adverse events (SAE) from the 
investigational medicinal product (IMP) administration throughout the entire study 
period (up to Day 30 after IMP administration). 
Study 
Design 
Single centre, randomized, open label, single dose, parallel-group design performed 
in two sequential parts.  
A total of sixty (60) healthy adult participants (male and female) will be enrolled in 
this study (24 subjects in Part 1 and 36 subjects in Part 2). Efforts will be made to 
ensure a reasonable gender balance. 
Inclusion/ 
Exclusion 
Criteria 
Inclusion criteria 
Participants must fulfil all of the following criteria to be eligible for enrolment in this 
trial: 
1. Female or Male aged ≥18 years to ≤55 years at the date of signing informed 
consent.  
2. Ability to provide written, personally signed, and dated informed consent to 
participate in the trial, in accordance with the ICH Good Clinical Practice (GCP) 
and applicable regulations, before any trial-related procedures. 
3. An understanding, ability, and willingness to fully comply with trial procedures and 
restrictions. 
4. Female participants must agree to follow contraceptive requirements as indicated 
in Section 13.2.2, from at least 30 days prior to first dosage to 16 weeks after last 
dosage.  
5. Agrees not to donate sperm or ova from the time of the first administration of trial 
medication until  twelve weeks after the end of the systemic exposure of the trial 
drug. 
6. Participants must have a body weight of 50 kg or greater and a BMI between 18.0 
kg/m² - 30.0 kg/m² (inclusive) at screening.  
7. Satisfactory medical assessment with no clinically significant or relevant 
abnormalities as determined by; medical history, physical examination, vital 
signs, 12-lead electrocardiogram (ECG) and clinical laboratory evaluation that is 
reasonably likely to interfere with the participant's participation in or ability to 
complete the trial as assessed by the Investigator.  
Exclusion criteria 
Participants will be excluded from enrolment in this trial if they fulfil any of the criteria 
below:  
1. Prior screen failure or randomisation in this trial. NOTE: Participants who initially 
failed due to temporary non-medically significant issues are eligible for re-
screening once the cause has resolved. 
2. Female participant who is pregnant (from history, examination or confirmed by a 
positive serum pregnancy test at screening and/or on Day -1) or breastfeeding. 
3. Male participants with a female partner(s) who is (are) pregnant or lactating at 
screening and/or on Day -1 or is (are) expected to be during the trial period. 
4. Has a mental incapacity or language barriers precluding adequate understanding, 
co-operation, or compliance with the trial requirements. 


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5. Unable or unwilling to follow a standardised diet and meal schedule or unable to 
fast, as required during the trial. 
6. Has milk intolerance. 
7. Unable to swallow tablets. 
8. Has veins on either arm that are unsuitable for intravenous puncture or 
cannulation (e.g., veins that are difficult to locate, or a tendency to rupture during 
puncture). 
9. Known or suspected intolerance or hypersensitivity to the investigational 
products, any closely related compound, or any of the stated ingredients. 
10. History of significant allergic reaction (e.g., anaphylaxis, angioedema) to any 
product (food, pharmaceutical, etc) but excluding untreated, asymptomatic, 
seasonal allergies. 
11. Donated blood or blood products (excluding plasma) within 90 days prior to trial 
medication administration. 
12. Has received or plans to receive a COVID-19 vaccination within two weeks before 
to one week after trial last visit.  
13. Treated with medication containing PQP within 90 days or five half-lives 
preceding the dose of trial medication (whichever is the longer). 
14. Ingested herbal remedies or dietary supplements containing St. John’s Wort in 
the 30 days before the planned Day 1 of the dosing Part. 
15. Taking medicinal products that are known to prolong the QTc interval (see 
http://www.crediblemeds.org/). An up-to-date list will be in the study specific 
manual. 
16. Use of any medication that is either a moderate or strong inhibitor or inducer of 
CYP3A4 within 30 days or five half-lives (whichever is longer) prior to the planned 
day of dosing (see Drug Development and Drug Interactions, Table of Substrates, 
Inhibitors and Inducers, FDA). Anup to date list will be in the study specific 
manual. 
17. Use of any other prescription medication (excluding hormonal contraception and 
hormone replacement therapy) within 14 days or ten half-lives (whichever is 
longer) prior to Day 1 of the dosing Part that the Investigator judges is likely to 
interfere with the trial or pose an additional risk in participating. 
18. Use of any over-the-counter medication (including multivitamin, herbal, or 
homeopathic preparations; excluding paracetamol - up to 3 g of paracetamol per 
day permitted while participants are in-house, whereas while participants are 
outpatients a maximum of 1 g paracetamol per day will be allowed) during the 
seven days or ten half-lives of the drug (whichever is longer) prior to Day 1 of the 
dosing Part, that the Investigator judges is likely to interfere with the trial or pose 
an additional risk in participating. 
19. Ingested any poppy seeds within the 24 hours prior to screening or admission. 
20. Current use of tobacco in any form (e.g., smoking or chewing) or other nicotine-
containing products in any form (e.g., gum, patch, electronic cigarettes). 
21. History or clinical evidence of substance and/or alcohol abuse within the two 
years before screening. Alcohol abuse is defined as regular weekly intake of more 
than 14 units (for both males and females). 
22. Participants must have not consumed other substances known to be potent 
inhibitors or inducers of CYP34A system such as grapefruit or cranberry juice-
containing products in the 30 days before the planned IMP administration. 


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23. Any history of seizures, epilepsy, photosensitivity or documented retinopathy. 
24. The history or presence of any of the following cardiac conditions known structural 
cardiac abnormalities; family history of long QT syndrome; cardiac syncope or 
recurrent, idiopathic syncope; exercise related clinically significant cardiac 
events. 
25. Has vital signs consistently outside of the normal range at screening or Day-1. 
26. Any clinically significant abnormalities in rhythm, conduction or morphology of 
resting ECG or clinically important abnormalities that may interfere with the 
interpretation of QTc interval changes. This includes participants with any of the 
following (at screening or Day -1):  
• 
sinus node dysfunction 
• 
clinically significant PR (PQ) interval prolongation (>220ms)  
• 
second- or third-degree atrioventricular (AV) block 
• 
sustained cardiac arrhythmia’s including (but not limited to) atrial fibrillation or 
supraventricular tachycardia, or any symptomatic arrhythmia, with the 
exception of isolated extra-systoles. 
• 
abnormal T-wave morphology which may impact on the QT/QTc assessment. 
• 
QT interval corrected using the Fridericia’s formula (QtcF) >450 ms  
• 
any other ECG abnormalities in the standard 12-lead ECG or an equivalent 
assessment which in the opinion of the Investigator will interfere with the ECG 
analysis 
• 
Participants with borderline abnormalities may be included if the deviations 
do not pose a safety risk, and if agreed between the appointed cardiologist 
and the PI.   
27. Positive test results for alcohol or drugs of abuse at screening or Day -1. 
28. Electrolyte imbalances, particularly results that are out of reference intervals for 
potassium, calcium or magnesium. 
29. Has a positive test for Hepatitis B surface Antigen (HBsAg), Hepatitis C Antibody 
(HCV Ab), or Human Immunodeficiency Virus Antibody (HIV Ab) at screening. 
30. Presence of malaria parasites by blood smear. 
31. Has total bilirubin, ALT or AST consistently >upper limit of normal (ULN) at 
screening (up to two repeats may be taken during the screening period; 
participants may be included if two out of the three total results are ≤ULN) or has 
total bilirubin >ULN on Day -1 (mild variations from baseline may be allowed if 
considered not clinically significant by the Investigator). 
32. Has a haemoglobin, platelet count, total white blood cell count, lymphocyte or 
monocyte count < lower limit of normal (LLN) (up to two repeats may be taken 
during the screening period and on Day -1 (participants may be included if two 
out of the three total results are greater or equal to LLN), at screening. Where 
there is a clear diurnal effect on the result participants may be included if 
variations are considered not clinically relevant by the Investigator. 
33. Current or recurrent disease (e.g., cardiovascular, haematological, neurological, 
endocrine, immunological, renal, hepatic or gastrointestinal or other conditions, 
including cholecystectomy or gastrectomy) that could affect the action, 
absorption, distribution, metabolism or excretion of PQP or could affect clinical 
assessments or clinical laboratory evaluations. 
34. Current or relevant history of physical or psychiatric illness that are not stable or 
may require a change in treatment, or use of prohibited therapies during the trial, 


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that make the participant unlikely to fully comply with the requirements of the trial 
or to complete the trial, or any condition that presents undue risk from the 
investigational product or trial procedures. 
35. Any other abnormal findings on vital signs, ECG, physical examination or 
laboratory assessments that the Investigator judges as likely to interfere with the 
trial or pose an additional risk in participating. 
36. Any other significant disease or disorder which, in the opinion of the Investigator, 
may either put the participant at risk because of participation in the trial, or may 
influence the result of the trial or the participant's ability to participate in the trial. 
37. Any conditions which in the opinion of the Investigator would make the participant 
unsuitable for enrolment or could interfere with the participation in or completion 
of the trial. 
Measureme
nts and 
Procedures 
Participants will be screened within a window of ≤ 45 days prior to in-house admission 
on Day -1 where preliminary assessments will be performed and fasting initiated. 
Study drug administration will be performed on the following day (Day 1) under fasted 
(Part 1) or fed (Part 2) conditions. After 10 hours of fasting have elapsed: 
For administration under fasted conditions: PQP tablet / dispersible granules will be 
immediately administered to study participants orally. 
For administration under fed conditions: The study participant will start the randomly 
allocated meal 30 minutes before administration of the drug product and should 
consume the entire meal in 30 minutes or less. Thereafter, investigators will 
immediately administer PQP dispersible granules to study participants orally. 
Additional water will be permitted ad lib except for the period 1 hour before until 1 
hour after administration of the drug product. Participants shall not consume any food 
for at least 4 hours after the dose. Thereafter, standardized meals scheduled at the 
same time reflecting breakfast, lunch or dinner will be provided throughout the in-
house period. 
Scheduled safety assessments e.g., vital signs and ECGs, and PK sample collections 
will continue till discharge on Day 3 (a total 4 in-house days). Participants will attend 
the trial unit clinic for outpatient visits on Days 8, 15, 22 and 30. 
Test 
Product 
PQP dispersible granules 320 mg dose equivalent dispersed in 25 ml of water; single 
dose (320 mg) given orally. 
Comparator 
Reference therapy:  
PQP hard tablet 320 mg; single dose (320 mg) given orally with 240 ml of water. 
Number of 
Participants 
This is a pilot BA/FE study, and the sample-size is not based on formal statistical 
considerations. The number assigned to each treatment Group (n=12) is considered 
adequate to characterise the PK of the prototype formulation of PQP in various study 
conditions. 
Study 
Duration 
4 to 6 Months. 
Study 
Schedule 
First Participant In (JULY-2023); estimated Last- Participant Out (DECEMBER-2023) 
Study 
Centre 
Single-centre: Bagamoyo Clinical Trials Unit, IHI – BRTC. 


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Statistical 
Considerati
ons 
This pilot Phase 1 trial is not designed to test specific hypotheses. The trial is intended 
to determine the PK parameters of the prototype formulation dispersion granules of 
PQP in fasting state (Part 1) and to provide a preliminary assessment of the effect of 
various fed states (Part 2) on the systemic exposure of PQP. 
The Safety analysis set will consist of all randomised participants who received the 
study product. The PK analysis set will consist of those participants in the safety set 
who have sufficient blood samples taken for at least one of the PK variables to be 
calculated.  
The statistical methods and reporting will follow ICH E9 and international 
recommendations, including CONSORT. A statistical analysis plan (SAP) containing 
detailed statistical methodology will be written and signed off before the database 
hard lock. The plan may be updated to reflect adaptive features of the trial as 
appropriate. 
GCP 
Statement 
This study will be conducted in compliance with the protocol, the current version of 
the Declaration of Helsinki, ICH-GCP E6(R2) as well as all Tanzanian legal and 
regulatory requirements as stipulated by NaTHREC and TMDA.  
 
 


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2 BACKGROUND INFORMATION 
In 2020, an estimated 241 million cases of malaria occurred worldwide, with more than 90% occurring 
in WHO African Region, leading to 627 000 deaths, of which 77% were in children under five years of 
age. In addition, there were an estimated 33.8 million pregnancies in the moderate to high transmission 
countries of the WHO African Region, of which 34 % (11.6 million) were exposed to malaria infection 
during pregnancy (8). 
Despite the strong public health evidence of chemoprevention, only sulfadoxine-pyrimethamine (SP) 
and sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) are currently recommended by WHO for 
chemoprevention, which use is currently threatened by increasing resistance to SP (2, 3). MMV’s 
strategy is to re-combine existing and approved antimalarials used in combination with other 
antimalarials for the treatment of malaria, for the purpose of malaria chemoprevention. As part of this 
strategy, a review of the potential efficacy and duration of protection, the safety and tolerability, as well 
as the risk of emergence of resistance of currently approved compounds has been conducted, with a 
view to identify a new combination of two registered compounds that may be suitable for malaria 
chemoprevention. 
Piperaquine (PQP), as the partner drug for such a new combination, was considered to have potential 
for this purpose. PQP is currently marketed in a fixed dose combination with the short acting antimalarial 
dihydroartemisinin (DHA) as Eurartesim® in Europe and is registered in Tanzania in several brand 
names as fixed dose combination with dihydroartemisinin (DHA) or Artemisinin, for treatment of acute 
uncomplicated malaria. The efficacy of PQP combined to the artemisinin derivatives has been 
demonstrated in the treatment of uncomplicated malaria in various clinical trials in different regions and 
has been in clinical use for at least 40 years and was approved by the European Medicine Agency in 
2011.  
PQP is a long acting antimalarial, whose extended half-life (about 22 days) confers a protection for one 
month with the standard 3-day regimen. Additionally, DHA-PQP was associated with a protective effect 
of over 75% (3). It is therefore assumed that a monthly based treatment with PQP (for 3 to 4 consecutive 
months during the malaria season) should achieve adequate chemoprevention efficacy. 
In healthy adult participants, PQP exposure from the currently approved hard tablet increased approx. 
3-fold with high fat/high calorie meal (European Medicine Agency). However, no significant impact on 
PQP exposure was observed with local low-fat meal in South-East Asia (6, 7, 8). For seasonal malaria 
chemoprevention (SMC) (and other use cases), no food restrictions are ideal, as food intake of young 
children before and after drug administration varies and cannot be controlled. A new child-friendly, 
taste-masked dispersible granule formulation of PQP is being developed to increase bioavailability and 
minimize the food effect. The paediatric formulation for this study has been selected based on in vitro 
dissolution in biorelevant media.  
The aim of this pilot bioavailability/food effect (BA/FE) study will be to evaluate in healthy adults and 
after single dose, the pharmacokinetic (PK) profile of a PQP oral granules prototype as compared to 
the hard tablet formulation when administered in fasting conditions (Part 1) and then in Part 2 to 
evaluate the effect of different food conditions on the PK profile of PQP after administration of the PQP 
oral granules prototype formulation. 
2.1 
Introduction 
Case management with highly effective antimalarial drugs has contributed to a decrease in malaria 
morbidity and mortality. However, preventive administration of antimalarial drugs is also recommended 
for use in selected high-risk populations, irrespective of malaria infection status, both to treat any 
unrecognized Plasmodium infections and to prevent new ones. These preventive treatments prevent 


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or cure undetected malarial illness with the goal to achieve therapeutic drug levels in the blood 
throughout the period of greatest risk (9). WHO strongly recommends with high-certainty evidence the 
following malaria chemo preventive therapies: SMC, intermittent preventive treatment in infants (IPTi), 
and intermittent preventive treatment in pregnancy (IPTp)(1). 
Since malaria chemoprevention is administered to otherwise healthy infants, children, and pregnant 
women (who are either parasite-free or have circulating parasites but are asymptomatic), treatments 
must be highly safe and well tolerated. PQP has not shown any teratogenic liabilities and is therefore 
expected to be a potential safe option for malaria prevention in pregnant women and women of child-
bearing potential (WOCBP) which is a key asset towards malaria eradication. 
Sulfadoxine-pyrimethamine (SP) is recommended for IPTp along with the antenatal care visits starting 
from the second trimester of pregnancy and IPTi along with infant vaccination taking place usually at 
10 weeks, 14 weeks and 9 months of age. Sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) is 
recommended for SMC as a monthly administration during the malaria season for three to four 
consecutive months to children between three months and five years of age in areas of highly seasonal 
malaria transmission (1). In this context, SPAQ demonstrated a protective efficacy of >80 % in Burkina 
Faso (4). 
2.1.1 General treatment / Administration 
PQP exposure from the currently approved hard tablet in healthy adult participants, increased 
approximately 3-fold with high fat/high calorie meals (European Medicine Agency). However, no 
significant impact on PQP exposure was observed with local low-fat meals in South-East Asia (6, 7, 8). 
The present new child-friendly, taste-masked dispersible granule formulation of PQP is being developed 
to increase bioavailability and minimize the food effect. For SMC (and other use cases), no food 
restrictions are ideal, as food intake of young children before and after drug administration varies and 
cannot be controlled. In the present study, the PK profile of a PQP oral dispersible granules (the 
paediatric formulation prototype) will be evaluated relative to the PQP hard tablet formulation in fasting 
conditions (Part 1), and when administered with different food restrictions (Part 2) to assess BA/FE, in 
healthy adults.  
2.1.2 Efficacy 
Not applicable for the present BA/FE trial. 
2.1.3 Mechanism of action, clearance and pharmacokinetics 
PQP’s mechanism of action is unknown, but it likely mirrors that of chloroquine, a close structural 
analogue. Chloroquine binds to toxic haem (derived from the patient’s haemoglobin) within the malaria 
parasite, preventing its detoxification via a polymerisation step (10) PQP is a highly lipophilic compound, 
is highly bound to proteins (>99%) and tends to accumulate in red blood cells. In humans, PQP has a 
Tmax of approximately five hours after hard tablet administration. PQP is mainly metabolized by 
CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. PQP is also a CYP3A4 inhibitor, and a 
clinical study of Eurartesim® with midazolam showed a modest increase in the exposure of midazolam 
(<two-fold)(10). The terminal elimination half-life of PQP is around 22 days for adult patients. 
2.1.4 Safety and tolerability 
Through their extensive use in many African and South-East Asian countries, the safety and tolerability 
of PQP for the treatment of uncomplicated malaria when combined to DHA, is well established. Safety 
data from a European registry have also been recently published for DHA-PQP (5). 


