Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 37
Healthy volunteers: yes

Brief summary:
The study is a clinical trial involving two medicines called piperaquine (PQP) and pyronaridine (PYR) which, in combination with dihydroartemisinin (DHA) and with artesunate (ART) respectively, have been in clinical use for over 20 years to treat acute episodes of malaria. PYR and PQP are both known to be well tolerated and provide effective treatment for malarial infection when administered in their licensed combinations, but have not been administered together in combination before.

This new combination is being considered for development for malaria prevention (i.e. chemoprophylaxis) in sub-Saharan Africa and therefore, the trial participants will be exclusively drawn from a population from that origin.

Detailed description:
In 2019, an estimated 229 million cases of malaria occurred worldwide, with approximately 94 % occurring in WHO African Region, leading to 409 000 deaths, of which about two thirds were in children under five years of age. In addition, there were an estimated 33 million pregnancies in the moderate to high transmission countries of the WHO African Region, of which 35 % (12 million) were exposed to malaria infection during pregnancy.

Case management with highly effective antimalarial drugs has contributed to the 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 or cure undetected malarial illness with the goal to achieve therapeutic drug levels in the blood throughout the period of greatest risk (WHO 2021). WHO strongly recommends with a high-certainty evidence the following malaria chemopreventive therapies: seasonal malaria chemoprevention (SMC), intermittent preventive treatment in infants (IPTi), and intermittent preventive treatment of malaria in pregnancy (IPTp).

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. The strategy of the study sponsor, Medicines for Malaria Venture (MMV) is to re-combine existing and approved antimalarials used individually 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 products has been conducted, with a view to identify a new combination of two registered products that may be suitable for malaria chemoprevention.

A combination of pyronaridine tetraphosphate (PYR) and piperaquine tetraphosphate (PQP) was considered to have potential for this purpose. In the European Union, PQP is marketed in a fixed dose combination with the short acting antimalarial dihydroartemisinin (DHA) as Eurartesim® for treatment of acute uncomplicated malaria. PYR in a fixed dose combination with artesunate (AS) received positive scientific opinion from EMA through Article 58 and is marketed in South Korea and in many malaria endemic countries in Africa and South-East Asia as Pyramax® for treatment of acute uncomplicated malaria. The efficacy of both PYR and PQP combined to the artemisinin derivatives have been demonstrated in the treatment of uncomplicated malaria in various clinical trials in different regions and these combinations have been in clinical use for at least 20 and 40 years, respectively.

This study in healthy adults will be the first one to evaluate combined administration of pyronaridine tetraphosphate (PYR) and piperaquine tetraphosphate (PQP) in humans. A parallel group design (n=40) including a placebo cohort will be used to evaluate safety/tolerability and PK of the two treatments either as monotherapy or in combination. To our knowledge, this study will be the first human study with this new combination. The approved adult malaria treatment doses of PQP and PYR have been chosen for this trial and four treatment arms that include the use of matched placebos will facilitate discrimination of the contribution of the treatments to any safety/tolerability signal and determine the pharmacokinetic of PYR and PQP when administered alone and in combination.

Given the ultimate target population, the study will be carried out in healthy black participants of sub-Saharan African origin (defined as participants whose biological parents are both black and are of sub-Saharan African origin).

Arms:
arm 1: Single dose in the morning on Days 1, 2 and 3 of the study Pyronaridine tetraphosphate 540 mg (three tablets) if body weight 50kg - \<65kg; OR, 720 mg (4 tablets) if body weight is ≥65 kg Piperaquine tetraphosphate 960 mg (three tablets) if body weight 50kg - \<75kg; OR, 1280 mg (4 tablets) if body weight ≥75kg arm 2: Single dose in the morning on Days 1, 2 and 3 of the study Pyronaridine tetraphosphate 540 mg (three tablets) if body weight 50kg - \<65kg; OR, 720 mg (4 tablets) if body weight is ≥65 kg Matched placebo for piperaquine (3 or 4 tablets based on body weight) arm 3: Single dose in the morning on Days 1, 2 and 3 of the study Piperaquine tetraphosphate 960 mg (three tablets) if body weight 50kg - \<75kg; OR, 1280 mg (4 tablets) if body weight ≥75kg Matched placebo for pyronaridine (3 or 4 tablets based on body weight) arm 4: Single dose in the morning on Days 1, 2 and 3 of the study Matched placebo for pyronaridine (3 or 4 tablets dependent on body weight) and matched placebo piperaquine (3 or 4 tablets dependent on body weight)

Interventions: intervention 1: Pyronaridine Tetraphosphate intervention 2: Piperaquine tetraphosphate intervention 3: Placebo
Intervention descriptions: intervention 1: A total of 24 participants will be dosed with pyronaridine tetraphosphate, sixteen participants will be additionally be dosed with piperaquine tetraphosphate, eight patients will additionally be dosed with placebo. intervention 2: A total of 24 participants will be dosed with piperaquine tetraphosphate, sixteen participants will be additionally be dosed with pyronaridine tetraphosphate, eight patients will additionally be dosed with placebo. intervention 3: Placebo tablets will be administered in combination with pyronaridine tetraphosphate (8 patients), OR, in combination with piperaquine tetraphosphate (8 patients), OR, only matched placebo tablets will be administered (8 patients)

Protocol document:
ICF_002.pdf: 
Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 1 of 33 
 
 
 
RPL ID Number:  
 
<INSERT VDB LABEL> 
Screening Number: 
 
 
Participant Information Sheet/Informed Consent Form 
 
Clinical Trial Title:  
A randomised, double-blind, placebo controlled, parallel group study 
in healthy adult volunteers to determine the safety and tolerability of 
pyronaridine (PYR) co-administered with piperaquine (PQP) under 
fasted conditions 
Short Title 
Safety and Tolerability of PYR co-administered with PQP (in fasted 
Healthy Volunteers  
Protocol Number: 
 
MMV_SMC_21_01 
 
 
 
Clinical Trial Sponsor: 
Medicines for Malaria Venture (MMV) 
ICC – Block G, 3rd Floor 
20, Route de Pré-Bois  
PO Box 1826 
1215 Geneva 15  
Switzerland 
 
 
 
 
Dear Volunteer, 
We thank you for your interest and possible participation in this clinical trial in healthy adult volunteers. 
Before you decide whether or not to take part, it is important for you to understand why the clinical trial 
is done, how we will use the information we collect about you and what the clinical trial involves. We 
also explain in this form possible risks and any discomfort you may feel during the clinical trial. 
Please take time to read the following information carefully and discuss it with others if you like. Please 
ask us if there is anything that is not clear or if you would like more information. If you are currently 
participating in any other clinical trial or have participated in a clinical trial within 90 days prior to the 
scheduled dosing, you cannot take part in this clinical trial. 
Once you have read this Participant Information Sheet, the Research Doctor will talk to you. 
The doctor will explain the clinical trial again and you can ask the doctor any questions you 
like. 
 
 
 
 
 
 
 
 
 
 
 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 2 of 33 
 
 
 
 
TABLE OF CONTENTS 
 
1. What is the purpose of this clinical trial? ..................................................................................... 3 
2. Summary of the clinical trial ..................................................................................................... 3 
3. Do I have to take part? ............................................................................................................ 5 
4. Why have I been invited? ......................................................................................................... 5 
5. What is the investigational medicine that is being tested? ............................................................. 7 
6. What are the side effects of any treatment received when taking part? ........................................... 8 
7. What will happen to me if I take part? ..................................................................................... 11 
8. Expenses and payments ........................................................................................................ 16 
9. What will I have to do? .......................................................................................................... 17 
10. Adaptive Changes allowed by the clinical trial protocol .............................................................. 20 
11. What are the possible benefits of taking part? ......................................................................... 20 
12. What are the possible disadvantages and risks of taking part? ................................................... 20 
13. What happens when the clinical trial stops or if I stop participating in the clinical trial early? .......... 20 
14. What if there is a problem?................................................................................................... 21 
15. What if relevant new information becomes available? ............................................................... 21 
16. Will my taking part in the clinical trial be kept confidential? ....................................................... 21 
17. What will happen to any samples I give? ................................................................................ 22 
18. Who is organising and funding the clinical trial? ....................................................................... 22 
19. Who has reviewed this clinical trial? ....................................................................................... 22 
20. Further information and contact details .................................................................................. 23 
Appendix 1 – Clinical Trial Plan ................................................................................................... 27 
Appendix 2 – What to do if there is a problem .............................................................................. 29 
Appendix 3 – Use of Personal Data .............................................................................................. 30 
Appendix 4 – Template for the Notification of changes made to this Participant Information/ Informed 
Consent Form .......................................................................................................................... 32 
 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 3 of 33 
1. What is the purpose of this clinical trial? 
 
We are inviting you to take part in a clinical trial involving two medicines, called piperaquine (PQP) and 
pyronaridine (PYR). Both of these medicines have been in clinical use for more than 20 years to treat acute 
episodes of malaria, but they have not been taken together before. This new combination will be explored 
for malaria prevention (i.e,. chemoprophylaxis) in Africa and more particularly for children living in areas 
where malaria is a risk. The volunteers in the trial will be healthy black male and female volunteers of Sub-
Saharan African origin (defined as volunteers whose biological parents are both black and are of Sub-
Saharan African origin).  
Malaria is an infectious disease that causes symptoms including fever and headache, and in severe cases, 
can progress to coma and death. Malaria is caused by a parasite from the Plasmodium family that is 
transmitted to people via the bite of a certain type of mosquito (Anopheles mosquito). In some areas of 
the world, the current medicine combinations that are used to prevent malaria are not effective because 
some Plasmodium parasites have become resistant to them. Therefore, it is important to find new 
medication combinations that are safe and effective to prevent this disease. We hope that PQP and PYR 
might be an effective combination for malaria. If found to be safe and tolerable when taken in combination, 
the medicines may be investigated to prevent malaria in people living in areas where malaria is a risk. 
The main aim of this trial is to find out how safe and well tolerated the investigational medicines, PQP and 
PYR, are in humans when taken alone and in combination and whether they affect the heart’s electrical 
system. This trial also aims to calculate how much of the medicines reach the bloodstream after they are 
swallowed and how long they stay in the body (i.e., pharmacokinetics); as well as whether some peoples’ 
bodies process the medicines differently if they have certain types of genes. Volunteers participating in this 
trial will have multiple blood tests and heart tracing tests (electrocardiograms [ECGs]) that will support the 
aims of the trial. 
 
2. Summary of the clinical trial 
 
We are conducting a clinical trial in 40 healthy, black, male and female volunteers, aged between 18 and 
45 years whose biological parents are both black and are of Sub-Saharan African origin. The main aims of 
this clinical trial are as follows: 
 
• 
To find out how safe and tolerable the investigational medicines are when they are taken together.  
• 
After PQP and PYR tablets are swallowed, to find out how much of the investigational medicines 
reach the blood and how long the medicines (and the chemicals the body breaks them into; i.e. 
metabolites) stay in the body for, by taking blood tests. This process is called pharmacokinetics. 
• 
To find out if, and in which ways, PQP alone or combined with PYR affects the heart’s electrical 
system, by measuring the activity of the heart using an electrocardiograph.  
• 
Some healthy people have different genes (called CYP gene variations) meaning that their livers 
process some medicines differently, as compared with other people. We will take blood tests to see 
which CYP gene variations you have,and may investigate whether your body reacts differently to 
the investigational medicines as a result. 
 
The clinical trial will take up to  approximately 52 days to complete, including the time before the clinical trial 
to determine if you are eligible to participate, the conduct of the clinical trial (comprising of an in-house period 
of eight days and a total of four outpatient visits if you are in the sentinel group (the first 10 volunteers to be 
dosed); or an in-house period of six days and five outpatient visits if you are in the non-sentinel group). The 
sentinel group contains the first volunteers to be dosed in each treatment arm, who will be dosed at least 
fifteen days before the non-sentinel group. As PQP and PYR have not been tested in combination before, 
the sentinel dosing strategy allows any safety concerns to be highlighted before giving the combination of 
PQP and PYR to a larger group of participants. This dosing strategy is done as an extra safety precaution 
in the event of any unexpected side effects and is a standard procedure for most studies.  NOTE: The 
shortened in-house period for the non-sentinel group will be confirmed following the review of 
safety and tolerability data from the sentinel group.  


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 4 of 33 
If you are eligible to participate, you will be randomly assigned to one of four treatment groups. One of the 
treatment groups will take both PQP and PYR, another will take PQP and placebo (dummy medicine), another 
will take PYR and placebo and the final group will take two placebo medicines. The placebo medicines will be 
given in the same way and look similar to the active investigational medicines so that no volunteer, or clinical 
staff member, will know who is taking which treatments.  
 
The clinical trial is made up of the following parts: 
 
• 
Screening visit: You will be required to attend a screening visit scheduled within 22 days before the 
start of the clinical trial. Screening will take place over one day or may be divided into more than one 
day.  
 
• 
Treatment Period: Participation requires an in-house period (which may vary depending upon 
whether you are in sentinel or non-sentinel group), outpatient visits and a final follow up visit. The 
planned period of your in-house stay may be extended, if necessary, for your safety. 
• 
The treatment period starts with admission to the unit on Day -1 (the day before you receive 
the investigational medicines) for additional safety checks. 
• 
You will receive the active investigational medicines and/or placebo on Days 1, 2 and 3. On 
these days we will also perform safety tests (described below) and take blood samples to 
measure the amount of each investigational medicine present in the blood. 
• 
Sentinel Group: On Days 4, 5, 6 and 7 you will not receive investigational medicines but will 
remain in the unit to continue to monitor your safety, side effects and we will monitor how 
much of the investigational medicines remain in your blood. Provided you feel well and there 
are no safety concerns, you will be discharged from the unit and allowed to go home on Day 7. 
• 
Non-Sentinel Group: On Days 4 and 5, you will not receive investigational medicines but will 
remain in the unit to continue to monitor your safety, side effects and we will monitor how 
much of the investigational medicines remain in your blood. Provided you feel well and there 
are no safety concerns, you will be discharged from the unit and allowed to go home on Day 5. 
 
• 
Outpatient visits:  
• 
During the outpatient visits you will have further safety tests as described below and we will 
continue to take blood tests to monitor how much of the investigational medicines are still 
present in your blood.  
• 
Volunteers in the Sentinel Group will attend for four out-patient visits on Days 8, 15, 22 
and a final follow-up visit on Day 30. 
• 
Volunteers who are not in the Sentinel Group will attend for five out-patient visits on 
Days, 6, 8, 15, 22 and a final follow-up visit on Day 30. 
 
The standard safety tests that will be conducted during the clinical trial, include safety blood and urine 
laboratory tests, vital signs (pulse rate, blood pressure, respiratory rate and body temperature), physical 
examinations, ECG (electrocardiogram – electrical heart recording), telemetry (real-time electrical heart 
monitoring), blood samples for pharmacokinetics (measurement of medicine levels in the blood) and 
observations of any adverse events (side-effects).   
The Research Doctor will be contactable 24 hours a day during the entire clinical trial in case you do not 
feel well or need any medical advice. 
During your participation in this clinical trial including follow-up visits, you will be asked not to travel too 
far from London Bridge without our consent because we may need to get in touch with you to attend 
additional visits that may need to be done at short notice.  
You will not receive any health benefits from taking PQP and PYR as these medicines are being given for 
research and development purposes only, but you will be compensated for your time. The Clinical Trial Plan 
can be found in Appendix 1. 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
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Page 5 of 33 
Please note that you will be required to have a swab for COVID-19 at regular intervals and ad-hoc (as 
required) during your residential stay at the Richmond Pharmacology unit. Please also note Public Health 
England will be notified within 72 hours should you test positive for SARS-CoV-2, in line with our legal duty. 
By signing this consent, you are allowing us to also use your anonymised COVID-19 test results for 
Richmond Pharmacology Ltd (“RPL”) research purposes. 
 
The table of contents on page 2 may help you to read this consent form more easily, by breaking the 
information down into questions that you may have. 
 
For further information please refer to our websites as below: 
 
https://www.richmondpharmacology.com/    
https://www.richmondresearchinstitute.org/ 
 
 
3. Do I have to take part? 
 
No. Your participation in this clinical trial is voluntary, and you may withdraw your consent to take part at 
any time, without stating your reasons.  
The Research Doctor may also decide to remove you from the clinical trial due to illness, side-effects, new 
information on the investigational medicines or if you are not following the clinical trial rules and 
restrictions. In addition, the Sponsor may end your participation in the clinical trial at any time without 
your consent. You are strongly advised to return to the unit for a follow-up visit if you decide not to continue 
with the clinical trial for any reason; this is for your safety.  
 
By signing a separate General Practitioner (GP)/Medical Practitioner Consent Form, you will give RPL 
permission to contact your GP. This is so that your GP can tell RPL if there is any reason why you should 
not take part in this Medicines for Malaria Venture (MMV) sponsored clinical trial. By signing the form, you 
are also giving RPL permission to inform your GP of any abnormal results seen at screening or during the 
clinical trial. This is because your GP needs to be aware of any change in your health status. If you do not 
wish this to happen then you should not participate in this MMV or any other RPL sponsored or conducted 
clinical trial. With respect to any other RPL sponsored or conducted clinical trial that you may participate 
in, unless it is an MMV sponsored clinical trial, MMV shall have no responsibility or liability to you or RPL 
regarding contacting, obtaining medical records and information from, or otherwise communicating with 
your GP as set forth in the separate General Practitioner (GP)/Medical Practitioner Consent Form. 
 
 
4. Why have I been invited? 
 
You will be suitable for this clinical trial if you fulfil the following criteria: 
 
1. You are a healthy male or female aged 18-45 years (inclusive).  
2. Both of your biological parents are black and are of Sub-Saharan African origin.  
3. You weigh more than 50 kg and your Body Mass Index (BMI) is between 18-28 kg/m2, inclusive. 
4. You are generally in good health based on medical history, physical examination, vital signs, 
laboratory blood and urine tests, and ECG performed at screening and/or prior to each 
investigational medicine administration. 
5. You agree to not donate sperm or ova (eggs) from the time that you first take the investigational 
medicines until three months after the last day that you take the investigational medicines. 
6. You agree to not donate blood from 90 days before the first day you are given the investigational 
medicines until three months after the last study visit. 
7. You will receive standardised meals, served at scheduled times throughout your residential stay. 
You agree to consume all your meals. These meals may contain meat, and provision for diets 
that are either meat-free, or free from certain meats is not available as part of this research study.  


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 6 of 33 
 
Contraceptive criteria:  
1. If you are a female volunteer: 
a. Women of non-childbearing potential do not require contraception. Non-childbearing 
potential is defined as physiologically incapable of becoming pregnant, e.g. post-
menopausal (no menstrual periods for at least 12 consecutive months with no alternative 
medical cause) or permanently sterile (permanent sterilisation methods include 
hysterectomy, removal of both fallopian tubes and/or both ovaries). If you are post-
menopausal, we will also confirm this with a blood test. 
 
b. Women of childbearing potential (if sexually active with a man) agree to use one or more 
forms of highly effective contraception as defined below, starting one complete menstrual 
cycle before the first day of taking the investigational medicines and continuing for 110 
days (slightly less than 16 weeks) after the final day of taking the medicines. Highly 
effective contraceptive methods for females are as follows: 
 
i. Combined (oestrogen- and progesterone- containing) hormonal contraception 
associated with inhibition of ovulation as follows:  
1. Oral (tablet i.e., ‘the combined pill’) 
2. Intravaginal  
3. Transdermal 
ii. Progestogen-only hormonal contraception associated with inhibition of ovulation as 
follows: 
1. Oral (tablet i.e., ‘the minipill’) 
2. Injectable 
3. Implantable 
iii. Intrauterine device (IUD; also known as ‘copper coils’) 
iv. Intrauterine hormone-releasing system (IUS) 
v. Bilateral tubal occlusion (i.e., female sterilisation with fallopian tubes ‘clipped’) 
vi. Infertile male partner (e.g., after ‘vasectomy’ or surgical removal of both testicles, 
with documented evidence of azoospermia [no sperm] if possible) 
OR 
c. 
Women of childbearing potential agree to remain abstinent. If abstinence is your preferred 
and usual lifestyle prior to starting the study, and you will remain abstinent for from one 
complete menstrual cycle before the first day you take the investigational medicines, until 
110 days (slightly less than 16 weeks) after the last day you take the investigational 
medicines, then you will be exempt from the contraception requirements. Abstinence is 
defined as not having any sexual intercourse with a male, and does not include having 
intercourse according to body temperature or lack of ovulation, using the ‘pulling out’ 
method, etc., or offering to be abstinent when this is not your usual lifestyle. 
OR 
2. If you are a male volunteer:  
a. If you are sexually active with a female partner of childbearing potential or a pregnant or 
breastfeeding partner, you must agree to use a male condom (with or without spermicide) 
from the first day of taking the investigational medicines and continue until 110 days 
(slightly less than 16 weeks) after the last day that you take the investigational medicines. 
If you are infertile (with documented evidence of azoospermia [no sperm] if possible) then 
you will be exempt from this contraception requirement. 
 
b. For male volunteers, abstinence from heterosexual intercourse from the first day you take 
the investigational medicines until 110 days (slightly less than 16 weeks) after the last day 
you take the investigational medicines is a permitted form of contraception.  
 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 7 of 33 
The Research doctor will discuss your method of contraception or abstinence with you and decide 
whether this meets the study criteria. 
 
A list of other inclusion criteria will be applied by the Research Doctor to assess your eligibility for the study. 
You can discuss these with the Research Doctor during the screening process. 
 
You will NOT be suitable for this clinical trial if you meet any of the following exclusion criteria:  
 
1. You have a current or recurrent disease that could affect the clinical or laboratory evaluations. 
2. You are pregnant or breastfeeding. 
3. You are not able to swallow up to eight tablets at the same time or consecutively. 
4. You have a history of human immunodeficiency virus (HIV) antibody positivity, Hepatitis B or 
Hepatitis C or you test positive for any of these conditions at screening. 
5. You have a history of photosensitivity. 
6. You have a history of seizures or epilepsy. 
7. A history of depression or suicidal ideation as per the Beck Depression Inventory. 
8. You have documented evidence of retinopathy. 
9. You have had malaria in the previous two years. 
10. You have used tobacco in any form (e.g., smoking or chewing) or other nicotine-containing products 
(e.g., gum, patch, electronic cigarettes) in any form six months before the first day you take the 
investigational medicines. 
11. You have positive test results for alcohol or drugs of abuse at screening or on admission or have a 
history of alcohol/drug abuse. 
12. You have had a COVID-19 vaccine within four weeks before the first dose, or you plan to receive 
the vaccine within one week after trial completion. 
 
A list of other exclusion criteria will be applied by the Research Doctor to assess your eligibility for the 
study. 
 
5. What is the investigational medicine that is being tested? 
 
The investigational medicines being tested are chemicals called piperaquine tetraphosphate (PQP) and 
pyronaridine tetraphosphate (PYR). These medicines which are registered in various countries have 
previously been tested in healthy volunteers and have been used (in different combinations) to treat acute 
malaria in patients for more than 20 years. They have not been tested for safety or tolerability when taken 
together.  
How do they work? 
The combination of the investigational medicines PQP and PYR is being developed as prevention of malaria 
infection. They are thought to work by stopping a malaria infection from taking hold in the red blood cells 
in the body.  
What dose will I receive? 
The investigational medicines will be in the form of tablets that you will swallow with a small glass (240 mL) 
of water. The three-day regimen and doses of both PQP and PYR are the recommended doses used to treat 
acute malaria. On Days 1, 2, and 3 of your in-house stay you will be dosed with the investigational 
medicines.  The number of tablets that you will be given to swallow are described below. 
• If you weigh between 50 kg and 64.99 kg, you will take on each day - 960 mg of PQP (three tablets) 
and 540 mg of PYR (three tablets) or placebo tablets. 
• If you weigh between 65 kg and 74.99 kg, you will take on each day - 960 mg PQP (three tablets) 
and 720 mg PYR (four tablets) or placebo tablets. 
• If you weigh 75 kg or more, you will take on each day - 1280 mg PQP (four tablets) and 720 mg 
PYR (four tablets) or placebo tablets. 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 8 of 33 
The first ten volunteers in this trial will be the “sentinel dosing group”, this means that the study will initially 
be conducted in these ten volunteers only. 15 days after their first dose, the data collected from all of the 
sentinel group’s tests will be checked by a Safety Review Committee (SRC), before the remaining 30 
volunteers are allowed to be enrolled into the non-sentinel group. The sentinel group will remain in-house 
until Day 7 to allow for additional safety monitoring. Following the review of the available safety and 
tolerability data, the SRC may decide to shorten the in-house period of non-sentinel group. You will be 
made aware of this, if such a decision is made. Sentinel dosing is an extra safety precaution and is a 
standard procedure for most early phase clinical trials.  
 
6. What are the side effects of any treatment received when taking 
part? 
 
The investigational medicines may cause some side effects. You may experience none, some or all of those 
described below.  
 
Side effects of piperaquine (PQP) 
The following side effects (called adverse events) have been experienced after people took PQP in the past. 
You may or may not experience any of these side effects: 
 
Common side effects (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)  
• fever 
• headache 
• feeling weak 
Uncommon side effects (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 effects (affect fewer than 1 in 1000 people who take the medicine): 
• convulsion (similar to an epileptic fit/seizure).  
Side effects of pyronaridine (PYR) 
The main safety concern with PYR in healthy participants and in malaria patients consists of raised levels 
of liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), but without 
bilirubin changes (another liver chemical). This means that the indicators of liver function have been shown 
to become high after participants took PYR. This has been a temporary change without the presence of 


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Page 9 of 33 
symptoms. We will be vigilant towards any changes in the liver function tests and will stop the medication 
if we have any safety concerns. 
The following side effects have been reported in people who took PYR, so you may or may not experience 
any of these side effects: 
Common side effects (affect more than 1 in 100 people, but fewer than 1 in 10 people, who take the 
medicine):  
• a slowing of heart rate (bradycardia) 
• increases in the liver enzymes 
• abdominal (tummy) pain 
• nausea and vomiting 
• changes in the number of some of the white blood cells (eosinophilia, neutropenia) 
• increased number of blood clotting cells (platelet count) 
• anaemia (reduced haemoglobin)  
• headache 
• feeling weak 
Uncommon side effects (affect more than 1 in 1000 people, but fewer than 1 in 100 people, who take the 
medicine):  
• a change in the heart’s electrical system (called prolonged QTc interval) and extra heart beats 
(called ventricular extrasystole) 
• sensation of heart palpitations  
• diarrhoea 
• constipation 
• heartburn/ indigestion 
• stomach inflammation (called gastritis) 
• dizziness 
• skin changes such as itchiness, redness/dryness and increased sweating 
• altered sensation e.g., pins and needles 
• insomnia  
• muscle aches 
• reduced appetite 
• cough 
Rare/ Very rare side effects (affect fewer than 1 in 1000 people who take the medicine): 
• hypersensitivity reaction (a form of allergic reaction) 
• heart rhythm and other heart electricity disturbances (called arrhythmia and first-degree 
atrioventricular block) 
• high and low blood pressure  
• hearing impaired and ringing in the ears   
• reduction in multiple types of blood cells (which can cause dangerous infection and sepsis risk if 
undetected and untreated) 
• increased bilirubin (a liver product which aids digestion). 
 
The Research Doctor is aware of the possible side-effects of the investigational medicines and you will be 
monitored closely. Should side-effects arise, they will be treated appropriately. As PQP and PYR have not 
been taken together before, there is a risk that you will experience new (not previously noticed) side 
effects. In addition to this, as the investigational medicines PQP and PYR have some overlapping side effects 
there is the risk of worsening of known side effects.  
 