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PQP as a combination antimalarial with DHA is well tolerated in both adults and children, with the main 
AEs reported being gastrointestinal disturbances such as nausea/vomiting, abdominal pain and 
diarrhoea (9, 10). 
2.1.5 Safety profile and potential risks 
Although transient asymptomatic alanine aminotransferase/aspartate aminotransferase (ALT/AST) 
elevations have been described, including in Phase 1 participants, these are generally mild in severity 
and considered as uncommon. PQP is known to induce QTc prolongation in human participants (11, 
12). The following aspects of the PK and adverse event (AE) profiles of PQP, were considered in 
determining the Inclusion and Exclusion criteria and in designing the tolerability and safety monitoring 
of this study: 
• 
PQP is known to cause a QTc interval prolongation, and this effect is concentration-related, 
• 
PQP has a terminal elimination half-life of approximately 22 days, however, approximately 1% of 
the plasmatic Cmax is predicted at 672 hours (i.e. 28 days) after the administration of 1280 mg in 
healthy adults (13). Therefore, a follow-up of 30 days is considered acceptable to ensure that 
possible delayed effects on safety laboratory tests are appropriately documented.  
As precautionary measures pertaining to QTc effects of PQP, the European Medicines Agency (EMA) 
has advised that:  
• 
DHA-PQP (Eurartesim®), not be administered with a meal to avoid food-induced increase in PQP 
Cmax and consequently possible clinically relevant QTc prolongation,  
• 
Baseline and post-dose electrocardiograms (ECGs) be obtained,  
• 
Recent exposure to concomitant drugs known to induce QTc prolongation be avoided (10,14).  
Therefore, during this study, healthy participants with risk factors for QTc prolongation will be excluded 
and enrolled participants will be monitored for QTc effects through ECG recording. 
Clinical monitoring will include periodic biochemistry and haematology measurements as well as regular 
physical examination and AE recording.  
Participants will remain in the Unit under medical supervision until 48 hours following the investigational 
medicinal product (IMP) administration and will be followed up to Day 30 (+/-1 day). 
Despite significant human Ether-a-go-go Related Gene (hERG) blockade with PQP and a mean 
prolongation of 15-20 msec (fasting state) demonstrated in multiple Phase 1 studies, a meta-analysis 
has recently concluded that patients treated with the registered three-day regimen of DHA-PQP are not 
at higher risk of torsades de pointes (TdP), ventricular tachycardia or other arrhythmias when compared 
with the normal population (14). Based on these observations, although inducing a QTc prolongation 
that exceeds the ICH/FDA regulatory threshold of 10 msec, PQP is currently not considered as a 
torsadogenic drug provided it is taken in a fasted state and other clinical risk factors for QTc prolongation 
(including electrolyte imbalance and/or concomitant medications) are appropriately controlled (15). 
Healthy volunteers with long QTc are also excluded from clinical trials. 
2.2 
Justification for the dosage and dosage plan 
This is a single-dose study and is considered sufficient to provide early assessment of the bioavailability 
of the PQP dispersible granules formulation (fasted) relative to the PQP hard tablet formulation (fasted) 
and understand the impact of food intake on the dispersible granules formulation. The rationale for the 
selected dose includes: 
• 
As the new formulation is intended to have an increased bioavailability, a lower dose of 320 mg for 
the PQP dispersible granules formulation (test) has been selected. For comparison purpose, the 


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same dose level of 320 mg PQP has been selected for the hard tablet (reference); both administered 
in fasting conditions (Part 1). This compares to the approved daily dose of 960 mg PQP in tablet of 
Eurartesim® administered over 3 days in adult subjects dosed in fasting conditions. 
• 
In the second study part, and based on the PK results of Part 1, it is intended to administer the same 
dose level of 320 mg PQP dispersible granules concomitant with different fed conditions. However, 
if from Part 1 of the study it is shown that PQP dispersible granules formulation provides a significant 
improvement in Cmax values in the fasted state, this dose level may be adjusted for Part 2, in order 
to take into account a potential 3-fold increase in exposure which is the observed food effect when 
film-coated tablets (Eurartesim®) are administered with a high fat/high calorie meal. Such dose 
adjustment will be based on the safety and preliminary PK interim results of the granule formulation 
in the fasted state. The PQP dose selected in Part 2 (as dispersible granules formulation) will take 
into account a 3-fold factor increase in exposure when administered with food (see above) with such 
predicted exposure in the presence of food being not higher than after the administration of 960 mg 
PQP in tablet of Eurartesim® in adult subjects dosed in fasting conditions. Furthermore, sufficient 
data will be available to address key questions on both, safety and PK parameters to enable the 
review and recommendation by the SRC for the optimal dose of the granule formulation to be 
administered in Part 2.  
 
 
 


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3 OBJECTIVES AND PURPOSE 
The present pilot BA/FE study aims to assess the relative bioavailability and food effect on the systemic 
exposure of a new child-friendly, taste-masked dispersible granule formulation of PQP among healthy 
adults. In addition, PK and safety profiles will be further evaluated and documented. 
3.1 
Study rationale and objectives 
3.1.1 Study rationale 
The present new child-friendly, taste-masked dispersible granule formulation of PQP is being developed 
to increase bioavailability and minimize the impact of food on PK exposure and consequently QTc 
effects. In healthy adult participants, the currently approved hard tablet had an approximately 3-fold 
increase in PQP exposure when administered with a high fat/high calorie meal (10). However, a local 
low-fat meal in South-East Asia had no significant impact on PQP exposure (6, 7, 8).  
In the present study performed in healthy subjects, the PK profile of a PQP oral dispersible granules 
formulation (the paediatric formulation prototype) will be compared to the PQP hard tablet formulation 
in fasting conditions (Part 1), and when administered in different fed states (Part 2) to assess the BA/FE. 
This assessment is important since for SMC (and other use cases), food restrictions for treatment with 
oral PQP are not ideal, as food intake of young children before and after drug administration varies and 
cannot be controlled. 
This study will establish whether the BA of the child-friendly dispersible granules formulation of PQP is 
improved in comparison to PQP hard tablet in fasting conditions and will inform dose selection of the 
granule formulation.  
The study will also determine whether there is an effect of food on the exposure of PQP from the child-
friendly dispersible granule formulation, and whether the magnitude of the food effect is similar, or 
decreased compared to the PQP hard tablet: 
• 
Studies with a high fat meal are required by Regulators to determine the “worst case food effect”. 
In addition, as recognized by regulators (FDA): when drug administration with a high-fat meal 
causes unacceptable toxicity or a loss of drug efficacy, a low-fat meal can have less or no impact 
on systemic exposures, improve patient compliance, and alleviate localized gastric irritation. In 
these circumstances, and assuming that no clinically relevant safety impact is expected, 
administration of the drug with a low-fat meal may be more advantageous to patients. 
• 
Given the low-fat content of standard meals within endemic regions, the food effect in African and 
Asian patients and in particular children in areas of SMC will likely be decreased.  
3.1.2 Primary objective 
o To determine the relative bioavailability of a single oral dose of PQP dispersible granule 
formulation (Test) as compared to PQP hard tablet formulation (Reference) in the fasted 
state. 
3.1.3 Secondary objectives 
o To assess the effect of different types of meal composition on the PK of single doses of PQP 
dispersible granule formulation in healthy adult participants. 
o To further evaluate the PK of a single oral dose of PQP granule formulation in the fasted 
state and different fed states in healthy adult participants. 


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o To further document safety/tolerability of PQP in healthy adult participants. 
3.1.4 Exploratory objectives 
o To further document PQP metabolite profiling and PK depending on results of former study 
(optional objective) as well as the results of genetic testing of CYP450s polymorphism 
(optional). 
o To evaluate the palatability of the new PQP granule formulation in healthy adult participants. 
3.2 
Scientific justification and rationale of study population 
This study includes male and female participants aged 18 to 55 years at the date of signing informed 
consent who are residing within and surrounding areas of Bagamoyo town. Both genders will be 
enrolled to generate data on both sexes. Data from this trial will support development of a new 
piperaquine formulation with a reduced impact of food which will be more practical for paediatric 
population. 
 


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4 STUDY DESIGN 
This is a randomized, open label, parallel-design study to evaluate the PK profile and relative 
bioavailability of single dose of a PQP oral granule formulation dispersed in water (test) as compared 
to the PQP hard tablet formulation (reference) in fasting conditions (Part 1) and to assess the BA/FE of 
the PQP dispersible granules formulation when administered with different food restrictions (Part 2) 
among African participants residing in Tanzania, in Bagamoyo Town and surrounding areas. A total of 
sixty (60) healthy adult participants (male and female) will be enrolled in Part 1 and Part 2.  
• 
Part 1: PQP tablet / dispersible granule administered in fasting condition of at least 10 hours 
o Group 1: PQP hard tablet, 320 mg (N=12)  
o Group 2: PQP dispersible granule, 320 mg (N=12) 
• 
Transition to Part 2: 
o To minimize the risk to healthy participants, a decision on transitioning from Part 1 to Part 
2, will be taken by the Safety Review Committee (SRC) see Section 13.7, based on the 
safety and preliminary PK interim report of the granule formulation, compared to the PQP 
hard tablet, with safety data obtained up to Day 15 and PK data obtained up to  Day 8. If 
necessary, doses may be readjusted for the Part 2 in order to assess the food effect. 
Description for the rationale and oversight related to the potential for dose adjustment is 
provided in Section 2.2.   
• 
Part 2: PQP dispersible granule administered in fed conditions (planned as 320 mg) 
o Group 3: High-fat meal (N=12) 
o Group 4: Low-fat meal representative of African diet (N=12) 
o Group 5: Whole milk 250 ml (N=12) 
In summary: Participants will be screened within a window of ≤ 45 days prior to in-house admission on 
Day -1. Each participant will be admitted to the trial unit on Day -1, and after a new eligibility check, will 
receive a single dose of PQP on Day 1 and will be discharged on Day 3 (a total 4 in-house days). 
Participants will attend the trial unit clinic for outpatient visits on Days 8, 15, 22 and 30. Details of 
procedures and parameters to be assessed at each study time points are outlined in Section 7 (Study 
Assessments and Visits) and summarized in Section 4.4 (Schedule of events). 
4.1 
Primary and secondary endpoint 
4.1.1 Primary endpoint 
• 
Relative bioavailability (Frel) using the ratio of the geometric means for the dispersible granule (test) 
over the hard tablet (reference) in fasted state for area under the plasma concentration-time curve 
from time zero to 72 hours (AUC0-72h), area under the plasma concentration-time curve from time 
zero to last detectable plasma concentration (AUC0-t), area under the plasma concentration-time 
curve from time zero to 168 hours (AUC0-168h), area under the plasma concentration-time curve 
from time zero extrapolated to infinity (AUC0-∞, and Maximum plasma concentration (Cmax)(see 
Section 10 for further details). 
4.1.2 Secondary endpoints 
• 
PK parameters for the hard tablet (fasted) and the dispersible granule formulations (fasted and fed); 
Cmax, AUC0-24h, AUC0-72h, AUC0-t, AUC0-168h, AUC0-∞, time to maximum plasma 
concentration (Tmax), terminal elimination rate constant (λz), terminal elimination half-life (t1/2), 
apparent volume of distribution during the terminal phase (Vz/F), apparent total plasma clearance 


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(Cl/F), and percentage of AUC that is due to extrapolation from tlast to infinity (%AUCextrap) (see 
Section 10 for further details). 
• 
Occurrence of AEs including serious adverse events (SAEs) from the IMP administration throughout 
the entire study period (up to Day 30). 
• 
Findings at different time points from: 
o Physical examination, vital signs, clinical laboratory safety parameters, 12-lead ECG 
parameters. See Section 8 for specific parameters and time points. 
4.2 
Measures to minimize bias 
4.2.1 Randomization 
Healthy adult participants (male and female) will be randomly allocated to one of the 5 following 
treatment groups, dosing will be carried out in the fasted or fed state: 
• 
During the study part 1, participants for fasted conditions will be randomly allocated to either group 
1 (n=12) or group 2 (n=12), in order to assess the relative bioavailability of the dispersible granules 
formulation as compared to hard table formulation. 
o Randomization will occur in blocks of 2 (each block contains 1 assignment from each of the 
groups 1 and 2). Dosing under fasting conditions is detailed in Section 6.2.1.  
• 
During the study part 2, participants for fed conditions will be randomly allocated to either group 3 
(n=12), 4 (n=12) or 5 (n=12), in order to assess the food effect after dosing of PQP dispersible 
granules formulation. 
o Randomization will occur in blocks of 3 (each block contains 1 assignment from each of the 
groups 3, 4 and 5). Dosing under fed conditions is detailed in Section 6.2.2. 
A computer-generated randomization schedule (produced by IQVIA) will be used and will be accessible 
only to the site delegated study staff who will prepare the treatment for each participant according to 
the randomization allocation. Specific instructions will be detailed in the relevant site manual. 
4.2.2 Blinding 
The trial will be open-label i.e., participant, investigator and sponsor will be unblinded to treatment and 
meal conditions assignation. Therefore, after treatment allocation by the site pharmacist according to 
the randomisation schedule, the study investigators will be provided with the explicit details related to 
the treatment (Part 1) or feeding conditions (Part 2). 
4.3 
Study duration and duration of participant’s participation 
Post administration duration of the study will be 30 days, plus the screening period of 7 to 45 days.  
It is estimated that the clinical portion of the study will be completed in approximately 4-6 months. 
 
 


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4.4 
Schedule of events 
Procedures* and Assessments 
SCREENING 
IN-HOUSE (IP ADMINISTRATION & FOLLOWUP) 
CLINIC 
FOLLOW-UP 
ᴬ  
ᴮ 
D (-1) to D3 
D5 to D30 
D 
(-45 
to 
-2) 
D 
(-15 
to 
-2) 
Admission  
Pre-Dose (h) Dose 
Post Dose; Hour (h) ± Minutes (m) 
Days(D)  
± 1 Day 
Fasting 
10 hrs 
IMP 
(-0.5) 0h 
±7m* 
±10m* 
9.5 0.5 
1h 2h 3h 4h 5h 6h 7h 8h 12h 24h 48h D5 D8 D 
15 
D 
22 
D 
30 
Fasting Condition 
PART 1 (Groups 1 & 2) 
Fasting (⇔) 
 
 
 
⇔ ⇔ NA IMP ⇔ ⇔ ⇔ ⇔ 
 
 
 
 
 
 
 
 
 
 
 
 
Fed Conditions 
PART 2 (Groups 3, 4 & 5) 
Fasting (⇔) & 
Fed 
 
 
 
⇔ ⇔ Fed 
IMP ⇔ ⇔ ⇔ ⇔ 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMED CONSENT 
x⁰ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DEMOGRAPHIC 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VITAL signs 
x 
 
X 
 
X 
  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight & Height (x)/ Weight Only (w) 
x 
 
w 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HISTORY: Medical, Prior medication, 
Drug & Alcohol abuse, Smoking 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HISTORY: Updates check 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PHYSICAL 
EXAMINATION 
Full 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom Directed 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Palatability Questionnaire 
 
 
 
 
 
 
XC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
Triplicate (T) or Single (S) 
 
S 
T 
 
T 
 
 
 
T 
 
T 
T 
T 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
CONTRACEPTION 
x** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ELIGIBILITY CHECK / REVIEW 
X 
X 
X 
   X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RANDOMIZATION 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE /SAE Recording (Continuous) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Assessments; 
[Numbers] = Blood volume (mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemistry: Panel 1 
ALT, AST, T.bil, K⁺, Ca²⁺, Mg²⁺, Na⁺, 
Cl⁻, HCO3⁻, Creat, T.Pr, Alb 
 
[2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[2] 
 
[2] 
Biochemistry: Panel 2 
ALT, AST, T.bil, K⁺, Ca²⁺, Mg²⁺ 
 
 
[2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[2] 
 
 
 
 
 
Haematology 
(HB, PLT, WBC, Neu, Eos, Lym) 
 
[1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] 
 
[1] 
Coagulation (PT, aPTT) 
 
[3] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TBS for Malaria parasitology 
 
[1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] 
Serology (HIV 1 & 2, Hepatitis B & C) 
[1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine for drugs of abuse  
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breath test for Alcohol 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (WOCBP) 
[1] 
 
[1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] 
FSH (post-menopausal females) 
[1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CYP genetic polymorphism sampling 
 
 
[10] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sampling (PQP & Metabolite) 
 
 
 
 
[2] 
 
 
[2] [2] [2] [2] [2] [2] [2] [2] [2] [2] [2] [2] [2] [2] [2] [2] 
BLOOD VOLUME per 
Participant (ml) 
PER VISIT 
3 
7 
13  
2 
 
 
2 2 2 2 2 2 2 2 2 
2 
4 
2 2 5 2 7 
Total for ALL scheduled study visits: 67 
Abbreviations: 
D: Day (where Day 1 is the first day that IMPs are administered) 
TBS: Thick Blood Smear 
FSH: Follicular Stimulating Hormone 
LABELS at Screening Period:  
* Procedures must be completed within specified window (±), with ECG and vitals performed prior to blood sampling 
** Contraception must be started for at least 30 days prior to dosing 
x⁰ Written informed consent must be obtained prior to any study procedures. 
xᴬ procedures must be repeated if performed >45 days prior to D1 
xᴮ procedures must be repeated if performed >15 days prior to D1 
Xc questionnaire to be completed within 10 minutes of IMP dosing 
[#] Blood volume in mL 
Note: COVID-19 tests will be carried out at regular intervals, prior to entry in the unit and throughout the residential period as per the 
latest COVID-19 Infection Control Guidelines and pre-entry algorithms 


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4.5 
Safety hold and early termination of the study 
If either of the following pausing criteria are met, trial activities will be put on temporary hold and the 
SRC chair will be consulted in order to perform thorough evaluation: 
• 
Severe non-serious adverse reactions considered as, at least, possibly related to the IMP 
administration in two subjects in the same part, independent of within or not within the same system-
organ-class.  
• 
One participant experiences an SAE deemed related to study product administration.  
If either of these two criteria is met by participants who received either of the study PQP products, the 
principal investigator (PI) will inform the sponsor for initiation of a temporary hold. After confirmation of 
the temporary hold, the Sponsor will request an ad hoc meeting of the SRC to review the event(s) and 
any associated safety data.  Following the SRC review and recommendation, a decision will be made 
by the PI and the Sponsor to either trigger a longer-term safety hold, terminate the study, or resume 
administration of investigational product.  The Institutional Review Boards (IRBs), ethical committee 
and regulatory authority will be promptly informed of this event, recommendations and decisions. 
Irrespective of the temporary hold criteria, the Sponsor, PI or applicable ethical committees or regulatory 
agencies may decide to put the study on hold based on any other constellation of AEs, or based on any 
other legitimate reason, such as: 
• 
Ethical concerns 
• 
Safety issues with the study drug 
• 
When the safety of the participants is doubtful or at risk 
• 
Inaccurate or incomplete data 
• 
Administrative decision 
• 
Unforeseen events such as endemic/pandemic 
If a safety-hold or study termination is deemed necessary, the applicable ethical committees and 
regulatory agencies will be notified.  For a safety hold to be lifted, there must be a written concurrence 
by the entity or entities that initiated the hold that the study can resume. 
 
 


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5 SELECTION OF THE STUDY PARTICIPANTS 
5.1 
Study setting 
The study will be conducted at the Bagamoyo Clinical Trial Facility (BCTF) in Bagamoyo, Tanzania 
where screening, enrolment and follow up of healthy participants will be done. BCTF is part of the 
Bagamoyo Research and Training Center (BRTC) located on the outskirts of Bagamoyo and therefore 
has access to the institutional research clinical laboratory with adequate facilities for the conduct of 
safety and several other assessments. Furthermore, during the study, the site will be equipped with an 
adequate number of 12-lead ECG machines to record digitalized cardiac parameters, which will be 
performed and reviewed in real-time by the delegated, experienced study clinician and subsequently 
transmitted for further assessment centrally by an ECG vendor. The team has several years of 
experience in the conduct of clinical trials from phase I to IV. The Investigators team have been trained 
on Protecting Human Research Participants. In addition, the site team has been trained on the 
principles of ICH-GCP. Regular advanced life support trainings (including certificates) are conducted 
on site by the emergency unit from Muhimbili National Hospital. The site has a well-equipped 
emergency care unit for handling medical emergencies and stabilization of participants with the on-call 
emergency response clinical team whenever there are participants in the facility. The team is trained 
and certified by the emergency department experts from the Muhimbili National Hospital. There is a 
standby ambulance for transporting participants, once stabilized, for further intensive care and 
management under the escort of the emergency response team on-call. The nearest emergency 
support service department is available within 5 minutes, with intensive care service department 
available within 30 minutes. The site is supported by the institutional quality assurance team. In addition, 
the Ifakara Health Institute (IHI) has put a COVID-19 response plan in place containing corresponding 
precaution measurements that are also implemented at the site. 
5.2 
Recruitment 
This study is planned to be conducted in healthy adult participants (male and female, including 
WOCBP). The expected population is to be enrolled from the study centre catchment area among the 
residents of Bagamoyo town and surrounding areas of Bagamoyo district. Initial work in the community 
will only commence after all approvals have been received from the relevant ethics committees and 
regulatory authority. Local authorities will be informed about the study in order to approach the 
community. Locally applicable methods of advertisement will be used to disseminate the study 
advertisement, including flyers and announcements via speakers. Targeted and potential community 
members will be invited to attend community sensitization meetings which will be conducted at 
designated community areas and may also involve ward leaders, community health workers as well as 
key opinion leaders in the community. To ensure adequate delivery of the information, meetings will 
primarily be conducted in Swahili. 
At the community sensitization meetings, Investigators will explain the current burden of malaria in 
particular among infants and children living in malaria endemic areas. The need for age-relevant 
formulation for malaria treatment and possible prophylaxis will be discussed in a culturally appropriate 
manner. Investigators will also explain the concept of the clinical trial and the community members will 
be made aware of the potential risks and unproven benefits of the investigational product to be used in 
this trial. The outline of the proposed trial including the rationale, aims and study procedures such as 
consenting, screening, the need for the use of contraception, randomization, inhouse observation and 
follow-up process will be shared. It will also be made clear that the study will require screening for 
malaria and other chronic conditions such as HIV and hepatitis. It will be made clear that screening 
processes will include a range of criteria to be checked covering clinical status as well as ability to 
comply with protocol, ethical and regulatory requirements. Moreover, it will be explained that exclusion 


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from participating in the trial does not mean the potential participant is unhealthy and that, the 
confidentiality of all this information will be protected. Opportunity will be provided for the community 
members to ask questions and get responses from the Investigators. Potentially interested participants 
will be asked to provide details that will enable the study team to generate list of potential participants 
who will be invited to the clinic-based sensitization meeting at BCTF. During the clinic sensitization 
meetings, Investigators will provide further details in the participant information sheet on the mechanism 
of the study product, risks, benefits and procedures such as blood sampling, in-patient stay, follow up 
visits and the need of efficient contraception. Study team members will discuss the existing 
understanding of the participants with regards to the study and will share more detailed information and 
clarify any questions in Swahili. At the same occasion they will confirm that the participants are able to 
read and write (to ensure adequate informed consent for participants). Those interested and considered 
as potential participants for screening will be provided with the participant information sheet to read at 
home and for opportunity to discuss with their family members. Potential candidates will be contacted 
and invited to a screening visit at the BCTF where they will undergo the individual informed consent 
process prior to any study screening procedures.  
To ensure that enrolment goals are met, this recruitment plan allows for longitudinal screening of 
participants. In addition, longitudinal compliance with study visits and procedures will be encouraged 
through the provision of a study calendar to participants, using multiple contact methods (phone calls, 
home visits by community mobilizers, having names and phone numbers of close contacts), 
transportation to the BCTF if needed. 
Adults will be recruited using a rolling recruitment, screening and enrolment process. This process will 
continue until all 60 study participants have been enrolled and dosed. The recruitment strategies are 
based on the experience from previous trials conducted by the clinical team in BCTF aiming to achieve 
adequate participant enrolment to reach target sample size. 
The planned total number of participants for this trial will be 60. This is a pilot BA/FE study and is not 
formally powered, however 12 healthy adult participants are considered sufficient to characterise the 
PK of the child-friendly taste-masked granule formulation of PQP. 
5.2.1 Inclusion criteria 
Participants must fulfil all of the following criteria to be eligible for enrolment in this trial: 
1. Female or Male aged ≥18 years to ≤55 years at the date of signing informed consent.  
2. Ability to provide written, personally signed, and dated informed consent to participate in the trial, in 
accordance with the ICH Good Clinical Practice (GCP) and applicable regulations, before any trial-
related procedures. 
3. An understanding, ability, and willingness to fully comply with trial procedures and restrictions. 
4. Female participants must agree to follow contraceptive requirements as indicated in Section 13.2.2, 
from at least 30 days prior to first dosage to 16 weeks after last dosage.  
5. Agrees not to donate sperm or ova from the time of the first administration of trial medication until 
twelve weeks after the end of the systemic exposure of the trial drug. 
6. Participants must have a body weight of 50 kg or greater and a BMI between 18.0 kg/m² - 30.0 
kg/m² (inclusive) at screening.  
7. Satisfactory medical assessment with no clinically significant or relevant abnormalities as 
determined by; medical history, physical examination, vital signs, 12-lead ECG and clinical 
laboratory evaluation that is reasonably likely to interfere with the participant's participation in or 
ability to complete the trial as assessed by the Investigator.  
5.2.2 Exclusion criteria 
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1. Prior screen failure or randomisation in this trial. NOTE: Participants who initially failed due to 
temporary non-medically significant issues are eligible for re-screening once the cause has 
resolved. 
2. Female participant who is pregnant (from history, examination or confirmed by a positive serum 
pregnancy test at screening and/or on Day -1) or breastfeeding. 
3. Male participants with a female partner(s) who is (are) pregnant or lactating at screening and/or on 
Day -1, or is (are) expected to be during the trial period. 
4. Has a mental incapacity or language barriers precluding adequate understanding, co-operation, or 
compliance with the trial requirements. 
5. Unable or unwilling to follow a standardised diet and meal schedule or unable to fast, as required 
during the trial. 
6. Has milk intolerance. 
7. Unable to swallow tablets. 
8. Has veins on either arm that are unsuitable for intravenous puncture or cannulation (e.g., veins that 
are difficult to locate, or a tendency to rupture during puncture). 
9. Known or suspected intolerance or hypersensitivity to the investigational products, any closely 
related compound, or any of the stated ingredients. 
10. History of significant allergic reaction (e.g., anaphylaxis, angioedema), to any product (food, 
pharmaceutical, etc) but excluding untreated, asymptomatic, seasonal allergies. 
11. Donated blood or blood products (excluding plasma) within 90 days prior to trial medication 
administration. 
12. Has received or plans to receive a COVID-19 vaccination within two weeks before to one week after 
trial last visit.  
13. Treated with medication containing PQP within 90 days or five half-lives preceding the dose of trial 
medication (whichever is the longer). 
14. Ingested herbal remedies or dietary supplements containing St. John’s Wort in the 30 days before 
the planned Day 1 of the dosing Part. 
15. Taking 
medicinal 
products 
that 
are 
known 
to 
prolong 
the 
QTc 
interval 
(see 
http://www.crediblemeds.org/). An up to date list will be in the study specific manual. 
16. Use of any medication that is either a moderate or strong inhibitor or inducer of CYP3A4 within 30 
days or five half-lives (whichever is longer) prior to the planned day of dosing (see Drug 
Development and Drug Interactions, Table of Substrates, Inhibitors and Inducers, FDA).  An up to 
date list will be in the study specific manual. 
17. Use of any other prescription medication (excluding hormonal contraception and hormone 
replacement therapy) within 14 days or ten half-lives (whichever is longer) prior to Day 1 of the 
dosing Part that the Investigator judges is likely to interfere with the trial or pose an additional risk 
in participating. 
18. Use of any over-the-counter medication (including multivitamin, herbal, or homeopathic 
preparations; excluding paracetamol - up to 3 g of paracetamol per day permitted while participants 
are in-house, whereas while participants are outpatients a maximum of 1 g paracetamol per day will 
be allowed) during the seven days or ten half-lives of the drug (whichever is longer) prior to Day 1 
of the dosing Part, that the Investigator judges is likely to interfere with the trial or pose an additional 
risk in participating. 
19. Ingested any poppy seeds within the 24 hours prior to screening or admission. 
20. Current use of tobacco in any form (e.g., smoking or chewing) or other nicotine-containing products 
in any form (e.g., gum, patch, electronic cigarettes).  
21. History or clinical evidence of substance and/or alcohol abuse within the two years before screening. 
Alcohol abuse is defined as regular weekly intake of more than 14 units (for both males and 
females).  


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22. Participants must have not consumed other substances known to be potent inhibitors or inducers 
of CYP34A system such as grapefruit or cranberry juice-containing products in the 30 days before 
the planned IMP administration. 
23. Any history of seizures, epilepsy, photosensitivity or documented retinopathy. 
24. The history or presence of any of the following cardiac conditions: known structural cardiac 
abnormalities; family history of long QT syndrome; cardiac syncope or recurrent, idiopathic syncope; 
exercise related clinically significant cardiac events. 
25. Has vital signs consistently outside of the normal range at screening or Day-1. 
26. Any clinically significant abnormalities in rhythm, conduction or morphology of resting ECG or 
clinically important abnormalities that may interfere with the interpretation of QTc interval changes. 
This includes participants with any of the following (at screening or Day -1):  
• 
sinus node dysfunction 
• 
clinically significant PR (PQ) interval prolongation (>220ms)  
• 
second- or third-degree atrioventricular (AV) block 
• 
sustained cardiac arrhythmia’s including (but not limited to) atrial fibrillation or supraventricular 
tachycardia, or any symptomatic arrhythmia, with the exception of isolated extra-systoles 
• 
abnormal T-wave morphology which may impact on the QT/QTc assessment 
• 
QT interval corrected using the Fridericia’s formula (QTcF) >450 ms  
• 
any other ECG abnormalities in the standard 12-lead ECG or an equivalent assessment which 
in the opinion of the Investigator will interfere with the ECG analysis 
• 
Participants with borderline abnormalities may be included if the deviations do not pose a safety 
risk, and if agreed between the appointed cardiologist and the PI.   
27. Positive test results for alcohol or drugs of abuse at screening or Day -1. 
28. Electrolyte imbalances, particularly results that are out of reference intervals for potassium, calcium 
or magnesium. 
29. Has a positive test for Hepatitis B surface Antigen (HBsAg), Hepatitis C Antibody (HCV Ab), or 
Human Immunodeficiency Virus Antibody (HIV Ab) at screening. 
30. Presence of malaria parasites by blood smear. 
31. Has total bilirubin, ALT or AST consistently >upper limit of normal (ULN) at screening (up to two 
repeats may be taken during the screening period; participants may be included if two out of the 
three total results are ≤ULN), or has total bilirubin >ULN on Day -1 (mild variations from baseline 
may be allowed if considered not clinically significant by the Investigator). 
32. Has a haemoglobin, platelet count, total white blood cell count, lymphocyte or monocyte count < 
lower limit of normal (LLN) (up to two repeats may be taken during the screening period and on Day 
-1 (participants may be included if two out of the three total results are greater or equal to LLN), at 
screening. Where there is a clear diurnal effect on the result participants may be included if 
variations are considered not clinically relevant by the Investigator. 
33. Current or recurrent disease (e.g., cardiovascular, haematological, neurological, endocrine, 
immunological, renal, hepatic or gastrointestinal or other conditions, including cholecystectomy or 
gastrectomy) that could affect the action, absorption, distribution, metabolism or excretion of PQP 
or could affect clinical assessments or clinical laboratory evaluations. 
34. Current or relevant history of physical or psychiatric illness that are not stable or may require a 
change in treatment, or use of prohibited therapies during the trial, that make the participant unlikely 
to fully comply with the requirements of the trial or to complete the trial, or any condition that presents 
undue risk from the investigational product or trial procedures. 
35. Any other abnormal findings on vital signs, ECG, physical examination or laboratory assessments 
that the Investigator judges as likely to interfere with the trial or pose an additional risk in 
participating. 


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36. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the 
participant at risk because of participation in the trial, or may influence the result of the trial or the 
participant's ability to participate in the trial. 
37. Any conditions which in the opinion of the Investigator would make the participant unsuitable for 
enrolment or could interfere with the participation in or completion of the trial. 
5.3 
Discontinuation of individual participants 
A participant has the right to withdraw from the study at any time and for any reason and is not obliged 
to give his or her reasons for doing so. Following the withdrawal of consent, with the exception of safety 
data, which should be collected if possible and in accordance with the participant’s agreement, no 
further evaluations should be performed and no attempts should be made to collect additional data. 
Data collected before withdrawal of consent may be retained and used, except when the participant 
explicitly asks the Investigator to destroy all identifiable samples taken from the participant and does 
not allow to analyse his/her data. Participant withdrawal and any agreements made with the participant 
will be documented in the participant’s charts and the investigator will ensure to implement all necessary 
steps. 
A participant can be discontinued from the study by the Investigator at any time in the interests of the 
participant’s health and well-being or for any of the following reasons:  
1. Administrative decision by the Investigator  
2. Participant non-compliance with study requirements  
3. Any event which requires discontinuation of the study involvement or results in inability to continue 
to comply with study procedures  
4. Recommendation by the SRC 
If, for any reason, a participant is discontinued from the study before the end of treatment evaluations, 
the Investigator is required, as feasible, to perform the safety procedures planned for the end of 
treatment. e.g., if a participant develops an AE of Grade 2 or higher, he/she will continue with close-up 
until the AE is resolved, stabilized, or is otherwise explained. The reason(s) for discontinuation will be 
recorded in the electronic case report form (eCRF) and source documents. 
5.4 
Replacement of individual participants 
On the day prior to study product dosing (Day-1), at least one additional participant will be invited as a 
backup for any other participant withdrawn prior to initiation of fasting. Replacement participants may 
be enrolled to ensure that a sufficient number of participants complete the trial unless AE rules preclude. 
Replacement participants must be agreed upon by the Investigator and the Sponsor.  