If you have any side effects that involve the skin, you may be examined by a dermatologist (skin doctor) 
and/or you may have photographs taken of the area of interest. The photographs will, whenever possible, 
be taken in such a way as to prevent disclosure of your identity. 


Sponsor: Medicines for Malaria Venture (MMV) 
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Page 10 of 33 
Could I have an allergic reaction? 
Any medicine, including PQP and PYR, may cause allergic reactions. If you have a very bad allergic reaction, 
it could be life threatening.  Signs and symptoms of an allergic reaction that could be life-threatening 
(anaphylaxis) are:  
• 
rash 
• 
hives (itchy raised rash) 
• 
having difficulty breathing 
• 
wheezing when you breathe 
• 
sudden drop in blood pressure (feeling faint or dizzy) 
• 
swelling around the face, mouth, lips, tongue, throat, or eyes 
• 
fast pulse  
• 
sweating. 
 
Richmond Pharmacology Ltd is a specialist clinical trials unit that regularly conducts trials where 
investigational medicines are given to people for the first time. There are trained doctors and clinical staff 
on-site and procedures in place (approved by the authorities) to deal with any side effects, including allergic 
reactions, that arise.  
 
Risks associated with clinical trial procedures 
Investigational medicine risks: There are potential risks associated with taking the investigational 
medicines. Please read Section 6 carefully. 
 
Investigational medicine administration: The investigational medicines will be given in the form of tablets 
that you will swallow with approximately 240 mL of water.  
 
Blood pressure and pulse rate: These will be measured using an inflatable cuff which will be placed on your 
arm. You may experience mild discomfort in your arm whilst the cuff is inflated.  
 
Blood sampling: On Days 1-3 a cannula (small plastic tube) will be placed in your arm using a small needle, 
the cannula will remain in place all day allowing us to take blood samples from you without having to insert 
a new needle into your vein every time. The cannula will be removed at night before you go to bed. On the 
other days in which blood tests are taken, blood will be drawn from the arm using a small needle. There is 
a small chance of infection by placing the cannula or needle in your arm, but every medical precaution will 
be taken to avoid an infection. You may experience a small bruise and/or soreness following these 
procedures. Very rarely, a blockage of a vein or a small nerve injury can occur, resulting in numbness and 
pain. If this occurs, it will resolve with time.  
 
ECG (electrical heart recording): Before each ECG you will be asked to lie down for ten minutes. Areas 
where small sticky pads will be attached to the skin will be cleaned, and if necessary, any hair will be 
clipped or shaved. The small sticky pads will be placed on your chest, shoulder, and hips 30 minutes prior 
to the first ECG of the day, and an ECG machine will measure the electrical activity of your heart. Like 
Elastoplast®, these sticky pads may be uncomfortable to remove. ECGs will be carried out regularly during 
the clinical trial (at screening, at multiple times per day on dosing days, on each day after dosing during 
every outpatient visit and on the final follow-up visit).  
 
Holter monitoring: You are required to wear a Holter monitor for 24 hours during the screening period. 
Similar to the ECG, small sticky pads will be placed on your chest and hips (twelve in total) and wires will 
connect the sticky pads to the Holter monitor. The Holter monitor is approximately the size of a large 
iPhone. You may experience some mild skin reactions such as slight redness, itchiness and irritation due 
to the sticky pads.  If this occurs, it will resolve with time. 
 
Telemetry: Your heart will be continuously monitored using a small device, about the size of an iPhone 
(telemetry). This will be attached to your body using sticky pads and you will wear the device for a period 


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Page 11 of 33 
of 24 hours on Days 1, 2 and 3. You may experience some mild skin reactions such as slight redness, 
itchiness and irritation due to the sticky pads. However, if this occurs, it will resolve with time. 
 
Bed rest: Following dosing with the investigational medicines you may have to remain in a semi-lying down 
position for approximately four hours for your own safety.  
 
If you have private medical insurance, you are advised to check with your insurance company whether 
participation in the clinical trial should be reported and to check if your participation will affect the medical 
insurance you receive. 
 
7. What will happen to me if I take part? 
 
 
What is done at the Screening Visit (Visit 1)? 
The Informed Consent Form must be completed and signed before the start of any clinical trial-related 
procedures. 
If you give informed consent, the following procedures will be performed: 
• 
The Research Doctor will check if you meet the points listed in the Inclusion and Exclusion Criteria 
(eligibility check). 
• 
Demographics (date of birth, sex and race or ethnic origin) will be recorded.  
• 
You will be asked some questions about your medical history. 
• 
You will be asked some questions about your smoking history, as well as your past and present 
medication use. 
• 
You will be asked to complete the Beck Depression Inventory, a short questionnaire to screen for 
depression. 
• 
The Research Doctor will perform a full physical examination. 
• 
Your vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) will be 
measured. 
• 
Your urine will be tested for drugs of abuse and to check your general health. 
• 
Your breath will be tested for alcohol. 
• 
Your height and body weight will be measured and your BMI (Body Mass Index) will be calculated. 
• 
A 12-lead ECG will be recorded. 
• 
A 24-hour Holter ECG will be attached. 
• 
A needle will be used to draw blood from a vein in your arm for safety blood tests (haematology 
[checking the cells in your blood], coagulation [measures the time it takes for your blood to clot] 
and biochemistry [checking how your organs are working]), follicle stimulating hormone [FSH] 
[postmenopausal females only to confirm that you are post-menopausal] and pregnancy blood test 
[females only]). 
You must also agree to an additional blood test being performed before the start of the clinical trial in order to 
test for HIV 1+2, Hepatitis B and Hepatitis C. We do this test for all volunteers, in order to reduce the risk to 
our staff in case they have an accidental ‘needle-stick’ injury. If the results of any of these tests are positive, 
you will be asked to return to the unit for a confidential appointment with a Research Doctor. He or she will 
provide you with advice, and depending on which test is positive, a repeat blood test may be done to confirm 
diagnosis. The Research Doctor will refer you to a specialist clinic depending on which test is positive. If you 
are found to be HIV positive, the Research Doctor will contact you and explain the results to you, and we will 
inform your GP. You will then be referred to an appropriate specialist clinic for further medical counselling and 
further investigation in the United Kingdom. Please note that you will not be able to participate in this clinical 
trial if you test positive for HIV, Hepatitis B or Hepatitis C or, if you refuse to allow collection of blood for these 
tests. 
Screening will take place over one or more days. The results of these screening examinations, among other 
things, will determine whether or not you can take part in the clinical trial. 
 


Sponsor: Medicines for Malaria Venture (MMV) 
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What is done during the Residential Visit? 
Throughout the in-house stay at the clinical unit: 
• 
You will be asked how you are feeling throughout the day and any medications, other than the 
investigational medicines you have taken will be recorded. 
• 
Standardised meals will be served at scheduled mealtimes; all food must be eaten. The final meal 
on Day 7 for the sentinel group (after assessments are finished) will be optional. The final meal on 
Day 5 for the non-sentinel group (after assessments are finished) will be optional. 
 
You will be admitted to the clinical unit on Day -1 (i.e., one day before the you receive the first dose of the 
investigational medicines) and will stay in the unit until Day 7 if in the sentinel group (i.e., eight days and 
seven nights in total) and the SRC may decide to shorten the in-house period of non-sentinel group in 
which case you will stay in the unit until Day 5  (i.e., six days and five nights in total). The break-down of 
all clinical trial procedures can be seen below: 
 
Day -1: 
The following procedures will be performed: 
• 
The Research Doctor will check that you meet all of the requirements listed in the Inclusion and 
Exclusion Criteria (eligibility check). 
• 
Your medical history will be updated. 
• 
Your urine will be tested for drugs of abuse and to check your general health. 
• 
Your breath will be tested for alcohol. 
• 
If you are a female volunteer who has not had the menopause, you will have a blood test to confirm 
that you are not pregnant. 
• 
Your vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) will be 
measured. 
• 
A 12-lead ECG will be recorded. 
• 
The Research Doctor will perform a physical examination. 
• 
Your weight be measured to allow staff to calculate your BMI. 
• 
Safety blood tests (haematology, coagulation and biochemistry) will be taken – a needle will be 
used to draw blood from a vein in your arm. 
 
Day 1 - Day 3: 
The following procedures will be performed: 
• 
You will swallow between six and eight tablets of investigational medicines (depending on your body 
weight), at the same time or consecutively. 
• 
You will not eat any food three hours before, and until four hours after, you take the investigational 
medicines. You will be allowed to drink water until one hour before taking the medicines, and from one 
hour after taking the medicines.  
• 
Your vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) will be 
measured. 
• 
12-lead ECGs will be recorded at pre-determined timepoints. 
• 
Real time ECG (telemetry) will be recorded from at least one hour before dosing on Day 1 until 
24 hours after the final day of dosing on Day 3. 
• 
The Research Doctor will perform a brief physical examination. 
• 
Safety blood tests (haematology, coagulation and biochemistry on Day 1 only; liver function blood 
tests only on Days 2 and 3), blood tests to measure PQP and PYR levels (i.e,. pharmacokinetics), 
and a blood genetic test (Day 1 only) will be taken – a cannula or needle will be used to draw blood 
from a vein in your arm.  
• 
On Day 1 and Day 3 only, your urine will be tested to check your general health. 
 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
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Page 13 of 33 
Day 4-Day 5 for Non-Sentinel Group:  
The following procedures will be performed: 
• 
Your vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) will be 
measured. 
• 
A 12-lead ECG will be recorded. 
• 
The Research Doctor will perform a brief physical examination. 
• 
Safety blood tests (haematology, coagulation and biochemistry) will be taken - a cannula or needle 
will be used to draw blood from a vein in your arm. 
• 
On Day 4 only, your blood will be taken to measure the PQP and PYR levels (i.e., PK analysis) - a 
cannula or needle will be used to draw blood from a vein in your arm. 
• 
On Day 5 only, your urine will be tested to check your general health. 
 
Following completion of Day 5 (last day of residential stay) procedures, you will be allowed to leave the unit 
provided the Research Doctor considers it safe for you to do so. Please note that you still need to abide the 
restrictions described in this document (See Section 9: What will I have to do?). When you are discharged 
from the unit, you will be issued with a clinical trial participation card, which you will need to carry with you 
at all times and show to any health care professionals that you see up to and including the follow-up visit. 
 
Day 4-Day 7 for Sentinel Group: 
The following procedures will be performed: 
• 
Your vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) will be 
measured. 
• 
A 12-lead ECG will be recorded. 
• 
The Research Doctor will perform a brief physical examination. 
• 
On Days 4, 5, 6 and 7, safety blood tests (haematology, coagulation and biochemistry) will be taken 
- a cannula or needle will be used to draw blood from a vein in your arm. 
• 
On Day 4 and 6, your blood will be taken to measure the PQP and PYR levels (i.e., PK analysis) - a 
cannula or needle will be used to draw blood from a vein in your arm. 
• 
On Day 5 and 7 only, your urine will be tested to check your general health. 
 
Following completion of procedures on Day 7 of the in-house stay you will be allowed to leave the unit 
provided the Research Doctor considers it safe for you to do so. Please note that you still need to abide the 
restrictions described in this document (See Section 9: What will I have to do?). When you are discharged 
from the unit, you will be issued with a clinical trial participation card, which you will need to carry with you 
at all times and show to any health care professionals that you see up to and including the follow-up visit. 
 
You may be strongly advised to remain resident in the unit until resolution of any safety issues, 
after which you will be discharged from the unit.  
 
What is done at the Outpatient and Follow-up Visits? 
 
Day 1 is counted as the first day you take the investigational medicine, and the outpatient follow-up visits 
for the non-sentinel group will be on Day 6, Day 8, Day 15, Day 22 and approximately Day 30. Sentinel 
group volunteers will have outpatient follow-up visits on Day 8, Day 15 and Day 22 and approximately Day 
30.  These dates will be fixed for all volunteers in the group. The dates will be provided before you are 
admitted so that you can ensure you are available for them. Your participation in the clinical trial will last 
for up to approximately 52 days in total, however this may be reduced if the Research Doctor confirms that 
you can be released from the clinical trial at an earlier date.  
 
Day 6 Non-Sentinel Group (Outpatient Visit): 
The following procedures will be performed: 
• 
The Research Doctor will ask about current and previous medication use. 


Sponsor: Medicines for Malaria Venture (MMV) 
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Page 14 of 33 
• 
Your vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) will be 
measured. 
• 
A 12-lead ECG will be recorded. 
• 
The Research Doctor will perform a brief physical examination. 
• 
Your blood will be taken for safety blood tests (haematology, coagulation and biochemistry) and to 
measure the PQP and PYR levels (i.e., PK analysis) - a needle will be used to draw blood from a 
vein in your arm. 
 
Day 8 Sentinel and Non-Sentinel Group (Outpatient Visit): 
The following procedures will be performed: 
• 
The Research Doctor will ask about current and previous medication use. 
• 
Your vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) will be 
measured. 
• 
A 12-lead ECG will be recorded. 
• 
The Research Doctor will perform a brief physical examination. 
• 
Blood tests will be taken for safety (haematology, coagulation and biochemistry) and to measure 
the PQP and PYR levels (i.e., PK analysis) - a needle will be used to draw blood from a vein in your 
arm. 
• 
Your urine will be tested to check your general health. 
 
Day 15 Sentinel and Non-Sentinel Group (Outpatient Visit): 
The following procedures will be performed: 
• 
The Research Doctor will ask about current and previous medication use. 
• 
Your vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) will be 
measured. 
• 
A 12-lead ECG will be recorded. 
• 
Blood tests will be taken for safety (haematology, coagulation and biochemistry) and to measure 
the PQP and PYR levels (i.e., PK analysis) - a needle will be used to draw blood from a vein in your 
arm. 
• 
Your urine will be tested to check your general health. 
 
Day 22 Sentinel and Non-Sentinel Group (Outpatient Visit): 
The following procedures will be performed: 
• 
The Research Doctor will ask about current and previous medication use. 
• 
Your vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) will be 
measured. 
• 
A 12-lead ECG will be recorded. 
• 
Your blood will be taken for safety (haematology, coagulation and biochemistry) and to measure 
the PQP and PYR levels (i.e., PK analysis) - a needle will be used to draw blood from a vein in your 
arm. 
 