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6 TREATMENT OF PARTICIPANTS 
6.1 
Identity of investigational products (treatment / medical device) 
6.1.1 Experimental intervention (Piperaquine tetraphosphate dispersible granules) 
• 
Piperaquine tetraphosphate dispersible granules are white to off-white granules that contain 26.67% 
w/w of piperaquine tetraphosphate. The granules have been developed and manufactured by 
Piramal Pharma Ltd. In Ahmedabad, India.  For a 320 mg dose, 1.2 g of granules should be weighed 
and dispersed in 25 ml of water for oral administration. 
• 
Dispersible granule formulation will be used in Part 1 for group 2 and in Part 2 for groups 3, 4 and 
5 (Section 4). 
• 
The procedure for final preparation, dosing / weighting of the dispersible granules and dispensing 
condition in respect to stability data will be provided in details in the pharmacy manual 
6.1.2 Comparator (Piperaquine tetraphosphate tablets) 
• 
Piperaquine tetraphosphate tablets, 320 mg, are white to off-white, round, bi-convex, uncoated 
tablets, plain on both sides.  The tablets for oral administration have been manufactured by Piramal 
Pharma Ltd. In Ahmedabad, India. 
• 
Tablet formulation will be used as comparator during Part 1, for group 1 (Section 4) 
• 
Tablet formulation will be administered orally under DOT (directly observed treatment) with 240 mL 
of water. 
6.2 
Administration of experimental and control interventions 
Dosing will be carried out in the fasted or fed conditions in Part 1 and 2 respectively. 
6.2.1 Administration under fasted conditions: Part 1 (Groups 1 and 2) 
• 
All participants will fast of all food and drink except water (minimum of 10 hours). During this period, 
water will be permitted ad lib except for the period 1 hour before until 1 hour after administration of 
the drug product. At the end of fasting period, participants will receive PQP tablets or dispersible 
granules depending on the randomization (Section 4.2.1). Participants will also not consume any 
food for at least 4 hours after the dose. 
• 
Participants should receive standardized meals scheduled at the same time throughout the in-house 
stay. 
6.2.2 Administration under fed conditions: Part 2 (Groups 3, 4 and 5) 
• 
All participants will fast of all food and drink except water (minimum of 10 hours). During this time, 
water will be allowed ad lib except for the period 1 hour before until 1 hour after drug administration. 
• 
At the end of fasting period, depending on randomization (Section 4.2.1), assigned food (high-fat 
meal, low-fat meal representative of African diet or 250 ml of whole milk) will be consumed entirely 
within a period of less than 30 minutes. 
• 
At 30 minutes after the start of breakfast / assigned food and beverage (see above), the PQP 
dispersible granules will be administered. No food will be allowed for at least 4 hours after the dose. 
• 
Subjects should receive standardized meals scheduled at the same time throughout the in-house 
stay. 
6.3 
General approach for preparing meals for administration under fed conditions 
A respective manual / SOP will be used with the help of dietitian and delegated kitchen staff to 
standardized regular meals based on the following basic guidance. 


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• 
for the present FE study, both high-fat and low-fat meals will be assessed. The requirement to derive 
exposure measures and PK parameters in fed conditions can be achieved by establishing the caloric 
and content breakdown (carbohydrates, proteins, and fat (>50% for high-fat meal vs 25% for low-
fat meal) for the test meals (16). 
• 
Efforts will be made to standardise the content, volume, and viscosity in standardizing the meal 
composition reflecting local African diet especially for the low-fat meals. The guidance below 
provides a description for the reference approach to estimate composition of the ingredients for 
standardization of the recipe used locally. Specific ingredients and amount for the recipe will be 
described in the respective study manual, including a list of the locally used ingredients adjusted to 
meet composition requirements. 
Table 1: FDA Guide for composition of fat in high-fat and low-fat meals 
Meal Type 
Total Kcal 
Fat 
Protein 
Carbohydrate 
Kcal  
Grams  
Percent  
Kcal 
Kcal 
High-Fat  
800-1000  
500-600  
55-65  
≥50  
150 
250 
Low-Fat  
400-500  
100-125  
11-14  
25 
- 
- 
6.3.1 Standard meals at regular intervals throughout the in-house stay. 
• 
During screening, participants will be informed about the sense and purpose of the dietary 
requirements and the percentage composition of the meals. 
• 
Any food allergy will lead to exclusion from the study. 
• 
During in-house stay, all participants of a trial will receive standard meals for breakfast, lunch, or 
dinner independent of any individual preferences. This will be initiated at the time of entering the 
clinical trial facility (pre-fast dinner) and resume at breakfast 4 hours post IMP. 
6.4 
Packaging, labelling and storage conditions  
PQP hard tablets and dispersible granules will be supplied to the clinical trial centre. The study IMP will 
be packed in HDPE bottles and dispatched with labels listing the batch numbers. The study drugs 
should be stored at less than 30 °C. 
6.5 
Dose modifications 
As described in Section 4, based on the safety and preliminary PK interim report of the granule 
formulation on Day 15, if necessary, doses may be readjusted for the Part 2 in order to assess the food 
effect for the optimal dose. 
6.6 
Compliance with study intervention 
 
The pharmacist will prepare the dose for each participant and label it with the participant ID. Additional 
details regarding the labelling, dispensing and inventory will be provided in the respective pharmacy 
manual. Study treatment will be administered under the direct supervision of investigator site personnel, 
who will monitor the participants to ensure treatment compliance.  
If vomiting occurs at any time following ingestion of the study product, no re-dosing will be provided and 
the participant will continue to be followed for safety and PK analyses. The onset time and frequency 
of vomiting will be documented in the source documents as an AE. Participants who have vomited after 
administration of the dose may be replaced at the discretion of the Investigator and the Sponsor. 
 
 


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6.7 
Concomitant interventions (treatments) 
Prior therapy as indicated in the exclusion criteria Section (Section 5.4) will not be permitted.  
No medications will be allowed while the participant is in the study except the use of contraceptives as 
described in Section 13.2.2 or when considered medically indicated by the investigator for the treatment 
of AEs/SAEs. In case of occasional headache and other pain, paracetamol (not exceeding 3g/day) may 
be administered at the discretion of the Investigator. If any medication or intervention listed in participant 
restrictions described in Sections 13.2.2 and 13.2.3 is required, the participant may be withdrawn from 
the study at the discretion of the Investigator and the Sponsor. 
Medications taken within specified periods before the first dose of study medication will be documented 
as a prior medication and may be exclusionary in reference to the exclusion criteria and / or participant 
restrictions described in Section 13.2.3. Medications taken after the first dose of study medication (e.g., 
to treat any AEs) will be documented as concomitant medications. 
6.8 
Study drug accountability 
The clinical site will be provided with PQP tablets and granules by the Sponsor (MMV) prior to the 
initiation of the study when the approval has been obtained from the relevant ethics committee and 
import licence from the regulatory authorities. The site pharmacist will be accountable for IMP and other 
medications by ensuring that they are all inventoried and stored as indicated in the Pharmacy Manual 
Additional details on the requirements and documentation for accountability will be described in the 
general study site internal quality assurance (QA) and Pharmacy Manuals. Accurate and adequate 
records maintenance from shipment to the sites until return or disposal including the physical location, 
dates (receipt, expiry, use, return), lot/batch number and quantities (received, used, destroyed) will be 
maintained. 
Study products and study accountability logs will be available to the sponsor or sponsor’s representative 
as part of the study monitoring procedures. 
6.9 
Return or destruction of study drug / medical device 
Unused IMP will either be destroyed in accordance with the site’s pharmacy manual and national law 
or returned to the Sponsor. 
 


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7 STUDY ASSESSMENTS AND VISITS 
For the study timepoints described below, when multiple procedures are scheduled at the same time 
point(s), the chronology of events will be specified in the relevant study specific manual and should be 
adhered to, where possible. 
7.1 
Clinical assessment parameters 
7.1.1 Vital signs 
The following vital sign parameters will be collected (blood pressure, heart rate, axillary temperature 
and respiratory rate) will be collected in supine position at indicated specified time points (Section 4.4 
Schedule of events): 
• 
axillary body temperature 
• 
after at least five minutes of supine / semi supine rest 
o Respiratory rate 
o Heart rate 
o Blood pressure (Systolic and Diastolic) 
If the result of the measurement is out of range, the Investigator will make an assessment of clinical 
significance and appropriate course of action will be taken as follows:  
o If out of range at screening, vital signs may be repeated as clinically indicated, if the 
abnormality is assessed as clinically significant, participant will be counselled and excluded. 
o If out of range after IMP administration, appropriate course of action will be followed as 
described in Section 8.2.3.  
7.1.2 Medical history and review of systems 
General questioning about the relevant past and present medical history, prior and concomitant 
treatment history, family and social history and review of systems. This information will primarily focus 
on the medical conditions relevant for enrolment criteria. 
7.1.3 Physical Examination 
A complete physical examination will assess general appearance including height and weight (at 
screening) and weight repeated (at Day-1) and the following body system: skin, lymph nodes, head, 
eyes, ears, nose, throat, respiratory, cardiovascular, abdomen, extremities, musculoskeletal, and 
neurological.  
A targeted symptom directed physical examination will be assessed at any study visits as deemed 
necessary by the Investigator based on history of presenting complaint or clinical observations. 
7.1.4 12-lead ECG safety recording 
Instructions for recording, handling, review, repeat and electronic transmission of the ECGs will be 
included in a separate ECG Manual. The following general guidance will apply; 
• 
To be performed after at least ten minutes of supine / semi supine rest 
• 
Triplicate ECG (three repeat ECGs, at least 1 minute apart) and Single ECG recorded in supine 
position; 
o will be performed for time-points indicated in Section 4.4 Schedule of events 
• 
Abnormal ECGs; may be confirmed by repeat and will be assessed for clinical significance by the 
investigator. 


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• 
All recorded ECGs will be reviewed by the investigator or delegate and the review will be 
documented in the CRF (for normality and clinical significance). If a participant shows an abnormal 
ECG, additional safety recordings may be performed, and the abnormality be followed to resolution 
if required. 
• 
If needed a cardiologist will be consulted for participant review and ECG assessment, particularly 
for abnormal assessments recorded post investigational product (IP). 
• 
All digitalized ECGs recorded at baseline (pre-dose on Day-1 and Day1) and post IMP 
administration will be transmitted electronically for central ECG assessment by the ECG vendor and 
the reports will be analysed and summarized cumulatively in reference to the clinical participant 
data at the final safety report. 
7.2 
Laboratory assessment parameters 
The following parameters for each laboratory test will be measured at indicated specified time points 
(Section 4.4 Schedule of events) using procedures outlined in the respective site laboratory manual. 
See Section 8 (Assessment of safety) for further details related to grading, assessment, reporting and 
follow-up of abnormal laboratory values. 
• 
Biochemistry: Defined in two Biochemistry Panels  
o Biochemistry Panel 1: Alanine Transaminase (ALT), Aspartate Transaminase (AST), Total 
bilirubin (T.bil), Potassium (K⁺), Calcium (Ca²⁺), Magnesium (Mg²⁺), Sodium (Na⁺), Chloride 
(Cl⁻), Bicarbonates (HCO3⁻), Creatinine (Creat), Total serum Proteins (T.Pr), Albumin (Alb) 
o Biochemistry Panel 2: ALT, AST, T.bil, K⁺, Ca²⁺, Mg²⁺ 
• 
Hematology and coagulation: Hemoglobin (HB), platelets (PLT), white blood cells (WBC) and 
WBC differentials (Neutrophils, Eosinophils, Lymphocytes), prothrombin time (PT) and activated 
partial thromboplastin time Coagulation (aPTT) 
• 
Malaria parasitology: Thick Blood Smear 
• 
Urinalysis performed by dipstick: Protein and blood (Note: Urinalysis should be deferred if a 
participant is menstruating, but should be performed as soon as possible). If deemed necessary,  
based on a clinically significant positive test, microscopic examination of urine and quantification of 
analytes (as appropriate) will be performed. 
• 
Serology: (HIV 1 & 2, Hepatitis B & C) 
• 
Drugs of abuse: Urine and Alcohol breath test: Benzodiazepines, Opiates, Amphetamines, 
Methamphetamines, Methadone, Cocaine, Cannabinoids, Barbiturates, Phencyclidine, Tricyclic 
antidepressants 
• 
Contraception requirements: 
o Serum pregnancy test for WOCBP 
o Follicular stimulating hormone (FSH) for post-menopausal female 
7.2.1 PK assessment 
Blood samples for PK assessment will be taken from either arm following procedures stipulated in the 
respective site sample collection manual. The exact date and time of PK blood sampling will be recorded 
in the source documents. Procedures for processing, storage and transfer plasma samples including 
the required controlled temperature environment will be detailed in the relevant PK manual provided by 
the Good Laboratory Practice (GLP) certified Bioanalytical Laboratory vendor. Blood volumes and time 
points for PK sampling are indicated in Section 4.4 (Schedule of events). 


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7.2.2 Exploratory assay 
Blood samples for CYP polymorphism will be collected as indicated in Section 4.4 (Schedule of events). 
This exploratory sample is optional and will only be indicated for those participants who will indicate 
their willingness to this optional sample in the tick-box provided in the respective consent form. 
7.2.3 Total blood volume 
The blood volumes planned to be collected from each participant during the course of this study are 
detailed in Section 4.4 (Schedule of events). The total blood volume collected during the scheduled 
study visits (of approximately 75 days) for any given participant will be approximately   
70 mL. Additional samples may be required in the event of AEs/SAEs, laboratory safety tests or in case 
a laboratory test needs to be repeated as judged by the Investigator.  
7.2.4 Exploratory questionnaire: Palatability 
A palatability / tasting questionnaire will be presented to each participant immediately after dosing and 
asked to be completed within 10 minutes of dosing with IMP.    
7.3 
STUDY VISITS 
7.3.1 Screening period (Day-45 to Day-2) 
Written informed consent will be obtained prior to any study procedures including a consent for 
collection of pharmacogenetic assessment. 
• 
All participants will be screened and assessed for eligibility prior to administration of the study 
medication.  For convenience and synchronization, to accomplish this, procedures at screening are 
allocated under columns (ᴬ) or, (ᴮ) as defined in Section 4.4 (Schedule of events). 
o ICF (informed consent form) must be signed prior to any other procedures and will be valid 
if performed less than or equal to 45 days prior to Day1.  
o With the exception of contraception for WOCBP which must be performed >=30 days prior 
to D1, all other events shown under screening column (ᴬ) must be performed within the valid 
ICF window and not later than Day-2. 
o Events indicated under screening column (ᴮ) must be performed within the valid ICF window 
and between Day-15 and Day-2. 
• 
This alignment of procedures, will provide the healthy participants with sufficient reflection time and 
ensure that investigators perform required procedures following protocol and clinically acceptable 
time windows prior to IMP administration (e.g., contraception for WOCBP >=30 days prior to study 
treatment) while maintaining compliance to GCP and protocol requirements (e.g., only after ICF is 
signed). 
• 
The selection criteria for the study may be reviewed upon completion of each set of screening 
assessments. Participants who fail at earlier procedures, e.g., screening column (ᴬ), may not 
necessarily continue with the subsequent screening procedures unless otherwise indicated or 
deemed necessary to do so. 
• 
As long as the chronological order of procedures and time windows to IMP administration are 
maintained, events under screening columns (ᴬ) and (ᴮ) may be completed in the same visit day, 
except contraception for WOCBP which must be performed >=30 days prior to study treatment.  
• 
Note: Depending on the latest COVID-19 Infection Control Guidelines; COVID-19 tests will be 
carried out at regular intervals, prior to entry in the unit and throughout the residential period as per 
and pre-entry algorithms. 


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In cases that re-screening is justified, certain procedures such as contraception and HIV testing may 
not be clinically justified within the timeframe of re-screening. The investigator’s medical justification for 
not repeating such procedures must be documented and proceed with justified assessments. On 
repeating screening, a new screening number will be assigned only if ICF window has expired, in which 
case, the previous screening number must not be re-used for the same or different study participant.  
7.3.2 In-house visit procedures 
Overall, in-house visits will cover the following main procedures / activities: 
• 
Admission of eligible participants to the trial facility one day prior to study treatment (Day-1) 
o Number and schedule of participants to be dosed in a single day will depend on a 
combination of factors targeted to optimize implementation of study assessments without 
risking the safety of participants or losing quality. The overall tentative study schedule will 
be used as a reference for future scheduling. 
o Replacement of participants during the in-house visits is described in Section 5.4.  
• 
Random treatment allocation and administration of study IMP on the following day (Day1) 
• 
Post IMP continuous assessments and safety monitoring (Day1, Day2) 
• 
Completion of in-house assessments and discharge from the trial facility (Day3).  
7.3.2.1 Day -1 
At the time of admission: 
• 
Eligibility review and confirmation of willingness to continue with study participation 
• 
Admission to in-house trial unit 
• 
In-house baseline assessments indicated for Day-1 
o Review medical history (including medications) for any updates since last seen by the study 
clinician 
o Body Weight 
o ECG (see Section 4.4) 
o Vital signs collection (see Section 7.1.1) 
o Symptom directed physical exam 
o Collection of relevant laboratory parameters including serum pregnancy test (WOCBP) (see 
Section 4.4) 
• 
Review of baseline assessment results indicated for Day-1 
• 
Fasting initiation and monitoring during the 10 hours of pre-IP fasting period (Section 6.2). 
7.3.2.2 Day 1 
• 
The following pre-IP baseline assessments and procedures will be initiated about 60 minutes before 
the end of 10 hours fasting duration (i.e., after 9 hours of fasting have elapsed): 
o Restricted water intake for the period 1 hour before until 1 hour after administration of the 
study IMP  
Completion of Pre-IP baseline assessment within 30 minutes prior to the end of 10 hours fasting 
duration, preferably in the following order: 
o Review of medical history for any updates 
o ECG (see Section 4.4) 
o Vital signs 
o PK Samples collection 
o Randomization (see Section 4.2.1) 


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• 
After 10 hours of fasting have elapsed, administration procedures for the study drug will vary 
between part 1 and part 2 depending on the dosing conditions as follows: 
Part 1: Administration under fasted conditions 
o At 10 hours of fasting; Investigators should immediately administer the drug product to study 
subjects (see Section  6.2.1).  
Part 2: Administration under fed conditions 
o At 10 hours of fasting; The study participant will start the randomly allocated meal 30 minutes 
before administration of the drug product, and should consume the meal in 30 minutes or 
less 
o Investigators should immediately administer the drug product to study subjects (see Section 
6.2.2). 
• 
Post IMP procedures and restrictions on Day1 
o Participants will be asked to complete the palatability questionnaire (within 10 minutes of 
dosing). 
o Participants will be requested to remain in a semi-supine position for the first four hours after 
dosing, except to use the bathroom. Participants may then be ambulatory but should not 
engage in strenuous activities. 
o Additional water is allowed ad lib except for the period 1 hour before until 1 hour after drug 
administration. 
o No food is allowed for at least 4 hours after the dose. 
o Standard meals will be provided at the standard schedule each day over the duration of in-
house stay. 
Vital signs, ECGs and PK samples collection: 
o Will be performed on a strict schedule (see Section 4.4 Schedule of events) beginning from 
1 hour to 12 hours post IMP on Day1. 
7.3.2.3 Days 2 and 3 
o Standard meals will be provided at the standard schedule each day over the duration of in-
house stay. 
Vital signs, ECGs and PK samples collection and AE review: 
o Procedures will be performed on a strict schedule at approximately 24 hours and 48 hours 
post IMP on Day2 and Day3 (see Section 4.4 Schedule of events) 
o On Day3 safety laboratory samples will also be collected 
Discharge on Day3 
o Participants will be discharged after the completion of procedures on Day3 
o At discharge, they will be reminded to contact the study team in case of any questions or 
concerns and will be reminded on the next visit day. Discharge procedures will be detailed 
in the relevant study manual. 
7.3.3 Clinic follow-up visits 
7.3.3.1 Days 5, 8, 15, 22 and 30 
Vital signs, ECGs and laboratory (safety and PK Samples) and AE review: 
o Procedures will be performed on a strict schedule (see Section 4.4 Schedule of events) 
o End of study (i.e. Day 30). 