Day 30 Sentinel and Non-Sentinel Group (Follow-up (Outpatient) Visit): 
The following procedures will be performed: 
• 
The Research Doctor will ask about current and previous medication use. 
• 
Your vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) will be 
measured. 
• 
A 12-lead ECG will be recorded. 
• 
The Research Doctor will perform a brief physical examination. 
• 
Safety blood tests (haematology, coagulation and biochemistry) will be taken - a needle will be 
used to draw blood from a vein in your arm. 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
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Page 15 of 33 
• 
If you are a female volunteer who has not had the menopause, you will also have a blood test to 
confirm that you are not pregnant. 
• 
Your urine will be tested to check your general health. 
 
Blood volume 
The total volume of blood that will be taken over the duration of the clinical trial will be less than the 
amount of a standard blood donation (470 mL). Additional blood samples and safety procedures/ 
measurements may be undertaken for safety reasons and to ensure the quality of the clinical trial data.   
Wearing of face masks during your stay in the unit 
Coronavirus (COVID-19) usually spreads by droplets from coughs, sneezes and speaking. These droplets can 
also be picked up from surfaces if you touch a surface and then your face without washing your hands first. 
This is why social distancing, regular hand hygiene, and covering coughs and sneezes is so important to 
control the spread of the virus. 
The best available scientific evidence is that, when used correctly, wearing a face covering may reduce the 
spread of coronavirus droplets in certain circumstances, which helps to protect others. 
 
During your time with us at Richmond Pharmacology you will be given face masks that must be worn at all 
times unless you are: 
• 
taking medication 
• 
eating or drinking 
• 
showering 
• 
washing or conducting other hygiene routines 
• 
sleeping. 
In line with UK Government recommendations, there are other situations where you also do not need to 
wear a face mask: 
• 
where putting on, wearing or removing a face covering will cause you severe distress 
• 
if you are speaking to or providing assistance to someone who relies on lip reading, clear sound 
or facial expressions to communicate 
• 
to avoid harm or injury, or the risk of harm or injury, to yourself or others 
• 
when interacting with police officers and other emergency workers. 
A face covering should: 
• 
cover your nose and mouth while allowing you to breathe comfortably 
• 
fit comfortably but securely against the side of the face 
• 
be secured to the head with ties or ear loops. 
When wearing a face covering you should: 
• 
wash your hands thoroughly with soap and water for 20 seconds or use hand sanitiser before 
putting a face covering on 
• 
avoid wearing the face mask on your neck or forehead 
• 
avoid touching the part of the face mask in contact with your mouth and nose, as it could be 
contaminated with the virus 
• 
change the face mask if it becomes damp or if you’ve touched it 
• 
avoid taking the face mask off and putting it back on a lot in quick succession. 
 
 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
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When removing a face mask: 
• 
wash your hands thoroughly with soap and water for 20 seconds or use hand sanitiser before 
removing the mask 
• 
only handle the straps, ties or clips of the face mask 
• 
do not give your face mask to someone else to use 
• 
dispose of the face mask carefully in the clinical waste bin 
• 
wash your hands thoroughly with soap and water for 20 seconds or use hand sanitiser once you 
remove your face mask. 
Possible changes 
The Covid-19 pandemic is an ongoing global healthcare crisis and Richmond Pharmacology are constantly 
adapting our health and safety measures in line with the latest scientific evidence and Government advice.  
You will be fully informed of any changes to our health and safety policy, including the requirement to wear 
face masks and other personal protective equipment as soon as practically possible.  
 
Source: 
https://www.gov.uk/government/publications/face-coverings-when-to-wear-one-and-how-to-make-your-
own/face-coverings-when-to-wear-one-and-how-to-make-your-own 
 
 
8. Expenses and payments 
 
Volunteer payment 
In recognition of the time and effort involved in taking part in this clinical trial, you will be paid £1,152 (if 
you are in the sentinel group) or £1,088 (if you are in the non-sentinel group and discharged on Day 5) on 
completion of the clinical trial, once follow-up results are confirmed, checked by the Research Doctor and 
confirmed there are no safety issues. i.e., the Research Doctor considers your participation in the clinical 
trial to be completed.  
We want you to cooperate with us to achieve the objectives of the clinical trial, so if you are dosed, we will 
give you a compliance payment of £580 (if you are in the sentinel group) or £544 (if you are in the non-
sentinel group) for your satisfactory compliance with this document (Participant Information/Informed 
Consent Form), the Richmond Pharmacology Volunteer Charter and all unit rules (unit regulations). 
However, the compliance payment is issued at the discretion of RPL, meaning RPL may not pay these 
monies if there is a justified reason not to do so within the terms of the contract with you the volunteer. 
The total amount that you could be paid for the clinical trial is £1,732 if you are in the sentinel group, or 
£1,632 if you are in the non-sentinel group. Payment will be paid to you up to 21 working days after 
completion of the clinical trial. 
You will be paid for the time you give up for the clinical trial site and this payment is only for time and NOT 
linked to risk or inconvenience. Therefore, payment is proportional to the time you spend on the clinical 
trial i.e., payment may be reduced or increased depending on your duration in the clinical trial (if you are 
required to attend the unit for fewer or more days than stated in the Clinical Trial Plan). You should not 
view participation in this clinical trial as equivalent to employment and under no circumstances should you 
participate in more than one clinical trial at a time. You will also be paid £20 for travel expenses to attend 
the screening visit, and £120 for travel expenses in the clinic/ follow-up stage of the trial. 
You will receive payment for your participation in this clinical trial as described in Table 1 below, depending 
on the number of follow-up visits you are requested to attend.  
If you are dosed with the investigational medicine and are required to attend the unit for a repeat test 
(outside of scheduled or requested visits prolonging your participation in the clinical trial) you will be paid 
£80 for a day visit or £100 for an overnight visit plus a contribution towards your travel expenses of £20. 
This is applicable for each visit (i.e., in addition to the visits above) that you are required to attend. 
 
 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
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Page 17 of 33 
Table 1 
REASON for WITHDRAWAL 
RE-IMBURSEMENT 
COMPLIANCE PAYMENT 
Clinical trial or investigational medicine 
related side effects* 
Pro-rata** 
Full 
Non 
clinical 
trial 
or 
investigational 
medicine related side effects* 
Pro-rata** 
Full 
Entire clinical trial stopped 
Pro-rata** 
Full 
Non-compliance or voluntary withdrawal 
None 
None 
*As judged by the Research Doctor. 
**Calculated according to the actual time spent in the clinical trial in relation to the total clinical 
trial period. 
  
For admission and in order to make sure that we start the clinical trial with the right number of volunteers, 
we will book more volunteers than will be dosed. The decision as to who is included on Day 1 of the clinical 
trial will be decided by the Research Doctor who will take into account your past medical history and the 
availability and quality of your medical history. The amount you will be paid if you are admitted but not 
dosed is £150. 
Should you not wish to receive payment for this clinical trial, then we suggest that you nominate a charity 
of your choice and we will arrange for a donation of the amounts that would otherwise be due to you.  
It is your responsibility to manage your own tax affairs. Information on how the clinical trial 
payments may impact your tax responsibilities can be found on the following website: 
www.hmrc.gov.uk/manuals/eimanual/eim71105.htm. For any further information, please 
contact your local tax office.  
 
 
9. What will I have to do? 
  
You must be willing to adhere to the restrictions stated below and be able to attend the scheduled visits.  
You must be prepared to attend and remain in the unit (in-house visit) for up to eight days and seven 
nights (depending upon whether you are in the sentinel or non-sentinel group as described earlier in this 
document), attend unit on various outpatient visits and attend a final follow up visit in the unit. Not including 
the screening period, the trial will take place over a period of approximately 31 days. You may need to 
attend additional follow up visits until the Research Doctor confirms that you are no longer required to do 
so. You will also be required not to leave the country for two weeks after you have completed the clinical 
trial as you may need to return for additional blood samples. 
 
It is important that you tell our clinical staff about any other medication you are taking before and during 
the clinical trial. The Research Doctor must be told immediately if you or your partner becomes pregnant 
within three months after taking the investigational medicines. 
 
If you have a medical need to take any medications and your GP/another Doctor prescribes or advises you 
to take them, you should follow the medical advice but please inform the Research Doctor as soon as 
possible afterwards using the contact details on the Subject ID card that you will be given, or the contact 
information in Section 20 (Further information and contact details) of this document. You should not stop 
taking any medication that has been prescribed by your GP/another Doctor. The requirement to take any 
new medication or change your existing medication may affect your continued participation in the clinical 
trial. 
 
 
 
 
 
 
 
 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 18 of 33 
Participation in the clinical trial will restrict your normal lifestyle as follows: 
 
Items you must not 
use / Things you must 
not do: 
When you must stop taking it / doing it 
from: 
How long you must 
not use these items / 
not do this for: 
Tobacco in any form 
(e.g., smoking or 
chewing) or other 
nicotine-containing 
products in any form 
(e.g., gum, patch, 
electronic cigarettes) 
You must abstain from tobacco or nicotine-
containing products from six months before the 
planned first day of dosing. 
Until the end of the trial 
(after final Follow-up 
visit).
 
 
 
Medication – 
Any prescription 
medications or over-the-
counter medications 
(including 
corticosteroids, aspirin, 
ibuprofen or other 
NSAIDs, decongestants, 
and antihistamines or 
herbal supplements) 
You will not be eligible for the trial if you take 
any medications from 14 days prior to first 
planned dosing of investigational medicine. If a 
doctor has prescribed any medication for you, 
you must tell the Research Physician.  
Until the end of the trial 
(after final Follow-up 
visit) unless medically 
necessary. 
Any herbal medications/ 
remedy or dietary 
supplements  
You must not take any herbal 
medicines/remedies or dietary supplements 
containing herbal remedies from 30 days before 
first planned dosing of the investigational 
medicines. 
 
Until the end of the trial 
(after final Follow-up 
visit).
 
 
 
Alcohol 
You must not consume alcohol within 48 hours 
before the planned first investigational medicine 
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. 
Until the end of the trial 
(after final Follow-up 
visit).
 
 
 
Energy drinks or drinks 
containing taurine, 
glucuronolactone (e.g., 
Red Bull) 
You must not consume any energy drinks 
containing taurine or glucuronolactone (e.g., 
Red Bull) within 48 hours before the planned 
first investigational medicine administration  
Until the end of the trial 
(after final Follow-up 
visit).
 
 
Caffeine and Xanthine-
containing products 
(e.g,. coffee, tea, colas 
and chocolates) 
You are not allowed to consume caffeine or 
xanthine-containing products for 48 hours before 
the planned first investigational medicine 
administration 
Until the end of the trial 
(after 
final 
Follow-up 
visit).  
Food or drink products 
containing cranberry, 
pomegranate, grapefruit, 
star fruit, grapefruit, 
pomelos, exotic citrus 
fruits or Seville oranges 
(including marmalade 
and juices made from 
these fruits) 
You must not consume any of these products for 
30 days before the planned first investigational 
medicine administration. 
Until the end of the trial 
(after 
final 
Follow-up 
visit). 
Recreational drugs 
Under no circumstances are you allowed to take 
drugs of abuse for the duration of the clinical 
trial. This could lead to unpredictable risks, 
which can seriously damage your health. 
Until the end of the trial 
(after 
final 
Follow-up 
visit). 
Poppy seeds  
You must not consume poppy-seed containing 
food within 24 hours before the screening visit 
because this can lead to a positive result of your 
urine test for drugs of abuse. 
Until the end of the trial 
(after 
final 
Follow-up 
visit). 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 19 of 33 
Strenuous physical 
activity 
You may not participate in any of these activities 
for 48 hours before screening, admission and 
the out-patient/follow-up visits. Strenuous 
exercise means more than your normal exercise 
regime at the time of screening but you can 
discuss this further with the Research Doctor if 
you are unsure about what this means. 
Until the end of the trial 
(after 
final 
Follow-up 
visit). 
Activity 
You will be requested to remain in a semi-lying 
down position for the first four hours after 
investigational medicine administration each 
day, except to use the bathroom. You may then 
walk around but should not engage in strenuous 
activities and should rest in a semi-lying down 
position for at least five minutes prior to any 
Vital Signs measurements or at least ten 
minutes prior to ECG measurements. 
Until the end of the trial 
(after 
final 
Follow-up 
visit). 
Blood donation 
You are not allowed to donate blood within 
90 days before the planned first investigational 
medicine administration.  
Three months after the 
end of the trial (after 
final Follow-up visit). 
Clinical trial 
You are not allowed to participate in this clinical 
trial if you have participated in another clinical 
trial within 90 days prior to screening or have 
participated in more than three clinical trials 
within one year prior to screening. 
Until the end of the trial 
(after final Follow-up 
visit). 
You must not have a 
COVID-19 vaccination 
You are not allowed to have a COVID-19 
vaccination from four weeks before the first 
investigational medicine administration. 
Until seven days after 
the end of the trial 
(after final Follow-up 
visit). 
Items you must use/ 
Things you must do: 
 
When you must start taking it / or doing it 
from: 
How long you must 
use these items / or 
do this for: 
Acceptable methods of 
Contraception 
Will be discussed with you by the Research 
Doctor, please refer to Section 4. 
Will be discussed with 
you by the Research 
Doctor, please refer to 
Section 4. 
Meals 
You will receive standardised meals, served at 
scheduled times throughout your residential 
stay. You are required to consume all your 
meals. These meals may contain meat, and 
provision for diets that are either meat-free, or 
free from certain meats is not available as part 
of this clinical trial.  
Throughout your 
residential stay. 
Fasting and water 
consumption 
On dosing days you will be required to fast for 
three hours before, and four hours after, taking 
the investigational medicine. You will be allowed 
to drink water until one hour before dosing, and 
from one hour after dosing. 
On Day 1, Day 2 and 
Day 3 of the trial. 
Unit Rules 
You will be required to observe and adhere to 
the unit rules during your in-house stays as 
stated in the Volunteer Charter and unit Rules 
(unit regulations). 
Throughout the clinical 
trial.  
Avoid excessive UV 
radiation exposure. 
From Admission (Day-1) you should use sun 
protective measures (such as a hat, sunglasses, 
protective clothing, and sunscreen SPF ≥30) and 
limit exposure to natural sunlight (including 
occupational exposure to the sun or sunbathing) 
and avoid artificial sunlight (tanning beds or 
phototherapy). Ideally, outdoor activities should 
You can resume usual 
sun exposure 110 days 
(slightly less than 16 
weeks) after the last 
dose 
of 
the 
investigational 
medicine. 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 20 of 33 
 
10. Adaptive Changes allowed by the clinical trial protocol 
 
The following changes can be made within pre-defined limits of the protocol: 
 
1. The in-house stay or outpatient/follow-up period may be extended for your safety. Based on the available 
safety and tolerability data from the sentinel group, the members of safety review committee may decide 
to shorten the in-house period for the non-sentinel group. 
2. Additional or fewer blood and urine samples may be taken (e.g., for safety or PK assessment) but the 
maximum blood volume stated in Section 7 (What will happen to me if I take part?) will not be exceeded. 
3. Additional safety tests such as vital signs and ECGs may be done. 
4. The timing of blood samples and other safety tests such as vital signs and ECGs may be adjusted. 
5. You may have to undergo additional safety investigations (e.g., you could be referred to a specialist) if 
required. 
6. One or more of the treatment arms may be removed, and/or treatment groups may be split into sub-
groups. 
 
We will inform you about any changes at the time we decide to introduce them by issuing you with a 
‘Notification of changes made to this Participant Information/ Informed Consent Form’, the template can 
be found in Appendix 4. 
 
 
11. What are the possible benefits of taking part? 
 
 
The investigational medicine you will receive is being given to you purely for research purposes – it is not 
intended that you will receive any benefit from it. 
 
Ultimately, it will be populations in malaria-endemic countries requiring malaria prevention treatments that 
may benefit from these studies. New, more effective and convenient medicines can only be developed by 
performing research and we would like to thank you for considering to participate in this clinical trial.   
 
 
12. What are the possible disadvantages and risks of taking part? 
 
The possible disadvantages are explained in Section 6 above. 
 
 
13. What happens when the clinical trial stops or if I stop 
participating in the clinical trial early? 
 
 
If the clinical trial stops or if you decide to withdraw from the clinical trial early, you understand that we 
will keep the information about you that we have already obtained and that we can process this information 
in accordance with the clinical trial protocol and this Informed Consent Form. 
Please refer to Appendix 3 for more information. 
 
be scheduled outside the hours that ultraviolet 
radiation is most intense or should be performed 
in the shade.  


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 21 of 33 
14. What if there is a problem? 
 
Any complaint about the way you have been treated during the clinical trial or any possible harm you may 
suffer will be addressed. Please see Section 20 below for contact details. Reimbursement will be available 
for any injury attributable to administration of the investigational medicine or any clinical intervention or 
procedure within the clinical trial.  
The detailed information is given in Appendix 2. 
 
15. What if relevant new information becomes available? 
 
Sometimes during the course of a research project, new information becomes available about the 
treatment/investigational medicine that is being studied. If this happens, the Research Doctor will tell you 
about it and discuss with you whether you want to continue in the clinical trial. If you decide to withdraw, 
the Research Doctor will make arrangements to continue your care if this proves necessary. If you decide 
to continue in the clinical trial, you will be asked to sign an updated consent form. There is a possibility 
that on receiving new information, the Research Doctor might consider it to be in your best interests to 
withdraw you from the clinical trial. 
If new information emerges during the trial, Richmond Pharmacology and the Sponsor reserve the right to 
terminate your participation in the clinical trial, at any time without your consent. 
 
16. Will my taking part in the clinical trial be kept confidential? 
Yes. By signing this form, you consent to the Research Doctor and his/her staff, the Sponsor (MMV), 
regulatory authorities and Ethics Committee collecting, storing, transferring and processing your personal 
data, including the following: your date of birth, your sex, your race or ethnic origin, personal data on your 
physical or mental health or condition and any other personal data obtained during your participation in 
the clinical trial or as a result of any follow-up assessments.  
Your personal data is processed in observance of confidentiality obligations. All persons involved in the 
processing of your personal data are subject to professional secrecy. 
 
Please refer to Appendix 3 for more information. 
 
 
 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 22 of 33 
 
17. What will happen to any samples I give? 
 
What happens to the different samples we collect from you is explained in the table below: 
 
Samples 
Processing and Analysis 
Retention 
Blood and urine 
(safety) 
Processed and analysed by a laboratory 
within the UK on an ongoing basis 
during the clinical trial. These samples 
will not have your personal details on 
them, however they will be coded in a 
way that is linked to you (see Appendix 
3). 
These samples will be retained for a 
maximum of three months to perform 
all tests described in the clinical trial 
protocol, after which they will be 
destroyed. 
Blood for 
pharmacokinetics 
Processed and analysed by a laboratory 
in Switzerland on an ongoing basis 
during the clinical trial. These samples 
will not have your personal details on 
them, however they will be coded in a 
way that is linked to you (see Appendix 
3). 
These samples will be retained until 
the clinical trial has been closed to 
perform all tests described in the 
clinical trial protocol, after which they 
will be destroyed.  
Back-up samples may be stored for up 
to 12 months after the clinical trial has 
been closed to measure the chemicals 
of 
the 
investigational 
drug 
PQP 
produced 
by 
the 
body 
(i.e.,metabolites), if a process for 
analysis becomes available. 
Blood for 
pharmacogenomics 
Processed and analysed by a laboratory 
in the UK or within the EU on an ongoing 
basis during the clinical trial. These 
samples will not have your personal 
details on them, however they will be 
coded in a way that is linked to you (see 
Appendix 3). 
These samples will be retained until 
the clinical trial has been closed to 
perform all tests described in the 
clinical trial protocol, after which they 
will be destroyed. 
 
The samples will not be used for any other research that you have not consented to on this form.   
 
Please contact the Research Doctor at any time, if you require more detailed explanations about this. 
Further detailed information about each visit/day and the precise schedule for the clinical trial will be 
distributed if you agree to participate in this clinical trial. 
 
 
18. Who is organising and funding the clinical trial? 
This clinical trial will be conducted in the UK and will be run by Richmond Pharmacology Ltd. (RPL) and 
funded by MMV (the sponsor for the clinical trial) which is a not-for-profit organization based in Switzerland. 
Richmond Pharmacology Ltd. is an independent clinical research unit, which performs clinical trials mostly 
on behalf of the pharmaceutical industry. Richmond Pharmacology Ltd. is located at London Bridge in 
London and St George’s University of London in Tooting. 
 
 
19. Who has reviewed this clinical trial? 
 
The protocol has been reviewed and approved by MMV and reviewed by members of the scientific review 
board at Richmond Pharmacology Ltd. This clinical trial has been approved by the Medicines and Healthcare 
products Regulatory Agency (MHRA) which is the regulatory authority in the UK. To protect your interests 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 23 of 33 
the clinical trial has been looked at by an independent group of people called a Research Ethics Committee. 
This clinical trial has been reviewed and given favourable opinion by NRES Committee South Central – 
Berkshire B (IRAS ID 307070). This clinical trial is regulated by both national and international guidelines. 
Richmond Pharmacology Ltd is under the inspection of the MHRA ensuring that the quality of our clinical 
trial is to acceptable standards. According to Good Clinical Practice (GCP) guidelines, UK law and other 
relevant legal, regulatory and scientific guidelines your clinical trial data must be stored and made 
accessible for at least 25 years after either medicine development stops OR after the last approval of a 
marketing authorisation in a country where GCP applies. 
 
 
20. Further information and contact details  
 
The Research Doctor and his/her staff will be pleased to help if you have any further questions about this 
clinical trial. Should you have any questions or experience a side effect, a member of staff is contactable 
on one of the telephone numbers below 24 hours a day. 
A side effect is any illness, symptom or discomfort you develop at any time during the clinical trial. The 
illness/symptom might be related to the clinical trial or it might be something completely unrelated like a 
cold or a headache or an injury. However, you must let us know about all of these events, even if 
you think that they might not be serious or important. While you are in the unit we will ask you 
frequently whether you have experienced any side effects. 
Prior to leaving the unit after you have been dosed, you will be provided with a Participant ID Card. You 
should carry this card at all times while you are involved in the clinical trial. The Participant ID Card contains 
your details (RPL ID, forename, surname and date of birth along with the clinical trial code C21007 and the 
following information (in italics): 
I am currently participating in a medical trial. I may be taking an investigational medicine. In case of an 
emergency please contact Richmond Pharmacology: 
Richmond Pharmacology Ltd 
 0207 042 5800 
1A Newcomen Street 
Monday-Friday:  08h00-19h00 
London Bridge 
 
London 
079 7942 2946 
SE1 1YR 
24-hour Medical Emergency (for any 
medical concerns) 
www.richmondpharmacology.com 
www.trials4us.com 
www.trials4patients.com 
 
 
 
 
 
The medically responsible person at Richmond Pharmacology is Dr Ulrike Lorch (RPL Medical Director) 
whose contact details are: 
Dr Ulrike Lorch  
Email: u.lorch@richmondpharmacology.com                                      Telephone: 0207 042 5800 
 
 
 
                         Thank you for considering taking part in this clinical trial. 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 24 of 33 
 
 
RPL Number:   
<INSERT VDB LABEL> 
Screening Number: 
 
 
Informed Consent Form 
 
Clinical Trial Title:  
A randomised, double-blind, placebo controlled, parallel group 
study in healthy adult volunteers to determine the tolerability and 
safety of pyronaridine (PYR) co-administered with piperaquine 
(PQP) under fasted conditions  
 
 
 
 
Please read the following statements and put your short signature 
in the box to show that you have read and understood them and that 
you agree with them. 
Please 
provide short 
signature in 
each box 
1   
I confirm that I have received verbal information on the above clinical 
trial and I understand and have read the Participant Information dated 
07/Feb/2022, Version 4.0 and have had the opportunity to ask 
questions and any questions I asked have been answered to my 
satisfaction.  
 
2   
I understand that my participation is voluntary and that I am free to 
withdraw at any time, without giving any reason, without my medical 
care or legal rights being affected. I am aware of any risks associated 
with withdrawal from clinical trial before end. 
 
3   
I understand that sections of any of my medical notes and clinical trial-
specific records may be looked at by responsible individuals from the 
sponsor or from regulatory authorities where it is relevant to my taking 
part in clinical trial. I give permission for these individuals to have 
access to my records. 
 
4   
By signing this consent form, I agree that my personal data, including 
photographs (this would only be applicable when monitoring possible 
side effects and will be taken in such a way as to prevent disclosure of 
your identity) and data relating to my physical or mental health or 
condition, and race or ethnic origin, may be collected and processed 
as described in the information sheet for the clinical trial.  
 
5   
I agree that some of my samples may be sent outside the UK for 
analysis; where they have data protection laws which may be different 
than what is found in the UK; and I accept that the transferred samples 
will not be covered under the Human Tissue Act (i.e., the laws that 
govern and protect the collection, storage, use and disposal of human 
tissue in the UK). 

 
 
 
 
 
 
 
 
 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 25 of 33 
 
RPL Number:   
<INSERT VDB LABEL> 
Screening Number: 
 
 
 
6   
I give my consent for my General Practitioner (GP) to be contacted and 
informed of my participation on the clinical trial and of any significant, 
abnormal results seen at screening or during the clinical trial. 
 
7   
I 
understand 
I 
will 
receive 
a 
copy 
of 
this 
Participant 
Information/Informed Consent Form. 
 
8  
 I understand that I have the option of being informed about the 
general outcome and results of the clinical trial, once available. 
 
9  
 I confirm that I voluntarily agree to take part in this clinical trial. 
 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 26 of 33 
 
 
RPL Number:   
<INSERT VDB LABEL> 
Screening Number: 
 
 
Volunteer: 
 
The Research Doctor supervising this clinical trial has given me an explanation of the nature, purpose and 
likely duration of the clinical trial, and what I will be expected to do. I have also been advised about any 
possible discomfort and ill effects on my health or well-being which may result from my participation. 
 
I understand that if I withdraw from the clinical trial at any time and for any reason, the information that 
I have provided will be kept and will continue to be used, transferred and processed. 
 
I have been given the opportunity to question the Research Doctor on all aspects of the clinical trial and 
have understood the advice and information given to me. I understand that the information for volunteers 
in its current version number 4.0 dated 07/FEB/2022 which has been handed out to me forms part of 
this written informed consent. 
 
 
 
____________________               ___________________              |__|__|.|__|__|__|.|__|__|__|__|  |__|__|.|__|__|        
 Signature of Volunteer 
    Full Name                                                  Date (DD/MMM/YYYY)  
           Time (24 HOUR CLOCK) 
 
 
 
 
 
 
 
 
 
Observer: 
Observer to signature of the volunteer and to the fact that they have read the document and freely given 
their consent. 
 
 
 
____________________          ____________________                |__|__|.|__|__|__|.|__|__|__|__| |__|__|.|__|__| 
Signature of Observer 
    Full Name                                                Date (DD/MMM/YYYY)                 
         Time (24 HOUR CLOCK) 
 
 
Research Doctor: 
I confirm that I have explained to the volunteer the nature, purpose and possible hazards of these 
procedures, and therefore sign on behalf of RPL. 
 