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7.3.4 Unscheduled visits 
Unscheduled visits may occur at any time during the study. They may occur after Day 30 to follow any 
AE/SAE occurring during the study period to resolution or stability. Clinical assessments will be 
performed at the discretion of the investigator as medically indicated. 
 


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8 ASSESSMENT OF SAFETY 
8.1 
Safety parameters 
Specify the study procedures and visits including permitted time windows that will be used for a concrete 
assessment of the safety, at which point and how the parameters be measured (methodology). 
8.1.1 Collection and reporting of adverse events 
The collection, evaluation and reporting of adverse events/reactions arising from this clinical study will 
be performed in accordance with: 
• 
“Detailed guidance on the collection, verification and presentation of adverse event/reaction reports 
arising from clinical trials on medicinal products for human use (‘CT-3’) (2011/C 172/01)”. 
• 
International Conference on Harmonization (ICH) guideline E2F “Note for guidance on development 
safety update reports (DSUR)”. 
• 
International Conference on Harmonization (ICH) guideline E2A “Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting”. 
It is the Investigator’s responsibility to document and report all AEs occurring in the clinical trial. The 
period of observation for collection of AEs extends from the time of signing consent to the final visit. 
All AEs must be recorded until the end of the study. All SAEs which come to the attention of the 
Investigator within 30 days from the end of the study treatment must also be recorded. 
The definitions of AEs, adverse drug reactions (ADRs), serious adverse events (SAEs) and SUSARs 
(Suspected Unexpected Serious Adverse Reactions) are given below. It is of the utmost importance 
that all staff involved in the conduct of clinical research are familiar with the content of this Section. 
8.1.2 Definition of adverse events  
According to ICH Topic E6, an adverse event (AE) is any unfavourable and unintended sign (including 
an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal 
product, whether or not considered related to it. 
An adverse drug reaction (ADR) is a response to a medicinal product which is noxious and unintended 
and which occurs at any dose (in pre-approval clinical experience) or at doses normally used in man 
for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function (in post-
approval clinical experience). The term “response” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility.  This means that there are facts 
(evidence) or arguments to suggest a causal relationship. 
According to ICH Topic E9, a treatment emergent adverse event/adverse reaction is an event that 
emerges during treatment, having been absent pre-treatment, or worsens relative to the pre-treatment 
state. 
In a clinical trial, in addition to the above mentioned “treatment-emergent” AEs/ADRs, any unfavourable 
and unintended sign, symptom or disease occurring in the study during any wash-out periods must also 
be recorded as an AE/ADR. 
 


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8.1.3 Types and recording of adverse events 
An AE/ADR may be: 
• 
a new symptom or medical condition; 
• 
a new diagnosis; 
• 
an intercurrent illness or an accident; 
• 
a worsening of a medical condition/diseases existing before the start of the clinical trial; 
• 
the recurrence of a disease; 
• 
an increase in frequency or intensity of episodic diseases; 
• 
a change in a laboratory parameter. 
The criteria for determining whether an abnormal test result should be reported as an AE/ADR are as 
follows: 
• 
the test result is associated with accompanying symptoms, and/or 
• 
it requires additional diagnostic testing or medical/surgical intervention, and/or 
• 
it leads to a change in trial dosing outside of protocol-stipulated dose adjustments, or discontinuation 
from the trial, significant additional concomitant drug treatment, or other therapy, and/or 
• 
it is considered to be an adverse event by the Investigator or Sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not constitute 
an AE/ADR. Any abnormal test result that is determined to be an error does not require reporting as an 
adverse event. 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that require 
surgery. The condition for which the surgery is required may be an AE/ADR. Planned surgical measures 
permitted by the clinical trial protocol and the condition(s) leading to these measures are not AEs, if the 
condition leading to the measure was present before inclusion in the trial. In the latter case the condition 
should be reported as medical history. 
These data will be recorded in the CRFs, regardless of whether they are thought to be associated with 
the study or the drug under investigation. 
8.2 
Grading of adverse events 
8.2.1 Standard Toxicity Grading 
For each AE, the Investigator will assess the maximum severity. In general, All AEs/SAEs (except 
laboratory abnormalities) will be graded by the Investigator using the AE severity grading according to 
the WHO system: 
WHO intensity grades are defined as follows: 
1 
Mild – No interference with routine activity. 
2 
Moderate – Interferes with performance of some activities of daily living, but responds to 
symptomatic therapy or rest. 
3 
Severe – Significantly limits ability to perform activities of daily living despite symptomatic 
therapy. 
4 
Very severe – Incapacitates patient despite symptomatic therapy; requires hospitalization 
WHO Handbook for Reporting Results of Cancer Treatment.  WHO Offset Publication No.  48.  World 
Health Organization; Geneva, Switzerland.  1979:16–21.  


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8.2.2 Grading of abnormal values for safety laboratory assessments 
The site manual for the reference intervals and grading for selected abnormal values, utilizes the 
population references for specified laboratory parameters to grade abnormal laboratory values using 
adopted schemes of reference for toxicity grading (17, 18, 19). 
8.2.3 Abnormal assessments to be considered as adverse events 
Each abnormal value will additionally be classified as clinically significant or not clinically significant 
according to the clinician’s medical judgment. In general, abnormalities that require intervention will be 
classified as clinically significant. Borderline abnormal laboratory findings and other objective 
measurements should NOT be routinely captured and reported as AEs, as they will be collected and 
analysed separately. However, abnormal laboratory findings or other objective measurements that meet 
the criteria for an SAE, result in discontinuation of the IMP, require medical intervention or are judged 
by the Investigator to be clinically significant changes from baseline values should be captured and 
reported on the AE pages of the eCRF. 
When recording an abnormal laboratory finding on the AE pages of the eCRF, a clinical diagnosis 
should be provided rather than the abnormal value itself, if this is available (for example, “anaemia” 
rather than “decreased red blood cell count” or “haemoglobin = 10.5 g/dL”). 
8.3 
Association of adverse events – relatedness to the medicinal (investigational) product 
A physician/investigator must make the assessment of relationship to investigational product for each 
AE. The investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product.  If there is no valid 
reason for suggesting a relationship, then the AE should be classified as “not related”. Otherwise, if 
there is any valid reason, even if undetermined or untested, for suspecting a possible cause-and-effect 
relationship between the investigational product and the occurrence of the AE, then the AE should be 
considered “related”. The causality assessment must be documented in the source document. 
The following additional guidance may be helpful: 
Term 
Relationship Definition 
Related/suspected 
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by the 
subject’s medical condition, other therapies, or accident. 
Not related/ 
not suspected 
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible 
temporal 
or 
biologic 
relationship 
exists 
between 
the 
investigational product and the event. 
The Investigator should also comment on the AE page of the eCRF whether an AE is not related to the 
study treatment, but it is related to the study participation of the subject (study procedures, wash-out 
periods etc.). 
 
 


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8.4 
Serious adverse events 
An AE/AR is defined as serious if: 
• 
it results in death; 
• 
it is life-threatening (the term "life-threatening" in the definition of "serious" refers to an event in 
which the subject was at immediate risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe); 
• 
it requires a hospitalisation or prolongs existing hospitalisation; 
• 
it results in persistent or significant disability/incapacity; 
• 
it is a congenital abnormality/birth defect; 
• 
it is considered medically important (medical and scientific judgement should be exercised in 
deciding whether other AE/ADRs are to be considered serious, such as important medical events 
that may not be immediately life-threatening but may jeopardise the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. Examples of such 
events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias; convulsions that do not result in hospitalisation; development of drug dependency or 
drug abuse).  
• 
For the purpose of this protocol an AE will be considered as serious should the AE constitute a 
possible Hy’s Law case (defined as a subject with any value of ALT or AST greater than or equal to 
3x ULN together with an increase in bilirubin to a value greater than 2xULN (>35% direct) and NOT 
associated to an ALP value greater than 2xULN.  
A non-serious AE/ADR is any symptom or sign which does not fulfil any of the above-mentioned 
seriousness criteria. 
The causality of SAEs (i.e. their relationship to study treatment) will be assessed in the same way as 
for non-serious AEs.   
Note that SAEs that could be associated with any study procedure should also be reported. 
A SUSAR is any SAE where a causal relationship with the IMP is at least a reasonable possibility, but 
is not listed in the Investigator Brochure and/or Summary of Product Characteristics (SmPC). 
8.5 
Expectedness of adverse reactions 
An adverse reaction, the nature or severity of which is not consistent with the applicable reference 
safety information (Investigator’s brochure [IB] for drugs in clinical development or SmPC for marketed 
drugs) is unexpected. Reports which add significant information on the specificity, increase in the 
occurrence or severity of a known and already documented serious adverse reaction are unexpected 
events. The expectedness of an adverse reaction is determined by the Sponsor in the reference safety 
information. This should be done from the perspective of events previously observed, not on the basis 
of what might be anticipated from the pharmacological properties of a medicinal product. 
For this protocol, the reference document for the assessment of expectedness is the Investigator’s Drug 
Brochure for PQP. AEs that are not related to the IMP do not need an expectedness assessment 
against the reference safety information. From a regulatory perspective, expectedness of a serious 
adverse reaction determines whether it does or does not need reporting in an expedited fashion. 
8.6 
Adverse events reporting obligations 
The window for reporting of AEs/SAEs starts with the signature of the informed consent  and ends with 
the participant’s last visit or the last planned data collection. Inability to fulfil pre-IP fasting requirement 
will be considered as screening failure. 


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8.7 
Recording of adverse events 
All (serious and non-serious) AEs detected by the Investigator or delegates, or spontaneously notified 
by the subject at each visit/examination must be reported in the respective section of the CRF. 
The following information should be reported for each AE, whether or not it can be attributed to the trial 
drug: 
• 
description of AE 
• 
date of onset/date of resolution 
• 
characteristics of the event (seriousness, intensity) 
• 
actions taken (treatment required must be reported in the eCRF) 
• 
outcome 
• 
relationship with trial drug (causality assessment) and/or study participation 
Findings and values related to physical examinations and measurements of ECG, vital signs, (axillary 
temperature, blood pressure, and heart rate) and laboratory parameters will be defined as AEs if they 
are considered clinically relevant deteriorations compared with baseline and pre-dose values, as judged 
by the Investigator. 
8.7.1 Adverse Event Reporting in eCRF 
Complete and accurate data on all AEs experienced for the duration of the reporting period, will be 
reported on an ongoing basis in the AE pages of the eCRF. 
It is important that each AE report include a description of the event, whether it is considered serious, 
its duration (onset and resolution dates), its severity, its relationship to the IMP, any other potential 
causality factors, any treatment given or other action taken (including dose modification or 
discontinuation of the IMP) and its outcome. 
Additional guidance can be found in the eCRF Completion Guidelines provided by the Contract 
Research Organization (CRO). 
8.7.2 Reporting mechanism to sponsor, Ethics Committees and Regulatory Authorities 
If any SAE/SUSAR occurs, the investigators will take appropriate action immediately and will strive to 
identify the causes of the events. Any SAE/SUSAR will be notified by the PI to the MMV Medical Director 
or delegate, see Figure 1. 
Any SAE/SUSAR will be notified by the Investigator to the MMV Medical Director, and to the 
pharmacovigilance provider (Prime Vigilance) within 24 hours by email or fax.  
• MMV Senior Medical Director: Dr Anne Claire Marrast, MD 
o Email: marrasta@mmv.org 
o Tel: + 41 79 323 70 65  
• Prime Vigilance Contact :  
o 
e-mail: MMV@primevigilance.com 
o 
Back up fax: +44 800 471 5694 
The initial report will be followed up by a full written report within three working days or five calendar 
days, whichever comes first, unless no further information is available. When new information becomes 
available a follow-up report will be provided as soon as possible. Further follow-up reports will be 
provided as and when new information becomes available. Photocopies of results, consultant report(s), 
a summary of the outcome of the reaction and the Investigator's opinion of IMP relationship to the 
SAE/SUSAR will accompany the SAE form if and when available.  


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The Sponsor will also perform an evaluation of the seriousness, causality and expectedness of all SAEs. 
All SAEs judged by either the Investigator or the Sponsor as having a reasonable suspected causal 
relationship to an IMP (i.e. definitively, probably or possibly related) will qualify as serious adverse 
reactions. If the Sponsor disagrees with the Investigator’s causality assessment, both the opinion of the 
Investigator and the Sponsor are provided with the report.
All SAEs will be included in the safety/pharmacovigilance database. 
All SAEs including SUSARs that are fatal or life-threatening should be reported to a Competent 
Authority and Ethics Committees within 24 hours followed by a complete report within 7 additional 
calendar days of their occurrence. All other SAEs and SUSARs that are not fatal or life-threatening 
must be filed as soon as possible but no later than 14 calendar days after first knowledge by the 
Sponsor.
Annual safety reporting to the national Competent Authority and the Ethics Committee will be in 
agreement with ICH guideline E2F “Note for guidance on development safety update reports (DSUR)”.
Figure 1.
Safety reporting mechanism to the sponsor, TMDA, NaTHREC and IHI-IRB.
In addition, any other safety issue which may alter the current benefit–risk assessment of the IMP will 
be reported by the Sponsor (or delegate) on an expedited basis to Health Authorities, Ethics 
Committees and the Investigator.
8.8
Follow-up observation for study participants with adverse reactions
All AEs must be documented and followed up until the event is either resolved or a satisfactory 
explanation is found, or the investigator considers it medically justifiable to terminate the follow-up.
Complete Report
Initial Reporting to;
TMDA, NIMR and IHI-IRB
Notification to Sponsor
Reporting Requirements
Reporting
Figure 1: Safety Reporting mechanism to the;
Sponsor, TMDA, NaTHREC and IHI-IRB
Fatal /life 
threatening 
SAEs and 
SUSARs
Within 24 hours
Expedited;
Within 24 hours
Expedited within 
7 Days
■Other SAEs and SUSARs
■protocol- defined event(s) such as stopping rules
■other safety issue which may alter the current benefit–risk 
assessment of the IMP
Within 24 hours
Expedited;
Within 14 Days


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Spontaneously reported SAEs will be collected until 30 days following the final study visit. SAEs 
experienced after this 30-day period will only be reported if the investigator suspects a causal 
relationship with the study drug.  
If a study participant experiences a clinically significant finding or a worsening of an ongoing medical 
condition after signing the Informed Consent, the event will be recorded as an adverse event. 
Any AEs that are unresolved at the participant’s last AE assessment in the study (i.e. at the follow up 
visit) are to be followed up by the Investigator for as long as medically indicated. MMV retains the right 
to request additional information for any participant with ongoing AE(s)/SAE(s) at the end of the study, 
if judged necessary. 
The Investigator will decide on  
• 
Study drug discontinued 
• 
Healthy participant withdrawn from study 
• 
Concomitant Medication required 
• 
Hospitalization required or prolonged (this should also be reported as an SAE 
• 
Other 
The PI or delegate will follow up all AEs wherever possible until the symptom has resolved or stabilised. 
The date of confirming outcome will be recorded. The course of AEs will be assessed by reference to 
the following as a guide. 
• 
Recovered: The AE has resolved and the participant returned to his condition prior to onset. 
• 
Recovered with sequelae: The AE resolved, but the participant has sequelae. 
• 
Recovering: The AE has almost resolved and the participant is returning to his condition prior to 
onset. 
• 
Death: The study participant died. Causal relationship is no object. 
• 
Ongoing: Even on the final day of observation the AE had not resolved and the participant’s 
condition remained unchanged. In case of death, the participant died of other causes not related to 
the AE from which there was no recovery. 
8.8.1 Pregnancy follow-up 
Through the Informed Consent Process all female participants will be instructed to immediately inform 
the Investigator if they become pregnant during the study or within the following 3 months after the last 
dosing and that, pregnancy should be followed through delivery or termination of the pregnancy.  
A Pregnancy Form will be completed by the Investigator and submitted to the MMV Study Medical 
Director and Prime Vigilance preferably within 24 hours after the Investigator becomes aware of the 
pregnancy. The event of pregnancy itself should not be recorded on the Adverse Event Section of the 
eCRF. The Investigator will provide counselling to the pregnant participant about the risks of the 
pregnancy and the possible effects on the fetus and thereafter, she will be asked to give written consent 
to allow for follow up and further collection of data on her pregnancy and the outcome of the child. 
Monitoring of the participant should continue until conclusion of the pregnancy. Any SAEs associated 
with the pregnancy (e.g., an event in the fetus, an event in the mother during or after the pregnancy, or 
a congenital anomaly or birth defect in the child, spontaneous abortion) will be reported on the Adverse 
Event Section of the eCRF if the database has not been locked at that time point. In addition, the 
updated Pregnancy Form will be regularly submitted with latest information on the course and outcome 
of the pregnancy as becomes available. The investigator should ensure that the new-born undergoes 
a thorough clinical investigation within the first 4 weeks after birth and that this assessment is thoroughly 
documented and submitted on a Pregnancy Form to the Sponsor. 


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Male participants may continue in the trial if pregnancy of their female partner occurs. A Pregnancy 
Form will be completed and submitted to the MMV Study Medical Director and Prime Vigilance 
preferably within 24 hours after the Investigator becomes aware of the pregnancy. 
9 DESCRIPTION OF DATA MANAGEMENT 
9.1 
Specification of source documents 
CRFs will be designed in collaboration between the site, sponsor and the contracted data management 
vendor (IQVIA), and will be used to record details of the trial and will serve as source documents for 
sponsor required data. The procedures for collecting the data are outlined in the respective data 
management manual / SOPs. Data in the individual participant files will include clinical information, 
blood sampling data for the specimens acquired to perform the different tests listed, and administrative 
information such as contact information. The forms will also include descriptions of AEs/ARs resulting 
in medical consultation or hospitalization. These forms, together with the investigator’s notes, are 
considered to be source data. Additional hospital notes including laboratory reports and clinical notes 
in the event of emergency or hospitalization will also be collected and included as source notes.  
9.2 
Data management system 
Data will be recorded using paper CRFs. The information will then be transcribed into the eCRFs within 
the electronic data capture system (eDC) by delegated data entry personnel. Data will be independently 
counter checked by study monitor(s) who will review the accuracy of data entry and transfer based on 
the study monitoring plan. The electronic system to be used will include only validated systems that are 
clinical trial compliant with audit trail capabilities. 
9.3 
Data security, access, archiving and back up 
All source documents will be kept in each participant’s folder. As required by the Tanzanian regulatory 
authority (TMDA), all records, documents and information related to this trial will be kept in safe custody 
at the clinical trial site for a period of not less than twenty years after study termination or premature 
termination of the clinical study. 
. 
 
 


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10 STATISTICS 
10.1 Hypothesis 
This pilot BA/FE phase 1 trial is not designed to test specific hypotheses. 
10.2 Determination of sample size  
This is an exploratory trial to evaluate PK and safety of each treatment group and the sample-size is 
not based on formal statistical power. The number assigned to each treatment arm (n=12) is considered 
adequate to assess the trial objectives. 
10.3 Description of statistical methods 
The statistical methods and reporting will follow ICH E9 and international recommendations, including 
CONSORT.  
10.4 Statistical Analysis Plan 
A statistical analysis plan (SAP) containing detailed statistical methodology will be written and signed 
off before the database hard lock. The plan may be updated to reflect adaptive features of the trial as 
appropriate.  
10.5 Analysis sets 
The analysis of data will be based on different analysis sets according to the purpose of analyses. 
Participant eligibility for each analysis set will be finalised before the database hard lock.  
The Safety analysis set will consist of all randomized participants who received at least one dose of the 
IMP.  
The PK analysis set will consist of those participants in the safety set who have sufficient blood samples 
taken for at least one of the PK variables to be calculated.  
In all populations, analyses will be based on the treatment received, regardless of the randomization 
(any such deviations will be reported). A participant who withdraws prior to the last planned observation 
in a trial period will be included in the analyses up to the time of discontinuation. 
10.6 Safety analyses 
Participant disposition will be summarised using descriptive statistics.   
Individual participant demographics (age, gender and race) and body measurement data (height, weight 
and BMI) will be listed and summarised descriptively by treatment group and overall. Other baseline 
characteristics (e.g., medical history, previous medication) will be listed only.  
All adverse event data will be listed and summarised by treatment group, by system organ class (SOC) 
and preferred term (as per Medical Dictionary for Regulatory Activities [MedDRA] coding), severity and 
relationship. Any SAEs and/ or AEs that led to withdrawal will be summarised and listed. 
Vital signs data (see Section 7.1.1) will be listed and summarized, along with changes from baseline, 
using descriptive statistics (mean, median, standard deviation, minimum, maximum). Out-of-reference-
range values will be flagged as high (H) or low (L) and as being clinically relevant or not: the number of 
participants presenting out-of-range and clinically relevant values will be summarized. 
All safety clinical laboratory data will be listed. Laboratory test results will also be compared to laboratory 
reference ranges and those values outside of the applicable range will be flagged as high (H) or low (L) 
and as being clinically relevant or not: the number of participants presenting out-of-range and clinically 
relevant values will be summarized. The quantitative laboratory data, along with changes from baseline 


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will be summarized using descriptive statistics (mean, median, standard deviation, minimum, 
maximum). Change from baseline values at each assessment will be calculated as the assessment 
value minus the baseline value. The qualitative urinalysis data will be listed only. 
All ECG data (PR, QRS, QT, QTcB, QTcF and HR) and overall ECG evaluation will be listed. ECG data, 
along with changes from baseline will be summarized using descriptive statistics (mean, median, 
standard deviation, minimum, maximum). Furthermore, categorical analysis of QTcF data will be 
presented as follows: 
• 
Absolute QTcF interval prolongation 
o QTcF interval > 450 ms 
o QTcF interval > 480 ms 
o QTcF interval > 500 ms 
• 
Change from baseline in QTcF interval 
o QTcF interval increases from baseline > 30 ms 
o QTcF interval increases from baseline > 60 ms 
Mean value of change from baseline QTcF parameters will be plotted by group and time point. Out-of-
reference-range values will be flagged as being clinically relevant or not: the number of participants 
presenting out-of-range and clinically relevant values will be summarised. 
10.7 PK Analyses 
The PK analyses will be performed by a PK analysis vendor (bioanalytical laboratory). PK parameters 
and concentrations data will be summarized using descriptive statistics by treatment, using tabular and 
graphical displays. 
Non-compartmental analysis will be used for estimation of pharmacokinetic parameters. The following 
pharmacokinetic parameters will be calculated for piperaquine: 
• 
Cmax Maximal plasma concentration 
• 
tmax Time at which the maximum plasma concentration occurs 
• 
t1/2 Terminal elimination half-life 
• 
AUC0-∞ Area under the plasma concentration-time curve from time 0 extrapolated to infinite time 
• 
AUC0-t Area under the plasma concentration curve from time zero up to the last quantifiable 
concentration 
• 
AUC00-24h Area under the plasma concentration curve from time zero to 24 hours 
• 
AUC0-72h Area under the plasma concentration curve from time zero to 72 hours 
• 
AUC0-168h Area under the plasma concentration curve from time zero to 168 hours 
• 
%AUCextrap Percentage of AUC that is due to extrapolation from tlast to infinity 
• 
CL/F Apparent total plasma clearance 
• 
Vz/F Apparent volume of distribution during the terminal phase 
• 
λz Terminal rate constant 
• 
Frel Relative Bioavailability (Note: If the dose is adjusted in Part 2 of the study the Frel calculations 
will be dose adjusted). 
The individual plasma concentration data, and the actual time for piperaquine administration and blood 
sampling will be used in the derivation of the PK parameters. If there is any doubt in the actual time a 
sample was taken, then the scheduled time will be used. AUC values will be calculated using the 
linear/log trapezoidal method, applying the linear trapezoidal rule up to Cmax and the log trapezoidal rule 
for the remainder of the curve. Samples below the lower limit of quantification (LLOQ) prior to the first 


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quantifiable concentration will be set to zero. Samples with concentrations below limit of quantification 
(LOQ) after the first quantifiable concentration will be set to ‘missing’ and omitted from the analysis. 
Other PK parameters will be calculated according to standard equations. Details of the PK analysis, 
including the primary and secondary analysis, will be documented in the PK analysis plan. 
10.8 Primary Analysis 
The relative bioavailability will be assessed using the ratio of the geometric means for the granule 
dispersible [test] over the hard tablet [reference] in fasted state for AUC0-72h, AUC0-t, AUC0-168h,  
AUC0-∞, and Cmax.  
10.9 Secondary Analyses 
• 
The relative bioavailability will be assessed using the ratio of the geometric means for the dispersible 
granules formulation between fed [high-fat meal, low-fat African meal, and milk] over the dispersible 
granule formulation fasted [reference] for AUC0-72h, AUC0-t, AUC0-168h, AUC0-∞, and Cmax. 
• 
PK parameters for the hard tablet (fasted) and the dispersible granule formulations (fasted and fed); 
Cmax, AUC0-24h, AUC0-72h, AUC0-t, AUC0-168h, AUC0-∞, time to maximum plasma concentration (tmax), 
terminal elimination rate constant (λz), terminal elimination half-life (t1/2), apparent volume of 
distribution during the terminal phase (Vz/F), apparent total plasma clearance (Cl/F), and 
percentage of AUC that is due to extrapolation from tlast to infinity (%AUCextrap). 
• 
AE counts and numbers of subjects with AEs will be summarized for each arm by MedDRA system 
organ class and preferred term. Concomitant medications, subject withdrawal, vital signs, laboratory 
tests, and ECG parameters will be summarized. 
10.10 Interim analyses 
No formal interim analysis is planned for this study, other than the safety/PK report that will be 
performed for the SRC review at the transition from Part 1 to Part 2. 
10.11 Deviation(s) from the original statistical plan  
As outlined above, the statistical analysis plan will be written and signed off before the database hard 
lock. Deviations from the original statistical analysis plans will be avoided, and in the unlikely event that 
they occur, will be reported and justification will be provided in the final report. 
10.12 Handling of data 
All data will be inspected for potential errors and a summary of missing data will be generated including 
the percentages of those with non-missing data, drop outs and replacement of participants. Unrecorded 
values will be treated as missing. The appropriateness of the method(s) for handling missing data may 
be reassessed at the data review prior to database lock. Further details on the data handling will be 
included in the site and/or study data management manual.  
 


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11 DUTIES OF THE INVESTIGATOR 
11.1 Investigator’s confirmation 
This study will be conducted in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice E6 (R2) (ICH-GCP), the EU Clinical Trials Directive 
(2001/20/ECC), IHI-IRB, NatHREC and TMDA. 
11.2 Safety reporting 
11.2.1 Serious adverse event reporting 
All SAEs are to be reported immediately (within 24 hours of awareness of the SAE by the Investigator) 
to the Sponsor in writing. All written reports should be transmitted to the Sponsor by e-mail using the 
SAE report form. This includes a description of the event, onset date and type, duration, severity, 
relationship to the IMP, outcome, measures taken and all other relevant clinical and laboratory data. In 
exceptional circumstances, an SAE (or follow-up information) may be reported by telephone, followed 
by a completed SAE report form. The initial report is to be followed by submission of additional 
information (follow-up SAE form) as it becomes available. Additional information related to safety 
assessment is provided in Section 8. 
Expedited reporting to local Regulatory Authorities (TMDA), Independent Ethics Committee (NatHREC) 
and Institutional Review Board (IHI-IRB) will be done by the Investigator on behalf of the Sponsor in 
following their reporting requirements. Reporting mechanism for expedited reporting is demonstrated in 
Figure 1. 
11.2.2 Project facilities and subcontracts 
• 
Screening and safety assessments will be done at Bagamoyo Research and Training Centre 
(BRTC) Laboratory of Ifakara Health Institute in Tanzania. This will be backed up by: 
o Lancet Laboratories Tanzania Conservation House, Second Floor, Ali Hassan Mwinyi Road 
o Muhimbili National Hospital, P.O Box 65000 in Dar-es-Salaam, Tanzania 
• 
See Section 1.2 for the list of providers involved in this clinical trial. 
 
 
 


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12 ETHICAL CONSIDERATIONS 
The study will be carried out in accordance to the protocol and with principles enunciated in the current 
version of the Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) issued by ICH, 
the local law and regulatory authority’s requirements. In agreement with local requirements, the 
Independent Ethics Committee (IEC) and regulatory authorities will receive regular safety reports and 
will be informed about study stop/end. 
12.1 Independent Ethics Committee (IEC) 
Prior to enrolment of any participant into this trial, the study protocol and the informed consent form will 
be reviewed and approved by the National Health Research Ethics Committee (NaTHREC) in Tanzania.  
Premature study end or interruption of the study will be reported within 14 days by the Sponsor or by 
the PI to the IRB and IECs. The regular end of the study and the final clinical study report will be 
submitted in accordance with the applicable timelines after the end of the study. 
12.2 Evaluation of the risk-benefit ratio 
Potential risks with PQP are mentioned in Section 20.5 . The participants will not profit from any direct 
benefit of the study drug, but they may profit from a comprehensive health check. If a chronic or 
underlying disease is identified, participants will be referred accordingly within the national health 
system. 
In addition, there is the potential that the gained knowledge about new drug formulation could help in 
malaria control efforts. This could lead to societal benefits if a new PQP formulation improves 
bioavailability and is less sensitive (PK) to the impact of food. 
12.3 Participant information and consent 
Written informed consent of a participant, using the NaTHREC approved consent form, must be 
obtained before any study procedure is performed. Upon showing interest, NaTHREC -approved 
language and an appropriate and study-specific Participant Information Sheet(s) (PIS) will be made 
available to the potential participant and the opportunity to discuss the study will be given.  
The participants will be fully informed orally by the delegated study staff about all aspects of the trial, 
the potential risks and their obligations. The following general principles will be emphasized:  
• 
The participation in the study is entirely voluntary  
• 
The refusal to participate involves no penalty or loss of medical benefits  
• 
The participant may withdraw from the study at any time  
• 
The participant is free to ask questions at any time to allow him or her to understand the purpose of 
the study and the procedures involved  
• 
The study involves research of an investigational drug  
• 
There is no direct benefit from participating  
• 
The participant’s general practitioner may be contacted to corroborate their medical history or seek 
additional information  
• 
The participant’s blood samples taken as part of the study will be stored at the site and samples 
may be sent outside Tanzania to collaborating laboratories. These samples will be identified only 
by code numbers.  
• 
The aims of the study and tests to be carried out will be explained  
• 
Reimbursement will be provided for participation as described in the protocol.  
• 
All relevant clinical and laboratory results (serology, lab tests and interpretations of physical exams) 
will be shared directly with the concerned participants  


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• 
Relevant aspects regarding data protection and confidentiality  
The participant will be given enough time to make an informed decision about his/her participation in 
the study. The participant will be asked to read, and consider the statement before signing and dating 
the Informed Consent Form. The consent form must be signed and dated by the delegated study staff 
at the same time as the participant signs. A copy of the fully signed form and PIS will be given to the 
participant and the original will be retained as part of the study records. 
12.4 Registration of clinical trial 
The study will be registered at: 
o ClinicalTrials.gov 
o Tanzania Clinical Trial Register (TzCTR) - imis2.tmda.go.tz/. 
12.5 Participant confidentiality 
The Investigator must assure that participants’ confidentiality will be maintained and that their identities 
are protected from unauthorized parties. Participant’s identity will not be disclosed to the Sponsor. The 
Investigator will maintain a Participant Identification List so that the participants can be identified. 
Individual participant medical information obtained as a result of this study is considered confidential 
and non-anonymized disclosure to third parties is prohibited. Participant confidentiality will be further 
ensured by utilizing participant identification codes to correspond to treatment data in the computer 
files. No patient identifiable data will be collected in the eEDC tool except for date of birth, as this 
information is critical for the inclusion of participants and for the statistical analysis of the data. However, 
data minimization is applied and only month and year of birth are collected for participants.  
As part of the informed consent process, the participants will be informed in writing that representatives 
of the Sponsor (like monitors, auditors, etc.), a Regulatory Authority or Ethics Committee may require 
direct access to parts of their medical records relevant to the study, including participants’ medical 
history, and that all personal data will be handled strictly confidentially and in accordance with local data 
protection laws.  
Blood samples collected for PK analysis, which cannot be done in Tanzania will be coded and shipped 
to Switzerland.  
If the results of the study are published, it will be done without providing identifying information on the 
participants. 
12.6 Participants requiring particular protection 
Only healthy and literate participants will be asked to participate in this phase I clinical trial. Female 
participants must understand and be able to follow the contraception requirements detailed in the ICF. 
12.7 Insurance 
A clinical trial insurance will be provided by the Sponsor. A copy of the certificate will be filed in the 
investigator site file and the trial master file.  
The Sponsor is insured to indemnify the Investigator against any claim for damages brought by a 
participant who suffers from a research related injury during the performance of the trial according to 
the protocol, except for claims that arise from malpractice and/or negligence. This is covered by the 
clinical trial’s host institute (IHI).  
In accordance with local regulations, the Sponsor will contract insurance for all study participants.  