 
 
____________________          ____________________              |__|__|.|__|__|__|.|__|__|__|__|  |__|__|.|__|__|           
Signature of Research Doctor         Full Name                                             Date (DD/MMM/YYYY)                 
       Time (24 HOUR CLOCK) 
 
 
 
 
 
Richmond Pharmacology Limited | 1a Newcomen Street| London Bridge | London | 
 SE1 1YR | Tel: 020 7042 5800


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 27 of 33 
Appendix 1 – Clinical Trial Plan 
Clinical Trial Plan - The timing of assessments may be adjusted following review of ongoing clinical trial data. 
Table 1 from Clinical Study Protocol v3.0, 07 Feb2022: Schedule of Assessments 
Procedure 
Screening 
(D-22 to D-
2) 
D-1 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Sentinel 
Group 
only 
D8 
D15 
D22 
Last 
visit 
D30 
(±1) 
In-house stay 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Outpatient visit 
 
 
 
 
 
 
 
 X 
  
X 
X 
X 
X 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility check 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history/ 
demographics 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Previous & current 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Smoking history and 
current 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Beck depression 
inventory questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drugs of abuse 
screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood test for HIV 1&2, 
Hepatitis B&C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood pregnancy test 
(females) 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
FSH (post-menopausal 
females) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational 
medicines 
administration 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Meals 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Safety and tolerability: 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 28 of 33 
Procedure 
Screening 
(D-22 to D-
2) 
D-1 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Sentinel 
Group 
only 
D8 
D15 
D22 
Last 
visit 
D30 
(±1) 
24-hour Holter ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Telemetry 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Height, weight and BMI 
calculation 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Safety blood tests 
(Biochemistry, 
Haematology, 
Coagulation) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
Pharmacokinetics blood 
tests 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
CYP genetic blood test 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Depending on whether volunteers are included in the sentinel or non-sentinel group, they may be discharged on Day 7 or Day 5. 
Volunteers in the sentinel group will attend the outpatient visits on days 8, 15 and 22. 
Volunteers in the non-sentinel group will attend the outpatient visits on days 6, 8, 15 and 22, provided they are discharged on Day 5. 
 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 29 of 33 
Appendix 2 – What to do if there is a problem 
 
1. 
If you suffer any side effects or injury, notify the Research Doctor immediately so that you can receive 
appropriate medical treatment.   
2. 
If you suffer injury caused directly by participation in the clinical trial, the sponsoring company MMV 
will pay you reimbursement in accordance with the Association of British Pharmaceutical Industry 
Clinical Trial Compensation Guidelines 2014 
[http://abpi.org.uk/media/1607/compensation_guidelines_2014.pdf]. A copy can be provided to you. 
3. 
Any dispute or disagreement as to the application of clause 2 and above shall be referred to an 
arbitrator to be agreed between yourself and the sponsor. If you and the Sponsor cannot agree on the 
identity of an arbitrator, the President of the Royal College of Physicians of London will be invited to 
appoint an arbitrator with the power to consult a barrister of 10 years standing on any issue of law 
including the amount of damages to be paid.  
4. 
The agreement to pay reimbursement shall be construed in accordance with English law and subject 
to the clause 3 above, the English courts shall have sole jurisdiction over any dispute which may arise 
out of it. 
5. 
You are not being asked to give up any of your legal rights by agreeing to take part in this clinical trial.  
Both Richmond Pharmacology and MMV have insurance policies in place for insuring against 
claims for their alleged liability.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 30 of 33 
Appendix 3 – Use of Personal Data 
 
 
The results of this clinical trial will be used for the further development of the new treatment and the other 
purposes described in this Participant Information/Informed Consent Form. The data from this clinical trial 
may be published. However, it is important for you to know that you will never be personally identified in 
any reports or publications produced following this clinical trial. Richmond Pharmacology will keep your 
name and contact details (i.e. your address, phone number, passport number and other data allowing us 
to contact you) confidential and will not pass this information to MMV or any other organisations involved 
in this clinical trial. Richmond Pharmacology will use this information as needed, to contact you about the 
clinical trial, and make sure that relevant information about the clinical trial is recorded for your care, and 
to oversee the quality of the clinical trial. Certain individuals from MMV and regulatory organisations may 
look at your medical and research records to check the accuracy of the clinical trial either on site or 
remotely. MMV will only receive information without any identifying information. The people outside 
Richmond Pharmacology who analyse the information will not be able to identify you and will not be able 
to find out your name or contact details. We will keep identifiable information about you from this clinical 
trial for at least 25 years after either medicine development stops OR after the last approval of a marketing 
authorisation in a country where GCP applies. 
Your personal information will not be removed or copied to be taken outside the Richmond Pharmacology 
premises or off-site secure archiving within the United Kingdom other than for the purpose of routine 
computer back-ups and in any case be stored in a secure access-controlled environment. In addition, the 
information may be disclosed on a strict need to know basis in case of medical emergencies. Otherwise, 
your identifying personal data will solely be accessible by authorised members of Richmond Pharmacology’s 
staff.  
MMV, who is based in Switzerland, is the sponsor for this clinical trial. RPL will be processing information 
from you and/or your medical records in order to undertake this clinical trial and will act as the data 
controller of the personal data you provide to us for the purpose of the clinical trial. This means that we are 
responsible for looking after your information and using it properly. MMV will be a data controller of the 
Clinical Trial Data (as defined below). 
Your rights to access, change or move your information are limited, as we need to manage your information 
in specific ways in order for the research to be reliable and accurate. If the clinical trial stops or if you 
withdraw from the clinical trial early, you agree that we will keep the information about you that we have 
already obtained and continue to use it as outlined in this document, but will stop collecting new information. 
To safeguard your rights, we will use the minimum personally-identifiable information possible. 
You can find out more about how we use your information at http://www.trials4us.co.uk/privacy-policy.php. 
Your personal data is held for your future identification related to this clinical trial for as long as is necessary 
to comply with currently applicable Good Clinical Practice guidelines, UK law and other relevant legal, 
regulatory and scientific requirements, which may be at least for the time the medicine investigated in this 
clinical trial is under research and/or on the market anywhere in the world. Richmond Pharmacology also 
permanently retains your identifying personal data on their Volunteer Database and as paper records, to 
be able to contact you at a later date either by e-mail, mail or telephone to supply or receive information 
including information about future studies in which you may want to participate. You may instruct Richmond 
Pharmacology not to contact you regarding future studies.  
Some of your identifying personal data (National Insurance Number or passport number) is also entered 
onto a UK register named TOPS-check so that other research units such as us can ensure you are not 
participating in more than one clinical trial at the same time. It is important to note however that this data 
can only be obtained by authorised users of the TOPS-check system who have your details already.  
The Research Doctor will use your “Clinical Trial Data” (the coded/anonymised information, i.e. your date 
of birth and a subject number, not your full name) to conduct the clinical trial, research and statistical 
analysis. The Sponsor may also use your Clinical Trial Data to conduct the clinical trial, to support 
applications for approval of the investigational medicine and for research related to the development of 
pharmaceutical products, diagnostics or medical aids. Your Clinical Trial Data shared with the Sponsor does 
not include your name or address. Instead the Research Doctor assigns a code number to the Clinical Trial 
Data sent to the Sponsor. Only the Research Doctor and his/her staff have access to the code key with 
which it is possible to connect your Clinical Trial Data to you. However, any of your personal data, which is 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 31 of 33 
available to the Research Doctor, may be reviewed, subject to strict controls, at the Research Doctor’s site 
by the Sponsor and/or its representatives, its contractors, regulatory authorities, the Ethics Committee or 
other supervisory bodies. 
The Sponsor may share your Clinical Trial Data with other companies within its group, with its service 
providers, its contractors and with other research institutions who will use your anonymised Clinical Trial 
Data only for the purposes described above. 
The Sponsor may transfer your Clinical Trial Data to countries outside of the UK and European Union (EU) 
for the purposes described in this document. Please be aware that the laws in such countries may not 
provide the same level of data protection as in the UK and may not stop your Clinical Trial Data from being 
shared with others. However, all data that is transferred will be coded and you will not be identified.  
You have the right to request information about your Clinical Trial Data held by the Research Doctor and 
Sponsor. You also have the right to request that any inaccuracies in such data be corrected. If you wish to 
make a request, then please contact the Research Doctor, who can help you contact the Sponsor if 
necessary. 
Richmond Pharmacology and the Sponsor are each responsible for their handling of your Clinical Trial Data 
in accordance with applicable Data Protection law(s). Your consent to the collection, storage, access, use 
and transfer of your Clinical Trial Data does not have a specific expiration date.  
To process your data lawfully we need to rely on one or more valid legal grounds. Our legitimate interest 
(except where your interests or fundamental rights override these) and your consent are the primary legal 
grounds for our processing of your personal information. There may be circumstances where we also rely 
on other valid legal grounds, such as our compliance with a legal obligation to which Richmond 
Pharmacology is subject to (for example, we have a regulatory duty to investigate and respond to 
complaints and may need to process your data as part of such investigation). 
Please note that if you fail to provide personal information when requested, we may be prevented from 
complying with our legal obligation (such as to ensure your health and safety). 
We suggest that you contact us via email DPO@richmondpharmacology.com about any questions or if you 
have a complaint in relation to how we process your personal data. However, you do have the right to 
contact the relevant supervisory authority directly. To contact the Information Commissioner’s Office in the 
United Kingdom, please visit the https://ico.org.uk/global/contact-us/ for instructions. 
“Applicable Data Protection Law” shall mean (a) the Data Protection Act 2018; (b), the UK GDPR (as defined 
in Section 3(10) of the Data Protection Act 2018) and/or (c) General Data Protection Regulation ((EU) 
2016/679), as applicable, and any other applicable privacy or data protection legislation applicable in the 
UK from time to time. 
 
 
 
 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 32 of 33 
Appendix 4 – Template for the Notification of changes made to this 
Participant Information/ Informed Consent Form 
 
This is a template of the form to notify and explain to volunteers any changes made to the 
clinical trial. The changes we may make are listed in Section 10. You do not have to sign this 
form now, it is just here for your information should changes be made to the clinical trial in the 
future. 
 
 
Template for the Notification of changes made to this Participant 
Information/ Informed Consent Form (Number X) 
 
 
This form is to notify you of the changes which may be implemented from Section 10 (Adaptive 
Changes allowed by the protocol) of this Participant Information Sheet.  
 
 
Change 1 
Summary of what is 
changing 
 
We will provide a summary sentence of what has changed.  
We will indicate which number in the list in Section 10 of the original ICF 
this change refers to. 
 
Details of change 
 
We will highlight which parts of the original ICF you signed this change 
applies to.  
 
Impact on you 
The effect on you will be explained (i.e. attendance of additional clinical 
trial days, additional or fewer samples taken, adjusting the time of 
sample collection or safety tests etc.).  
 
Impact on payment  
Any payment changes will be stated, if applicable.  
 
 
 
Change 2 – Additional tables will be added depending on the number of changes  
Summary of what is 
changing 
 
We will provide a summary sentence of what has changed.  
We will indicate which number in the list in Section 10 of the original ICF 
this change refers to. 
 
Details of change 
 
We will highlight which parts of the original ICF you signed this change 
applies to.  
 
Impact on you 
The effect on you will be explained (i.e. attendance of additional clinical 
trial days, additional or fewer samples taken, adjusting the time of 
sample collection or safety tests etc.).  
 
Impact on payment  
Any payment changes will be stated, if applicable.  
 
 
 
 
 


Sponsor: Medicines for Malaria Venture (MMV) 
Sponsor Study Code: MMV_SMC_21_01 
RPL Study Code: C21007 
Regulatory Green Light sign off: XX XXX XXXX 
 
Effective From XX XXX XXXX 
MMV_SMC_21_01_C21007 ICF_V4.0_07Feb2022.docx 
SOP-125-TEM-14-26-Participant Information and Informed Consent Template 
 
Page 33 of 33 
RPL Number:   
 
<INSERT VDB LABEL> 
Screening Number: 
 
 
Volunteer: 
 
This notification form has been provided to you for your information and we require you to sign to 
acknowledge receipt of this form and that you understand the changes being made. You have previously 
consented to such changes as part of the original informed consent process, but should you have any 
questions, you should ask the Research Doctor to further explain anything that you may not understand. 
If you are not happy with these changes, you have the right to withdraw consent. If you are happy with 
the changes and would like to continue in the clinical trial, you will be required to sign and date two copies: 
one will be provided to you and one for RPL records.   
 
 
 
 
 
 
TEMPLATE ONLY – DO NOT SIGN 
 
____________________         ____________________                |__|__|.|__|__|__|.|__|__|__|__|  |__|__|.|__|__|        
Signature of Volunteer 
   Full Name                                                Date (DD/MMM/YYYY) 
 
        Time (24 HOUR CLOCK) 
 
 
 
 
 
 
 
 
 
 
Richmond Pharmacology Limited | 1A Newcomen Street | London Bridge | London | 
SE1 1YR | Tel: 020 7042 5800 
 
 

Prot_000.pdf: 
Clinical Study Protocol Amendment [Non-substantial] 2  
 
Sponsor’s Reference: MMV_SMC_21_01 
RPL Study Code: C21007 
Date: 07 FEB 2022 
 
C21007_MMV_Protocol Non Substantial Amendment 2_v1.0_07Feb2022.docx 
 
SOP-125-TEM-17-2_Protocol SA and NSA Template_21Aug2019 
Page 1 of 6 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Non-Substantial Amendment 2 
 
Sponsor’s Reference Number: MMV_SMC_21_01 
Richmond Pharmacology Study Number: C21007 
EudraCT Number: 2021-005698-21 
 
TITLE: 
A randomised, double-blind, placebo controlled, parallel group 
study in healthy adult volunteers to determine the tolerability 
and safety of pyronaridine (PYR) co-administered with piperaquine 
(PQP) under fasted conditions 
PHASE: 
Phase I 
DRUG: 
Pyronaridine and Piperaquine 
SPONSOR: 
Medicines for Malaria Venture (MMV) 
PRINCIPAL 
INVESTIGATOR: 
Dr Ulrike Lorch MD FRCA FFPM  
Richmond Pharmacology Ltd. 
Telephone: +44 (0)20 8664 5200 Fax: +44 (0)20 8664 5201 
STUDY CENTRE: 
Richmond Pharmacology Ltd. 
London Bridge, 1A Newcomen Street, SE1 1YR  
Version 
and Date: 
Version 1.0 
07 February 2022 
 
Information in this protocol is confidential and should not be disclosed, other 
than to those directly involved in the execution or the ethical/regulatory review 
of the study, without written authorisation from MMV or its affiliates. 
 