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The Bagamoyo Clinical Trial Unit (BCTU) will be primarily responsible for providing participant’s medical 
care whether it is related or not related to the study for the duration of the trial. If specialist, emergency 
care or hospitalization is needed, this will be provided at no cost to the participant at the Bagamoyo 
District Hospital or referral centers in Dar-es-Salaam, Tanzania.  
For all unrelated conditions to the study procedures, the participant will be responsible for seeking and 
funding this care through the normal channels provided by the Ministry of Health and Social Welfare of 
Tanzania. The obligation to provide medical care for conditions arising during the trial that are not 
related to study product or study procedure will end with the last study visit of the participant. 
12.8 Participant reimbursement 
Participants will not be paid for their participation, but all expenses related to trial participation will be 
covered by the study. This will include meals during their in-patient stay and reimbursement for the 
transport fare (incurred when coming to BCTU for scheduled or unscheduled visits). In addition, they 
will be given 25,000 TZS (~USD 11) as compensation for their time at each scheduled visit and meals 
or snacks during the study related visits at the site. 
12.9 Protocol amendments 
All protocol modifications must be documented in writing. A protocol amendment can be initiated by 
either the Sponsor or any Investigator. The Investigator will provide the reasons for the proposed 
amendment in writing and will discuss with the Sponsor and the PI. Any protocol amendment must be 
approved and signed by the Sponsor and the PI and must be submitted to the appropriate IEC for 
information and approval, in accordance with local requirements, and to Regulatory Authorities if 
required. Approval by IEC (and Regulatory Authority, if applicable) must be received before any 
changes can be implemented, except for changes necessary to eliminate an immediate hazard to study 
participants, or when the change involves only logistical or administrative aspects of the study, e.g. 
change of telephone number(s). 
 
 


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13 QUALITY CONTROL AND QUALITY ASSURANCE: DESCRIPTION OF MEASURES 
The PI will ensure that all study personnel are appropriately qualified and trained on all important study 
related aspects, including a protocol-specific training, GCP training, training on data entry and handling, 
study interventions and assessments and applicable documentation is maintained on site. 
13.1 Risk management 
The risk management log will be set up by the Sponsor. Potential risks to the study, their assessment 
and management will be documented by the Sponsor in a Risk Management Log. The log will be 
updated continuously throughout the study duration.  
Special attention will be paid to risks associated with participant safety, critical study procedures and 
critical data. 
13.2 Risk identification, assessment and mitigation  
13.2.1 Study-specific preventive measures 
Participants will require adherence to the preventive measure as described or indicated in Sections 
13.2.2 and 13.2.3 below. 
13.2.2 Birth control and pregnancy testing 
Target group for birth control 
Contraception required  
Female 
participants 
of 
non-
childbearing potential (WONCBP): 
Defined as either postmenopausal 
(evidence of menopause based on a 
combination of amenorrhea for at 
least one year and increased serum 
follicle-stimulating hormone (FSH) 
level 
(>30 
IU/L), 
or 
surgical 
sterilisation 
(evidence 
of 
hysterectomy 
and/or 
bilateral 
oophorectomy) 
None 
Female participants of childbearing 
potential (WOCBP) 
 
 
Reliable contraception in accordance with the Tanzania 
Clinical Trial Guidelines (https://www.tmda.go.tz/), must start 
one complete menstrual cycle prior to the first day of dosing 
and continue until 16 weeks after the IMP administration (to 
cover a full menstrual cycle of 30 days starting after 5 half-
lives of last dose of IMP).  
Note: Highly effective birth control methods include: 
combined 
(estrogen 
and 
progestogen 
containing) 
oral/intravaginal/transdermal 
hormonal 
contraception 
associated with inhibition of ovulation, progestogen-only 
oral/injectable/implantable 
hormonal 
contraception 
associated with inhibition of ovulation, intrauterine device, 
intrauterine hormone-releasing system, bilateral tubal 
occlusion, vasectomised partner or sexual abstinence. 


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13.2.3 Participant restrictions 
Items participants must 
not consume or do 
When participants must stop 
When participants can re-start 
Tobacco in any form 
(e.g., 
smoking 
or 
chewing) 
or 
other 
nicotine-containing 
products in any form 
(e.g., 
gum, 
patch, 
electronic cigarettes) 
Any time at the facility during trial 
participation 
When not in the facility 
Meals/snacks/water 
See Section 6 
See Section 6  
Not consume any other 
substances known to be 
potent 
inhibitors 
or 
inducers of the CYP3A4 
system. 
This 
includes 
food or drink products 
containing 
cranberry, 
pomegranate, star fruit, 
grapefruit, 
pomelos, 
exotic citrus fruits or 
Seville 
oranges 
(including 
marmalade 
and juices made from 
these fruits)  
Within 30 days or five half-lives 
(whichever is longer) before the 
planned 
first 
trial 
drug 
administration. 
After trial completion/last visit.  
Caffeine-containing 
or 
Xanthine-containing 
products  
48 hours before the planned first 
trial drug administration and each 
out-patient/ follow-up visit. 
After trial completion/last visit.  
Energy drinks or drinks 
containing 
taurine, 
glucuronolactone 
(e.g. 
Red Bull)  
48 hours before the planned first 
trial drug administration and each 
out-patient/ follow-up visit. 
After trial completion/last visit.  
Alcohol 
 
48 hours before the planned first 
trial drug administration and each 
out-patient/ follow-up visit. On other 
days: less than 14 units a week and 
less than three units in one day is 
permitted.  
After trial completion/last visit.   
Strenuous 
physical 
activity  
48 hours 
before 
screening, 
admission and out-patient/follow-up 
visit.  
After trial completion/last visit. 
Activity 
Participants will be requested to 
remain in a semi-supine position for 
the first four hours after dosing each 
day, except to use the bathroom. 
 


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Items participants must 
not consume or do 
When participants must stop 
When participants can re-start 
Participants 
may 
then 
be 
ambulatory but should not engage 
in strenuous activities and should 
rest 
semi-supine 
for 
at 
least 
five minutes prior to any vital signs 
or at least ten minutes prior to ECG 
measurement. 
Any 
prescription 
medication  
14 days or five half-lives (whichever 
is longer) before the planned first 
trial drug administration. 
After trial completion/last visit. 
If participants have a medical 
need to take any medication or 
have any medications prescribed 
to them by a doctor, they should 
follow the medical advice but 
inform the Investigator as soon as 
possible afterwards. Participants 
should be informed not to stop 
taking any medication that has 
been prescribed by their general 
practitioner or other doctor. 
Any 
over-the-counter 
medication  
Seven days 
or 
five half-lives 
(whichever is longer) before the 
planned 
first 
trial 
drug 
administration. 
Any herbal remedy or 
dietary 
supplement 
containing St John's Wort 
30 days before the planned first trial 
drug administration. 
After trial completion/last visit. 
Blood 
and 
plasma 
donation 
90 days before the planned first trial 
drug administration. 
Three 
months 
after 
trial 
completion/last visit. 
Contraception: 
Participants must comply 
with 
the 
appropriate 
contraceptive 
requirements 
As indicated in Section 13.2.2 
As indicated in Section 13.2.2 
COVID-19 vaccination 
Four weeks before the planned first 
trial drug administration 
Seven days 
after 
trial 
completion/last visit. 
13.3 Monitoring 
To ensure compliance with the protocol, monitoring visits by a professional representative of the 
sponsor will be scheduled to take place regularly, and at appropriate intervals according to the 
monitoring plan.  
Monitoring will be conducted according to ICH-GCP. The individuals responsible for monitoring the 
study will have access to all records necessary to ensure the integrity/validity of the recorded data and 
will periodically review the progress of the study. The monitor must contact the site prior to the start of 
the study to discuss the protocol and data collection procedures with the site personnel.  
The investigator must agree to allow the monitor direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the monitor to discuss findings and any relevant issues. 


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Additional site visits may be made during the course of the trial and at the end of the surveillance period 
as delineated in a monitoring plan approved by IHI and the Sponsor. 
The monitoring plan will include the percentage of participant charts to be reviewed, which and what 
proportion of data fields will be monitored, as well as who will be responsible for conducting the 
monitoring visits and who will be responsible for ensuring that monitoring findings are addressed. 
Additionally, the sponsor will perform a Site Qualification visit to assess the suitability of the site for 
conducting the trial. The trial will only begin following a written approval from the sponsor. 
13.4 Audits and inspections 
For the purpose of compliance with ICH-GCP and regulatory guidelines, it may be possible that the 
sponsor/designee or a national ethics or regulatory authority may conduct a site audit/inspection. This 
may occur at any time from start to conclusion of the study.  
The QA designated site staff will conduct internal audits to check that the trial is being conducted, data 
recorded, analyzed and accurately reported according to the protocol, sponsor’s SOPs and in 
compliance with ICH GCP. The audits will also include laboratory activities according to an agreed audit 
schedule. 
The investigator agrees to allow the auditor direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor to discuss findings and any relevant issues.  
If a regulatory authority requests an inspection, the investigator must inform the sponsor or its designee 
immediately about this request. The investigator(s) and the study coordinator(s) must make the relevant 
records available for inspection and must be available to respond to reasonable requests and audit 
queries made by authorized representatives of regulatory agencies. The sponsor will provide any 
needed assistance in responding to regulatory audits or correspondence. 
13.5 Confidentiality, data protection 
The study will be monitored by the CRO subcontracted by the sponsor. CRO representatives and 
representatives of the local Regulatory Authorities and Ethics Committees will be allowed access to all 
information resulting from this study including the access to study-related documentation. The subjects' 
confidentiality will be respected as required by local law. 
All parties agree to adhere to the principles of medical confidentiality in relation to Clinical Study 
Subjects involved in the Clinical Study. Neither party shall disclose the identity of Clinical Study Subjects 
to third parties without prior written consent of the Clinical Study Subject. 
The trial staff will ensure that the participants’ anonymity is maintained. The participants will be identified 
only by a participant study ID on all trial documents, study participant card, and any electronic database. 
All documents will be stored securely and only accessible by trial staff and authorized personnel only. 
The trial will comply with the Data Protection Act, 1998, which requires data to be anonymized as soon 
as it is practical to do so. 
13.6 Storage of biological material and related health data 
The data and remaining biological materials related to the trial will be stored at the IHI archive and 
laboratories in Bagamoyo. All study data will be archived for a minimum of 25 years after study 
termination or premature termination of the clinical trial. The samples will be destroyed after the 
specified period. Participants will be asked for their consent to allow institutional ethics review boards 
to use anonymized data and aliquots of the samples for assessments of other markers of infectious 
disease or protection.  


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13.7 Safety Review Committee (SRC) 
A formal Safety Review Committee (SRC) will be established by the sponsor to oversee the study.  
The SRC will evaluate the data at the interim analysis and provide recommendations to the Sponsor 
with regard to continuation of the study (more details are provided in the SRC charter). 
The SRC’s composition, responsibilities and procedures will be pre-specified in details by a safety 
monitoring charter. The members of the SRC are responsible for decisions related to the safety of 
participants and the continuation of the study.  The SRC will assess all preliminary safety and available 
PK data whenever indicated as a result of safety concerns.  They will decide on the appropriateness of 
subsequent cohorts and the continuation of the study. 
At the minimum, the SRC will include the following members (more details are provided in the SRC 
charter): 
• 
the principal investigator or delegate 
• 
the medical monitor or delegate 
• 
the medical director or delegate 
• 
the independent local safety monitor 
 
 


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14 FUNDING 
The study will be funded by the sponsor (Medicines for Malaria Venture (MMV)). The Sponsor, the 
Principal Investigator and supporting organizations / institutions declare to have no conflict of interest.  
The Investigators, including the Principal Investigator and/or any sub-Investigators, directly involved in 
the treatment or evaluation of participants may be requested to provide a financial disclosure. All 
relevant documentation will be filed in the Trial Master File. 
15 DISSEMINATION OF RESULTS AND PUBLICATION POLICY 
15.1 Dissemination to scientific community; incl. lead in publications 
All data and results generated in the study will be owned by the Sponsor, who may utilize them in 
various ways, such as for submission to the regulatory authorities.  
The Sponsor will make the results derived from the study freely publicly available through appropriate 
open access databases, repositories and similar tools. The Sponsor will not specifically protect them 
as intellectual property, i.e. not to file any patent application, or otherwise protect, assert or take any 
action to enforce any rights on such results.  
The Investigators will be involved in writing and/or reviewing drafts of the manuscripts, abstracts, press 
releases and any other publications arising from the study. Apart from obvious flaws to the conduct of 
the study, which may preclude data publication, safety and efficacy data will be published under the 
supervision, review and formal authorization of the Sponsor.  
Authorship follows the International Committee of Medical Journal Editors (ICMJE) principles, 
publications will follow CONSORT statement.  
Authorship for publication in scientific journals will be offered to each party that has substantially 
contributed to the work reported in the publication. It is expected that authorship of such publications 
will be led by the Sponsor.  
The final clinical study report will be the responsibility of the Sponsor and will be submitted to the 
regulatory authorities and ethics committee(s), if required by these bodies when available.  
The Sponsor encourages the communication and/or publication of the results, in accordance with the 
terms of the Clinical Trial Agreement. 
15.2 Information of community and policy makers 
Study outcomes will be disseminated to study communities and local authorities at the end of the study. 
A final safety report will be submitted to all ethics committees and regulatory authorities.  


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16 REFERENCES 
 
 
1  
Ashley E.A. et al., Treatment and prevention of malaria in children. Lancet Child Adolesc Health, 2020; 
4(10): 775-89. 
2 
Saito M. et al., Deleterious effects of malaria in pregnancy on the developing fetus: a review on prevention 
and treatment with antimalarial drugs. Lancet Child Adolesc Health. 2020; 4(10): 761-74. 
3  
Zongo I. et al., Randomized noninferiority trial of dihydroartemisinin-piperaquine compared with 
sulfadoxine-pyrimethamine plus amodiaquine for seasonal malaria chemoprevention in Burkina Faso. 
Antimicrob Agents Chemother. 2015; 59(8):4387-96. 
4  
Vignier N. et al., Longitudinal study based on a safety registry for malaria patients treated with artenimol-
piperaquine in six European countries. Malaria J. 2021; 20(1):214. 
5  
Hai T.N. et al., The influence of food on the pharmacokinetics of piperaquine in healthy Vietnamese 
volunteers. Acta Trop. 2008; 107(2):145-9 
6  
Annerberg A. et al., A small amount of fat does not affect piperaquine exposure in patients with malaria. 
Antimicrob Agents Chemother. 2011; 55(9):3971-6. 
7  
Tarning J. et al., Population pharmacokinetic assessment of the effect of food on piperaquine 
bioavailability in patients with uncomplicated malaria. Antimicrob Agents Chemother. 2014; 58(4):2052-
8. 
8  
WHO 2021, World Malaria Report. https://www.who.int/teams/global-malaria-programme/reports/world-
malaria-report-2021 
9  
Myint, H.Y. et al., Efficacy and safety of dihydroartemisinin-piperaquine. Trans R Soc Trop Med Hyg. 
2007; 101(9): 858-66. 
10  
Ratcliff, A. et al., Two fixed-dose artemisinin combinations for drug-resistant falciparum and vivax malaria 
in Papua, Indonesia: an open-label randomised comparison. Lancet. 2007; 369(9563):757-65. 
11  
Karunajeewa, H., et al., Safety evaluation of fixed combination piperaquine plus dihydroartemisinin 
(Artekin) in Cambodian children and adults with malaria. Br J Clin Pharmacol. 2004; 57(1):93-9. 
12  
Mytton, O.T. et al., Electrocardiographic safety evaluation of dihydroartemisinin piperaquine in the 
treatment of uncomplicated falciparum malaria. Am J Trop Med Hyg. 2007; 77(3): 447-50. 
13  
Stein DS, Jain JP, Kangas M, Lefèvre G, Machineni S, Griffin P, Lickliter J. Open-label, single-dose, 
parallel-group study in healthy volunteers to determine the drug-drug interaction potential between 
KAE609 (cipargamin) and piperaquine. Antimicrob Agents Chemother. 2015; 59(6):3493-500.  
 
 


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14  
Chan X.H. et al., Risk of sudden unexplained death after use of dihydroartemisinin–piperaquine for 
malaria: a systematic review and Bayesian meta-analysis. Lancet Infect Dis. 2018; 18(8):913-23. 
15  
Credible Meds. Clinical Factors Associated with Prolonged QTc and/or TdP. Crediblemeds.org. 
https://www.crediblemeds.org/research-scientists. Published 2013. Accessed 12 October 2021. 
16  
Assessing the Effects of Food on Drugs in INDs and NDAs – FDA. June 2022. Available at 
https://www.fda.gov › media › download. 
17  
FDA Guidance for industry: Toxicity grading scale for healthy adult and adolescent volunteers enrolled in 
preventive vaccine clinical trials. 2007. Available at https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/toxicity-grading-scale-healthy-adult-and-adolescent-volunteers-enrolled-
preventive-vaccine-clinical (last accessed 03 OCTOBER 2021). 
18  
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected 
Version 2.1 July 2017. 
19  
Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. Published: November 27, 2017, 
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, National Institutes of Health, National 
Cancer Institute. 