 
 


Clinical Study Protocol Amendment [Non-substantial] 2  
 
Sponsor’s Reference: MMV_SMC_21_01 
RPL Study Code: C21007 
Date: 07 FEB 2022 
 
C21007_MMV_Protocol Non Substantial Amendment 2_v1.0_07Feb2022.docx 
 
SOP-125-TEM-17-2_Protocol SA and NSA Template_21Aug2019 
Page 2 of 6 
 
Amendment [Non-Substantial] 2 Signature Page 
 
Protocol No: MMV_SMC_21_01: 
This protocol amendment has been subjected to an internal MMV peer review. 
A randomised, double-blind, placebo controlled, parallel group study in healthy adult 
volunteers to determine the tolerability and safety of pyronaridine (PYR) co-administered 
with piperaquine (PQP) under fasted conditions 
 
I agree to the terms of this protocol amendment (non-substantial). 
Sponsor’s Signatories:  
 
Stephan Chalon, MD, PhD 
 
 
Signature:  
Date: 
 
 
Andrea Kümmerle, PhD 
 
 
Signature:  
Date: 
 
 
 
 
 
 
 
08-Feb-2022
08-Feb-2022




Clinical Study Protocol Amendment [Non-substantial] 2  
 
Sponsor’s Reference: MMV_SMC_21_01 
RPL Study Code: C21007 
Date: 07 FEB 2022 
 
C21007_MMV_Protocol Non Substantial Amendment 2_v1.0_07Feb2022.docx 
 
SOP-125-TEM-17-2_Protocol SA and NSA Template_21Aug2019 
Page 4 of 6 
 
Reason for amendment 
 
The purpose of this Non-Substantial Amendment 02 is to document changes made to the 
Clinical Study Protocol (Version 2.0, dated 10 JAN 2022).  
 
The following changes have been incorporated: 
 
1. An administrative error has been identified within the schedule of assessment table 
in the currently approved Protocol V2.0 dated 10 JAN 2022. Text describing the 
trial design in the protocol Section 3.0 states that “Non-sentinel group participants 
may be discharged on Day 5 and return for outpatient assessments on days 6, 8, 
15 and 22, provided there are no clinically significant safety and tolerability signals 
and the SRC are in agreement” i.e., participants in the non-sentinel group may be 
discharged on Day 5, provided that the data from the sentinel group demonstrate 
acceptable safety and tolerability, and based on Safety Review Committee (SRC) 
decision. However, an ‘X’ mark on Day 7 column of the schedule of assessments, 
Table 5, indicated that non-sentinel group participants would be expected to attend 
for an outpatient visit on this day.  
 
2. The corresponding ‘X’ on Day 7 for PK measurement was also added in error and 
is being removed to ensure consistency with the protocol design.  
 
These administrative errors in the schedule of assessments have been corrected to 
reflect the trial design. 
 
 
3. An administrative error has been identified in the Synopsis Figure 1 and Section 
3.0 Figure 2 – Trial Flow Chart. The outpatient visit for the non-sentinel group of 
participants was missing and has been added to the figure. 
 
4. An administrative error was found in Section 4.4, Table 10 – Cohort and Trial Rules. 
In the first two rows, number of participants has been updated from ≤50 % to ≥ 
50%.  
 
 
The sponsor considers these changes as non-substantial as they are administrative 
changes only, correcting protocol drafting errors. Furthermore, safety of the trial 
participants is not affected as the safety procedures planned on Day 7 are being conducted 
on Day 6 and Day 8 as planned in the sentinel group. 
 
 
The Participant Information Sheet and Informed Consent Form (PIS/ICF) is also being 
updated to align with the SOA in the updated clinical study protocol. 
 
 


Clinical Study Protocol Amendment [Non-substantial] 2  
 
Sponsor’s Reference: MMV_SMC_21_01 
RPL Study Code: C21007 
Date: 07 FEB 2022 
 
C21007_MMV_Protocol Non Substantial Amendment 2_v1.0_07Feb2022.docx 
 
SOP-125-TEM-17-2_Protocol SA and NSA Template_21Aug2019 
Page 5 of 6 
 
 
Sections of the protocol affected by the Non-Substantial Amendment: 
1 
Section 3.0 Trial Design– Table 5 – Schedule of Assessments and relevant 
Footnote 11  
2 
Synopsis – Figure 1 – Trial Flow Chart – The figure has been updated to 
reflect the trial design. 
3 
Section 3.0 - Figure 2 – Trial Flow Chart – The figure has been updated to 
reflect the trial design. 
4 
Section 4.4 – Adverse Reaction Rules – Table 10 – Cohort and Trial Rules – 
Text has been updated to correct a typographical error in the first two rows.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol Amendment [Non-substantial] 2  
 
Sponsor’s Reference: MMV_SMC_21_01 
RPL Study Code: C21007 
Date: 07 FEB 2022 
 
C21007_MMV_Protocol Non Substantial Amendment 2_v1.0_07Feb2022.docx 
 
SOP-125-TEM-17-2_Protocol SA and NSA Template_21Aug2019 
Page 6 of 6 
 
Persons who initiated the Amendment 
MMV and Richmond Pharmacology Ltd 
 
Sponsor: 
Medicines for Malaria Venture (MMV)  
 
Centres affected by the Amendment: 
Richmond Pharmacology Ltd, UK 
 
 


 
 
 
 
  
CLINICAL TRIAL PROTOCOL 
Sponsor’s Reference Number: MMV_SMC_21_01 
Richmond Pharmacology Trial Number: C21007 
EudraCT Number: 2021-005698-21 
 
 
TITLE: 
A randomised, double-blind, placebo controlled, parallel group 
study in healthy adult volunteers to determine the tolerability 
and safety of pyronaridine (PYR) co-administered with 
piperaquine (PQP) under fasted conditions  
PHASE: 
Phase I 
DRUGS: 
Pyronaridine and Piperaquine  
SPONSOR: 
Medicines for Malaria Venture (MMV) 
PRINCIPAL 
INVESTIGATOR: 
Dr Ulrike Lorch MD FRCA FFPM 
Richmond Pharmacology Ltd.  
Telephone: +44 (0)20 7042 5800 
 
Fax: 
+44 (0)20 7378 9135 
TRIAL CENTRE: 
Richmond Pharmacology Ltd. 
1a Newcomen Street, London Bridge, 
London SE1 1YR, UK  
Protocol Version 
and Date: 
Version 3.0 
07-FEB-2022 
 
Information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the 
ethical/regulatory review of the trial, without written authorisation from 
MMV or its affiliates. 


Medicines for Malaria Venture 
CONFIDENTIAL 
 
Protocol Ref: MMV_SMC_21_01 
Version 3.0   
 
  
RPL Trial No. C21007 
07-FEB-2022 
 
C21007_MMV_SMC_21_01_Clinical Study Protocol_V3.0_07Feb2022.docx 
SOP-125-TEM-03-07-Clinical Study Protocol Template_13Jul2021  
Page 2 of 96 
TABLE OF CONTENTS   
 
PROTOCOL APPROVAL SIGNATURES ............................................................... 7 
INVESTIGATOR’S AGREEMENT ........................................................................... 8 
TRIAL PERSONNEL .................................................................................................. 9 
LIST OF ABBREVIATIONS................................................................................... 11 
TRIAL SYNOPSIS ................................................................................................... 15 
1. 
INTRODUCTION ............................................................................................. 21 
1.1 
Rationale for conducting trial ...................................................................... 24 
1.2 
Risk-benefit evaluation ................................................................................ 25 
1.2.1 
Potential benefits ........................................................................................ 25 
1.2.2 
Potential risks ............................................................................................. 25 
2. 
TRIAL OBJECTIVES AND OUTCOMES ..................................................... 30 
2.1 
Objectives ....................................................................................................... 30 
2.1.1 
Primary ......................................................................................................... 30 
2.1.2 
Secondary .................................................................................................... 30 
2.1.3 
Exploratory .................................................................................................. 30 
2.2 
Endpoints ........................................................................................................ 31 
2.2.1 
Primary ......................................................................................................... 31 
2.2.2 
Secondary .................................................................................................... 31 
2.2.3 
Exploratory .................................................................................................. 31 
3. 
TRIAL DESIGN ................................................................................................ 31 
3.1 
Overall trial design ........................................................................................ 31 
3.2 
Order of procedures, scheduling time windows and protocol 
deviations ........................................................................................................ 37 
3.3 
Adaptive design ............................................................................................. 39 
3.4 
Rationale for trial design, doses and control groups ............................. 42 
3.4.1 
Justification for the selected dose level ................................................. 42 
3.4.2 
Choice of participants for trial ................................................................. 43 
3.4.3 
Route and rate of administration ............................................................ 43 
3.4.4 
Precautions to be applied for dosing between participants in sentinel 
group and participants in the main group ............................................. 43 
3.4.5 
Monitoring and communication of Adverse Events/Reactions .......... 43 
3.4.6 
Investigator site facilities and personnel ............................................... 44 


Medicines for Malaria Venture 
CONFIDENTIAL 
 
Protocol Ref: MMV_SMC_21_01 
Version 3.0   
 
  
RPL Trial No. C21007 
07-FEB-2022 
 
C21007_MMV_SMC_21_01_Clinical Study Protocol_V3.0_07Feb2022.docx 
SOP-125-TEM-03-07-Clinical Study Protocol Template_13Jul2021  
Page 3 of 96 
4. 
DECISION-MAKING, RULES AND LIMITS ............................................. 44 
4.1 
Definitions ....................................................................................................... 44 
4.2 
Rules and limits governing decision-making ........................................... 44 
4.3 
Safety Review Committee ........................................................................... 45 
4.3.1 
SRC Meeting ................................................................................................ 45 
4.4 
Adverse Reaction (AR) rules ....................................................................... 46 
5. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS ........................ 50 
5.1 
Number and Source of participants ........................................................... 50 
5.2 
Replacement participants ............................................................................ 50 
5.3 
Inclusion Criteria ........................................................................................... 50 
5.4 
Exclusion Criteria ........................................................................................... 52 
5.5 
Participant restrictions ................................................................................. 55 
5.6 
Criteria for withdrawal .................................................................................. 58 
5.6.1 
Handling of withdrawals ............................................................................ 58 
6. 
TRIAL AND CONCOMITANT TREATMENTS ........................................... 59 
6.1 
Investigational Medicinal Products (IMPs) ............................................... 60 
6.1.1 
Packaging and labelling of IMPs .............................................................. 61 
6.1.2 
Drug administration ................................................................................... 61 
6.1.3 
Storage of IMPs .......................................................................................... 63 
6.1.4 
Drug accountability .................................................................................... 63 
6.2 
Treatment allocation and blinding ............................................................. 63 
6.2.1 
Participant randomisation ......................................................................... 63 
6.2.2 
Methods for ensuring blinding ................................................................. 64 
6.2.3 
Methods for unblinding the trial .............................................................. 64 
6.3 
Concomitant medications/permitted medications .................................. 64 
6.4 
COVID-19 vaccinations ................................................................................ 65 
7. 
TRIAL METHODOLOGY ................................................................................. 65 
7.1 
Medical history ............................................................................................... 65 
7.2 
Eligibility check .............................................................................................. 65 
7.3 
Prior and concomitant medication check .................................................. 65 
7.4 
Beck depression inventory .......................................................................... 65 
7.5 
Meals ................................................................................................................ 65 
7.6 
Clinical laboratory assessments ................................................................. 66 
7.6.1 
Haematology, biochemistry and coagulation ....................................... 67 
7.6.2 
Serology ....................................................................................................... 67 
7.6.3 
Pregnancy testing ...................................................................................... 67 


Medicines for Malaria Venture 
CONFIDENTIAL 
 
Protocol Ref: MMV_SMC_21_01 
Version 3.0   
 
  
RPL Trial No. C21007 
07-FEB-2022 
 
C21007_MMV_SMC_21_01_Clinical Study Protocol_V3.0_07Feb2022.docx 
SOP-125-TEM-03-07-Clinical Study Protocol Template_13Jul2021  
Page 4 of 96 
7.6.4 
Urinalysis ..................................................................................................... 67 
7.6.5 
Drugs of abuse ............................................................................................ 67 
7.6.6 
FSH assessment ......................................................................................... 68 
7.7 
Alcohol breath test ........................................................................................ 68 
7.8 
Vital Signs (blood pressure, pulse rate, respiratory rate and tympanic 
temperature) .................................................................................................. 68 
7.9 
Electrocardiographic (ECG) measurements ............................................. 68 
7.9.1 
Recording of 12-lead ECGs ...................................................................... 68 
7.9.2 
Safety review of 12-lead ECGs ................................................................ 69 
7.9.3 
24-hour Holter ECG ................................................................................... 69 
7.9.4 
Real Time ECG Telemetry ......................................................................... 69 
7.9.5 
Analysing and over-reading 12-lead ECG for the purpose of 
intensive cardiac assessments ................................................................ 69 
7.10 Physical examination, height, weight and BMI ....................................... 70 
7.11 Pharmacokinetic assessments .................................................................... 70 
7.11.1 PK blood samples ....................................................................................... 70 
7.12 Volume of blood sampling ........................................................................... 70 
7.13 CYP (polymorphism) sampling ................................................................... 70 
8. 
ADVERSE EVENTS .......................................................................................... 71 
8.1 
Definitions ....................................................................................................... 71 
8.2 
Classification .................................................................................................. 73 
8.2.1 
Assessment of severity ............................................................................. 73 
8.2.2 
Assessment of causality ............................................................................ 74 
8.2.3 
Practical application of severity grading and causality assessment in 
relation to AR rules .................................................................................... 76 
8.2.4 
Expectedness (reference safety information) ...................................... 77 
8.2.5 
Adverse Events of Special Interest (AESI) ........................................... 77 
8.3 
Recording of adverse events and follow-up ............................................. 78 
8.4 
Reporting of Serious Adverse Events ........................................................ 78 
8.5 
Pregnancy ....................................................................................................... 79 
8.5.1 
Pregnancy in female partners of male participants ............................ 80 
9. 
QUALITY ASSURANCE AND QUALITY CONTROL ................................ 80 
9.1 
Quality Assurance and Quality Control ..................................................... 80 
9.2 
Monitoring ....................................................................................................... 81 
10. STATISTICAL ANALYSIS ............................................................................. 81 
10.1 Statistical analysis plan ................................................................................ 81 