SAP_001.pdf: 
 
CONFIDENTIAL Pharmacokinetic Analysis Plan MMV_SMC_22_01 Version 2.0 
02nd October 2023   Page 1 of 9 
 
 
 
PHARMACOKINETIC DATA ANALYSIS PLAN 
A randomized, open label, two-part, parallel-group, phase I study to evaluate the 
pharmacokinetics of Piperaquine oral dispersible Granules Formulation compared 
to Piperaquine hard Tablets administered as a single dose in fasting condition 
(Part 1) and of Piperaquine oral dispersible Granules Formulation administered as 
single dose in various fed states (Part 2) in healthy adult participants 
PharmaKinetic Study Number: 
PHK2020-174 
 
Sponsor Study Number: 
MMV_SMC_22_01 
 
 
Sponsor: 
Medicines for Malaria Venture (MMV)  
ICC – Block G, 3rd floor  
20, Route de Pré-Bois  
PO Box 1826  
1215 Geneva 15  
Switzerland 
 
 
Date of Analysis Plan: 
02nd October 2023 
 
 
Version Number: 
Version 2.0 
 
 
  


CONFIDENTIAL Pharmacokinetic Analysis Plan MMV_SMC_22_01 Version 2.0
02nd October 2023   Page 2 of 9
Approval Signatures
This PK analysis plan has been approved by.
On behalf of Sponsor,
On behalf of 
PharmaKinetic,
1
Document Version History
Version Number
Reason for Update
Updated By:
Date
Version 1.0
First version issue
Rachael White
8th August 2023
Version 2.0
Version updated to include AUC(0-24) 
as a required PK parameter
Rachael White 
2nd October 2023


 
CONFIDENTIAL Pharmacokinetic Analysis Plan MMV_SMC_22_01 Version 2.0 
02nd October 2023   Page 3 of 9 
2 Table of Contents 
1 
Document Version History ............................................................................................ 2 
2 
Table of Contents ........................................................................................................... 3 
3 
Study Design .................................................................................................................. 4 
3.1 
Outline Design and Pharmacokinetic Objectives ........................................... 4 
3.1.1 
Pharmacokinetic Objectives ........................................................................... 4 
3.1.2 
Pharmacokinetic Endpoints ............................................................................ 5 
4 
Populations for Analysis ................................................................................................ 5 
4.1 
Pharmacokinetic Population ........................................................................... 5 
5 
Pharmacokinetic Data Analysis ..................................................................................... 5 
5.1 
Pharmacokinetic Parameter Estimation .......................................................... 5 
5.1.1 
Imputation of Non-Numerical or Negative Values ........................................ 5 
5.1.2 
Rules for Pharmacokinetic Parameter Estimation using WinNonlin ............. 6 
5.1.3 
Data Quality ................................................................................................... 6 
5.1.4 
Definition of Pharmacokinetic Parameters ..................................................... 6 
5.2 
Statistical Analysis ......................................................................................... 8 
5.3 
Interim Analysis ............................................................................................. 8 
 


 
CONFIDENTIAL Pharmacokinetic Analysis Plan MMV_SMC_22_01 Version 2.0 
02nd October 2023   Page 4 of 9 
3 Study Design 
3.1 
Outline Design and Pharmacokinetic Objectives 
This is a randomized, open label, parallel-design study to evaluate the PK profile and relative 
bioavailability of single dose of a PQP oral granule formulation dispersed in water (test) as 
compared to the PQP hard tablet formulation (reference) in fasting conditions (Part 1) and to assess 
the BA/FE of the PQP dispersible granules formulation when administered with different food 
restrictions (Part 2) among African participants residing in Tanzania, in Bagamoyo Town and 
surrounding areas. A total of sixty (60) healthy adult participants (male and female) will be enrolled 
in Part 1 and Part 2. 
Part 1: PQP tablet / dispersible granule administered in fasting condition of at least 10 hours 
 
Group 1: PQP hard tablet, 320 mg (N=12) 
 
Group 2: PQP dispersible granule, 320 mg (N=12) 
 
Transition to Part 2: 
 
To minimize the risk to healthy participants, a decision on transitioning from Part 1 to Part 2, 
will be taken by the Safety Review Committee (SRC), based on the safety and preliminary PK 
interim report of the granule formulation, compared to the PQP hard tablet, with safety data 
obtained up to Day 15 and PK data obtained up to Day 8. If necessary, doses may be readjusted 
for the Part 2 in order to assess the food effect, to ensure that the predicted exposure of PQP 
from the granule formulation in the fed state doesn’t exceed the exposure achieved in adults 
administered a dose of 960 mg PQP in a tablet of Eurartesim® in fasted conditions. Note, the 
observed food effect when film-coated tablets (Eurartesim®) are administered with a high 
fat/high calorie meal is a 3-fold increase in exposure.  
Part 2: PQP dispersible granule administered in fed conditions (planned as 320 mg) 
 
Group 3: High-fat meal (N=12) 
 
Group 4: Low-fat meal representative of African diet (N=12) 
 
Group 5: Whole milk 250 ml (N=12) 
 
3.1.1 
Pharmacokinetic Objectives 
Primary:  
 
To determine the relative bioavailability of a single oral dose of PQP dispersible granule 
formulation (Test) as compared to PQP hard tablet formulation (Reference) in the fasted state. 
Secondary:  
 
To assess the effect of different types of meal composition on the PK of single doses of PQP 
dispersible granule formulation in healthy adult participants.  
 
To further evaluate the PK of a single oral dose of PQP granule formulation in the fasted state 
and different fed states in healthy adult participants. 
 
 


 
CONFIDENTIAL Pharmacokinetic Analysis Plan MMV_SMC_22_01 Version 2.0 
02nd October 2023   Page 5 of 9 
3.1.2 
Pharmacokinetic Endpoints 
 
Primary:  
 
Relative bioavailability (Frel) using the ratio of the geometric means for the dispersible granule 
(test) over the hard tablet (reference) in fasted state for area under the plasma concentration-
time curve from time zero to 72 hours (AUC0-72h), area under the plasma concentration-time 
curve from time zero to last detectable plasma concentration (AUC0-t), area under the plasma 
concentration-time curve from time zero to 168 hours (AUC0-168h), area under the plasma 
concentration-time curve from time zero extrapolated to infinity (AUC0-∞), and Maximum 
plasma concentration (Cmax). 
Secondary 
 
The Frel using the ratio of the geometric means for the dispersible granules formulation between 
fed [high-fat meal, low-fat African meal, and milk] over the dispersible granule formulation 
fasted [reference] for AUC0-72h, AUC0-t, AUC0-168h, AUC0-∞, and Cmax. If the dose is adjusted in 
Part 2 of the study the Frel calculations will be dose adjusted. 
 
PK parameters for the hard tablet (fasted) and the dispersible granule formulations (fasted and 
fed); Cmax, AUC0-24h, AUC0-72h, AUC0-t, AUC0-168h, AUC0-∞, time to maximum plasma 
concentration (Tmax), terminal elimination rate constant (λz), terminal elimination half-life (t1/2), 
apparent volume of distribution during the terminal phase (Vz/F), apparent total plasma 
clearance (Cl/F), and percentage of AUC that is due to extrapolation from tlast to infinity 
(%AUCextrap).  
4 Populations for Analysis 
4.1 
Pharmacokinetic Population 
The PK Population will include all subjects who have received at least one dose of IMP and who have 
a minimum of 1 valid post-dose analytical result for pharmacokinetic parameter estimation. The 
pharmacokinetic population will be confirmed once all PQP plasma concentration data have been 
received.  The PK population will be used to list and to summarise PK data. 
The following PK subsets may also be defined for statistical comparisons; 
PK subset 1: If any subjects vomit within 4 hours after dosing, their PK data will be assessed, and a 
decision may be taken to remove these subjects from the statistical comparisons.  This would be defined 
as PK subset 2. This subset will only be deemed necessary if vomiting appears to impact the resulting 
PK parameters. The generation of this subset will be justified and will be documented formally where 
needed.   
5 Pharmacokinetic Data Analysis 
5.1 
Pharmacokinetic Parameter Estimation  
The estimation of pharmacokinetic parameters by non-compartmental analysis methods will be 
performed using Phoenix WinNonlin software (v8.3 or a more recent version, Certara USA, Inc., USA). 
5.1.1 
Imputation of Non-Numerical or Negative Values 
The imputation of non-numerical or negative values reported in the input data set will be performed as 
follows: 


 
CONFIDENTIAL Pharmacokinetic Analysis Plan MMV_SMC_22_01 Version 2.0 
02nd October 2023   Page 6 of 9 
 
Pre-dose sample times will be entered as zero 
 
Values that are below the limit of quantification (BLQ) obtained prior to the Cmax will be 
entered as zero 
 
Values that are BLQ after the Cmax will be treated as missing 
 
Values that are quantifiable after at least 2 consecutive BLQ values after Cmax will be treated 
as missing for the calculation of PK parameters 
 
Values that are reported as “No Result” or “No Sample” etc. will be treated as missing 
5.1.2 
Rules for Pharmacokinetic Parameter Estimation using WinNonlin 
Plasma concentration vs time profiles of PQP (and metabolite) will be generated for each subject. 
Pharmacokinetic parameters will be estimated using standard Phoenix WinNonlin methods, details of 
which may be found in the documentation accompanying the WinNonlin software package. The 
following constraints will apply: 
Parameter Estimation 
Constraint 
Trapezoidal Method 
Linear/log trapezoidal rule  
Number of Points used for Lambda-z 
At least 3 post Cmax, not including Cmax 
Minimum Requirements for AUC  
At least 3 consecutive quantifiable concentrations 
Sampling Times used in analysis  
Actual sampling times; when no actual sampling time 
is available the nominal sampling time will be used 
Rounded Dose Level   
3 Significant Figures or 2 decimal places 
 
Where possible, the elimination rate constant (lambda-z) will be calculated for all subjects. The value 
of lambda-z will be determined by the slope of the regression line of the natural log transformed 
concentrations vs time.  
The choice of data points for determination of lambda-z will be applied by the Phoenix software as a 
default method, the pharmacokineticist who may adjust the selection in order to provide a more 
appropriate fit and records of this will be documented in the software data.  
5.1.3 
Data Quality 
The following flags/footnotes may be applied to the pharmacokinetic parameters: 
Flag 
Footnote 
a 
Rsq of regression was <0.8 
b 
Extrapolated portion of AUC(0-inf) >20% 
c 
Insufficient post-Cmax data points for estimation of lambda-z 
d 
Entire profile BLQ, no pharmacokinetic parameters could be calculated 
 
In the event that a reliable lambda-z cannot be determined, or the extrapolated portion of AUC(0-inf) is 
>20%, then the parameter estimates derived using lambda-z and/or AUC(0-inf) may be deemed unreliable 
and excluded from the summary statistics. Additional flags may be applied based on emerging data. 
5.1.4 
Definition of Pharmacokinetic Parameters 
The following pharmacokinetic parameters for PQP (and metabolite) in plasma will be estimated where 
possible and appropriate for each subject and treatment.  
 


 
CONFIDENTIAL Pharmacokinetic Analysis Plan MMV_SMC_22_01 Version 2.0 
02nd October 2023   Page 7 of 9 
Table 1 
Pharmacokinetic Parameters and Reporting Specifications  
Data transfer 
Term 
Parameter 
Definition 
DP or 
SF 
No. of 
DP/SF 
TMAX 
Tmax 
Time at which the maximum 
observed plasma concentration 
occurs 
DP 
2 
CMAX 
Cmax 
Maximum observed plasma 
concentration 
SF 
3 
AUC024 
AUC(0-24) 
Area under the curve from time 
zero to 24 h  
SF 
3 
AUC072 
AUC(0-72) 
Area under the curve from time 
zero to 72 h  
SF 
3 
AUC0168 
AUC(0-168) 
Area under the plasma 
concentration curve from time 
zero to 168 hours 
SF 
3 
AUCLST 
AUC(0-t) 
Area under the plasma 
concentration curve from time 
zero up to the last quantifiable 
concentration 
SF 
3 
AUCIFO 
AUC(0-inf) 
Area under the curve from time 
zero extrapolated to infinite time 
SF 
3 
AUCPEO 
%AUCextrap 
Percentage of AUC that is due to 
extrapolation from tlast to infinity 
DP 
2 
LAMZHL 
t1/2 
Apparent terminal elimination 
half-life 
DP 
2 
LAMZ 
Lambda-z 
Terminal Rate constant 
DP 
4 
CLFO 
CL/F 
Apparent total plasma clearance 
after extravascular administration 
SF 
3 
VZFO 
Vz/F 
Apparent volume of distribution 
during the terminal phase after 
extravascular administration 
SF 
3 
FRELCMAX* 
Frel Cmax 
Relative bioavailability calculated 
as the ratio of the Cmax test/Cmax 
reference 
DP 
3 
FRELAUC72* 
Frel AUC(0-72) 
Relative bioavailability calculated 
as the ratio of the AUC(0-72) test/ 
AUC(0-72)  reference 
DP 
3 
FRELAUC168* 
Frel AUC(0-168) 
Relative bioavailability calculated 
as the ratio of the AUC(0-168) test/ 
AUC(0-168) reference 
DP 
3 
FRELAUCLST* 
Frel AUC(0-t) 
 
Relative bioavailability calculated 
as the ratio of the AUC(0-t) test/ 
AUC(0-t) reference 
DP 
3 
FRELAUCINF* 
Frel AUC(0-inf) 
Relative bioavailability calculated 
as the ratio of the AUC(0-inf) test/ 
AUC(0-inf) reference 
DP 
3 
DP=decimal places 
SF=significant figures 
* The Frel Values will be generated for the comparisons listed in section 4.2. For Part 2 of the study, the calculations may be 
done on dose corrected parameters if the dose is adjusted in this part of the study. 


 
CONFIDENTIAL Pharmacokinetic Analysis Plan MMV_SMC_22_01 Version 2.0 
02nd October 2023   Page 8 of 9 
5.2 
Statistical Analysis  
The relative bioavailability will be assessed for PQP using the ratio of the geometric means for AUC(0-
72), AUC(0-t), AUC(0-168), AUC(0-inf), and Cmax as follows:  
 
For Part 1 the comparisons will be Group 2 PQP dispersible granule (320 mg, fasted) [test] over 
the Group 1 PQP hard tablet (320 mg, fasted) [reference]. 
 
For Part 2 the data from Part 1 Group 2 PQP dispersible granule (320 mg, fasted) will be used 
as the reference against the following fed test conditions (and dose adjusted where relevant): 
- 
High-fat meal (Group 3) 
- 
Low-fat meal representative of African diet (Group 4) 
- 
Whole milk (Group 5) 
A linear mixed effect model will be used to obtain the geometric means ratios, with the logarithm of 
the PK parameter as response variable, the sequence, treatment and the period as fixed effects, and the 
subject within sequence as random effect. Least square mean differences (test – reference) will be 
extracted from the model with two-sided 90% confidence intervals. Mean ratios will be reported with 
90% confidence limits after back transformation from the log-scale. The assumption of normality of the 
distributions will be made when running exploratory bioequivalence analysis.  
Bioequivalence analysis will be performed using the Bioequivalence module contained within Phoenix 
WinNonlin. The following will be selected when analysing the study data 
In the Bioequivalence Model tab the following will be selected 
• 
Type of study will be assigned as a Parallel Study 
• 
Type of bioequivalence will be set to Average 
• 
The reference formulation will be set depending on the study part as described above 
 
In the Bioequivalence Fixed effects tab the following will be selected 
• 
Sequence, Formulation and Period are added to the Model specification 
• 
Ln(x) is added to the dependent variables  
Normally the random effects are populated however the following should be carried through to this 
menu 
• 
Subject (Sequence) should be in the random effects model field 
Bioequivalence is demonstrated when the 90% confidence interval for parameter is contained between 
80 and 125.  
5.3 
Interim Analysis  
There will be one interim analysis after dosing of Groups 1 and 2, to review safety data obtained up to 
Day 15 and PK data obtained up to Day 8, to aid the transition from Part 1 of the study into Part 2.  
 
For interim analysis purposes the bioanalytical data and generated pharmacokinetic parameters 
will be tabulated and summarised according to the nominal timepoint in an interim report.  
 
The following PK parameters for the hard tablet (fasted) and the dispersible granule 
formulations (fasted) will be generated; Cmax, AUC0-24h, AUC0-72h, AUC0-t, time to maximum 
plasma concentration (Tmax).  
 
Interim analysis will be conducted using QC’d data available at the time of analysis and will 
use nominal sampling timepoints.  
 


 
CONFIDENTIAL Pharmacokinetic Analysis Plan MMV_SMC_22_01 Version 2.0 
02nd October 2023   Page 9 of 9 
Summary statistics (i.e., mean, median, SD, CV%, minimum, maximum, n, geometric mean, geometric 
SD and geometric CV%) will be calculated for blood concentrations for each time point and treatment. 
The same will be done for the PK parameters (except tmax) which will be listed for each individual and 
summarised by treatment. The tmax summary statistics will be provided as n, minimum, median and 
maximum only. 
 
Arithmetical mean blood concentration vs. time curve will be produced by treatment on both 
linear/linear and log10/linear scales. An arithmetic mean comparison plot of tablet fed and granule fed 
data will also be presented on both linear/linear and log10/linear scales. 
 
Spaghetti plots of individual blood concentrations against nominal sampling times after dosing for each 
treatment will be produced on both a linear/linear and log10/linear scale. Each subject’s concentration 
profile will be represented on these plots with a different symbol and a legend will be included on the 
plots to define the symbols used. 
 
Bioequivalence on Part 1 data will be performed as described in section 4.2 for Cmax, AUC0-72 and AUC0-
t and tabulated to form part of the interim PK report.  
The interim report will contain a dose recommendation of PQP dispersible granule for use in Part 2 of 
the study, based upon ensuring that the Cmax of PQP granule formulation administered with a high fat 
meal, will not be predicted to exceed the geometric mean of Cmax 98 ng/ml with CV 39% obtained from 
PQP tablet (960 mg) administered in the fasted state (see study MMV_P21_01). An assumption will be 
made that the exposure of PQP in the dispersible granule formulation administered in the fasted state 
will increase 3-fold when administered with a high fat meal, in line with the exposure increase seen 
when film-coated tablets (Eurartesim®) are administered with a high fat/high calorie meal.  
  
 


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