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10.2 Analysis sets ................................................................................................... 81 
10.2.1 Safety set ..................................................................................................... 81 
10.2.2 PK set ............................................................................................................ 81 
10.2.3 ECG set ......................................................................................................... 81 
10.3 Statistical analysis of safety ........................................................................ 82 
10.4 ECG analysis ................................................................................................... 83 
10.4.1 Baseline ........................................................................................................ 83 
10.4.2 Heart rate correction ................................................................................. 83 
10.4.3 Per timepoint analysis ............................................................................... 84 
10.4.4 Hysteresis .................................................................................................... 84 
10.4.5 Concentration-QTc analysis ...................................................................... 84 
10.4.6 Assay sensitivity ......................................................................................... 84 
10.5 Pharmacokinetics .......................................................................................... 85 
10.5.1 Evaluation of pharmacokinetic parameters .......................................... 85 
10.5.2 Statistical analysis on PK parameters .................................................... 85 
10.6 Handling of missing and incomplete data ................................................ 86 
10.7 Determination of sample size ..................................................................... 86 
11. DATA MANAGEMENT .................................................................................... 86 
11.1 Case Report Forms ........................................................................................ 87 
12. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ............... 87 
12.1 Sponsor’s responsibilities ............................................................................ 87 
12.1.1 GCP compliance .......................................................................................... 87 
12.1.2 Regulatory approval .................................................................................. 88 
12.1.3 Indemnity/liability and insurance ........................................................... 88 
12.1.4 Protocol management ............................................................................... 88 
12.1.5 End of trial notification .............................................................................. 88 
12.1.6 Posting or submission of summary of clinical trial report to 
competent authorities of member states concerned and RECs ........ 88 
12.2 Investigator’s responsibilities ..................................................................... 89 
12.2.1 GCP compliance .......................................................................................... 89 
12.2.2 Protocol adherence and Investigator agreement ................................ 89 
12.2.3 Documentation and retention of records............................................... 89 
12.3 Ethical considerations ................................................................................... 89 
12.3.1 Informed consent ....................................................................................... 89 
12.3.2 Research Ethics Committee (REC) approval ......................................... 90 
12.4 Confidentiality ................................................................................................ 90 
12.5 Publication policy ........................................................................................... 91 


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13. REFERENCES ................................................................................................... 92 
14. APPENDIX 1 .................................................................................................... 95 
 
LIST OF TABLES 
Table 1: Planned treatment arms and IMP administration ............................... 18 
Table 2: Class effect risk and risk mitigation features ...................................... 27 
Table 3: Clinical and non-clinical known risks and mitigation features ......... 28 
Table 4: Planned treatment arms and IMP administration ............................... 32 
Table 5: Schedule of Assessments ........................................................................ 34 
Table 6 Schedule of Assessments (continued) ................................................... 36 
Table 7: Adaptive protocol features ...................................................................... 39 
Table 8: Minimum data requirements to proceed from sentinel dosing to 
dosing remaining participants .............................................................. 45 
Table 9: Individual rules (decision 1) ................................................................... 47 
Table 10: Cohort and trial rules (decisions 3 and 4) ......................................... 48 
Table 11: Participant restrictions ........................................................................... 56 
Table 12: IMP or placebo for each anticipated dose level ................................ 62 
Table 13: Laboratory parameters .......................................................................... 66 
Table 14: Categorical grading of AE/ARs ............................................................. 74 
Table 15: PK parameters ......................................................................................... 85 
 
LIST OF FIGURES 
 
Figure 1: Trial flow chart ......................................................................................... 19 
Figure 2: Trial flow chart ......................................................................................... 33 
Figure 3: Trial treatments and concomitant therapies ...................................... 60 
 
 


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PROTOCOL APPROVAL SIGNATURES 
Version 3.0, dated 07-FEB-2022 
Sponsor’s Approval 
This protocol has been approved by Medicines for Malaria Venture (MMV). 
Sponsor’s Signatory:  
 
 
Name: 
Signature: 
Stephan Chalon MD PhD 
 
 
Date: 
 
DD-MMM-YYYY 
 
 
 
Name: 
Signature: 
Andrea Kümmerle PhD 
 
 
Date: 
 
DD-MMM-YYYY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
08-Feb-2022
08-Feb-2022




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TRIAL PERSONNEL 
 
Sponsor’s 
Representative 
 
Keith Berelowitz M.Sc. 
Richmond Pharmacology Ltd. 
1a Newcomen Street, London Bridge 
  
Sponsor’s Medical 
Director/Contact 
 
Dr Stephan Chalon MD PhD  
Phone: +41 79 962 9244 (Mobile)  
email: chalons@mmv.org  
 
Sponsor’s Clinical 
Lead/Contact 
 
Dr Andrea Kümmerle PhD  
Phone: +41 79 532 02 50 (Mobile)  
email: kuemmerlea@mmv.org  
 
Sponsor’s Medical 
Monitor 
 
 
 
 
 
 
Sponsor site 
 
Dr Annick Janin MD  
Medical Monitor 
AKJ Consulting 
659 Rue de la Combe de l’eau 01220 Divonne-les-Bains, 
France 
External Tel: +33 (0)6 29 54 71 90   
e-mail: janina-consultants@mmv.org 
 
Medicines for Malaria Venture (MMV)  
ICC – Block G, 3rd floor  
20, Route de Pré-Bois  
PO Box 1826  
1215 Geneva 15  
Switzerland  
 
Trial Site 
Richmond Pharmacology Ltd. 
1a Newcomen Street, London Bridge, 
London SE1 1YR, UK  
 
Principal 
Investigator 
 
 
Dr Ulrike Lorch MD FRCA FFPM  
Phone: +44 (0)20 70425800  
email: u.lorch@richmondpharmacology.com 
 
Co-Investigators 
 
Dr Jörg Täubel MD FFPM FESC 
Dr Andrew Stokes MB BCh BAO MSc 
 
Clinical Laboratory 
 
 
The Doctor’s Laboratory  
The Halo Building, 1 Mabledon Place 
London, WC1H 9AX, UK 
  
Bioanalytical 
Laboratory 
Anita Kress 
Swiss BioQuant AG  


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PK Statistical 
Analysis and 
Reporting 
Kägenstrasse 18  
4153 Reinach  
Switzerland  
Phone: +41 61 716 9824 
email: anita.kress@swissbioquant.com 
 
Rachael White 
PharmaKinetic 
BioCity, Pennyfoot Street 
Nottingham NG1 1GF 
United Kingdom 
Telephone: +44 7712 897059 
E-Mail: rachael@pharmakinetic.co.uk 
 
Data Management 
 
Richmond Pharmacology Ltd.  
 
Statistics 
Richmond Pharmacology Ltd.  
 
 
Qualified Person 
Dilawaiz Afaqui 
 
Pharmaco-
vigilance 
 
Oliver Abschütz 
PrimeVigilance  
The Surrey Research Park,  
1 Occam Court, Occam Road,  
Guildford, Surrey, GU2 7HJ,  
United Kingdom  
email: oliver.abschuetz @primevigilance.com 
Mobile: +49 (0)1578 3053780 
Head Office: +44 1483 307920 
 
Clinical Project 
Manager 
 
Kapilkumar Undaviya M.Sc. 
Richmond Pharmacology Ltd. 
 
Medical Writing 
 
 
Dr Andrew Stokes MB BCh BAO MSc 
Dr Jasmin Walravens-Evans MB BS BSc 
 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Explanation 
Ab 
Antibody 
ABPI 
Association of the British Pharmaceutical Industry 
ACT 
Artemisinin-based Combination Therapies 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AIC 
Akaike Information Criterion 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AR 
Adverse Reaction 
AS 
Artesunate 
AST 
Aspartate aminotransferase 
%AUCextrap 
Percentage of AUC that is due to extrapolation from last to 
infinity 
AUC 
Area under the concentration-time curve 
AUC0- 
Area under the plasma concentration-time curve from time 
zero extrapolated to infinite time 
AUC0-t 
Area under the plasma concentration curve from time zero 
up to the last quantifiable concentration 
AV 
Atrioventricular 
β-hCG 
Beta-human chorionic gonadotrophin 
BW 
Body weight 
BMI 
Body Mass Index 
CI 
Confidence interval 
CL/F 
Apparent total plasma clearance 
Cmax 
Maximal plasma concentration 
CRF 
Case Report Form 
CSP 
Clinical Study Protocol 
CV 
Coefficient of Variation 
CYP2C19 
Cytochrome P2C19 
CYP2C9 
Cytochrome P2C9 


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Abbreviation 
Explanation 
CYP3A4 
Cytochrome P3A4 
CYP450 
Cytochrome P450 
D 
Day 
DBP 
Diastolic blood pressure 
DHA 
Dihydroartemisinin 
DHP 
Data Handling Protocol 
DHP STW 
Data Handling Protocol for Scheduling Time Windows 
DSUR 
Development Safety Update Report 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
ET 
Early Termination 
fm 
Fraction metabolised 
FSH 
Follicular Stimulating Hormone 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
h 
Hours 
Hb 
Haemoglobin 
HBc 
Hepatitis B core 
HBsAg 
Hepatitis B surface Antigen 
HCV 
Hepatitis C Virus 
hERG 
the human Ether-à-go-go-Related Gene 
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
IPTp 
Intermittent preventive treatment of malaria in pregnancy 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 


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Abbreviation 
Explanation 
LLN 
Lower Limit of Normal 
LOQ 
Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMV 
Medicines for Malaria Venture 
MTS 
Master Treatment Schedule 
MUSE® 
MUSE® Cardiology Information System 
N 
Number of participants 
n 
Number of samples 
NHS 
National Health Service 
n(LLOQ) 
The number of samples <LLOQ 
PBPK 
Physiologically based pharmacokinetic 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PQP 
Piperaquine tetraphosphate 
PR 
Duration of the PR interval 
PT 
Preferred Term 
PYR 
Pyronaridine tetraphosphate 
QRS 
Duration of the QRS interval 
QT 
Duration of the QT interval 
QTc 
Duration of the QT interval adjusted for heart rate 
REC 
Research Ethics Committee 
RPL 
Richmond Pharmacology Ltd. 
RR 
Respiratory rate 
RSI 
Reference Safety Information 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SAS® 
Statistical Analysis System® 
SBP 
Systolic blood pressure 
SD 
Standard Deviation 


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Abbreviation 
Explanation 
SMC 
Seasonal malaria chemoprevention 
SP 
Sulfadoxine-pyrimethamine 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SOM 
Study Operations Manual 
SOP 
Standard Operating Procedure 
SPAQ 
Sulfadoxine-pyrimethamine plus amodiaquine 
SRC 
Safety Review Committee 
t1/2 
Terminal Elimination Half-life 
TdP 
Torsades de Pointes 
TEAE 
Treatment-Emergent Adverse Event 
tmax 
Time to reach maximum plasma concentration  
ULN 
Upper Limit of Normal 
Vz/F 
Apparent volume of distribution during the terminal phase 
WHO 
World Health Organization 
WNCBP 
Female participants of non-childbearing potential 
WOCBP 
Female participants of childbearing potential 
λz 
Terminal Rate Constant 
 
For the purposes of this protocol, ‘Investigator’ refers to the Principal 
Investigator or their delegate.  


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TRIAL SYNOPSIS 
Protocol Reference: 
MMV_SMC_21_01 
Trial drugs: Pyronaridine and piperaquine 
Title of the trial: A randomised, double-blind, placebo controlled, parallel group study in healthy 
adult volunteers to determine the tolerability and safety of pyronaridine (PYR) co-administered 
with piperaquine (PQP) under fasted conditions. 
Principal Investigator: Dr Ulrike Lorch MD FRCA FFPM 
Trial centre:  
Richmond Pharmacology Ltd. 
London Bridge, 1A Newcomen Street, SE1 1YR, UK 
Trial parts: N/A 
Clinical phase: 1 (the trial does not have therapeutic or 
prophylactic intent and does not plan to assess efficacy) 
Objectives 
Endpoints 
Statistical analyses 
Primary 
• 
To determine the safety 
and tolerability of the 
registered dose for 
treatment of acute 
uncomplicated malaria 
of PYR (once daily for 
three days) and the 
registered dose for the 
treatment of acute 
uncomplicated malaria 
of PQP (once daily for 
three days) when 
administered alone and 
in combination, in 
comparison with 
placebo. 
 
• 
The incidence, severity 
and relationship of 
Treatment-Emergent 
Adverse Events (TEAEs). 
• 
Proportion of participants 
with clinically significant 
changes in laboratory 
safety tests 
(haematology, 
biochemistry, coagulation 
and urinalysis).  
• 
Proportion of participants 
with morphological and/or 
rhythm abnormalities on 
electrocardiogram (ECG). 
• 
Proportion of participants 
with clinically significant 
changes in ECG time 
intervals (PR, QRS, QT 
and QTc intervals) and 
clinically significant 
changes against baseline 
Holter. 
• 
Proportion of participants 
with clinically significant 
changes in vital signs 
(systolic blood pressure, 
diastolic blood pressure 
and pulse rate). 
 
 
 
• 
Adverse Events (AE), 
Adverse Events of Special 
Interest (AESI), Serious 
Adverse Events (SAEs), vital 
signs, ECG parameters, and 
clinical laboratory data will 
be listed and summarised 
using descriptive statistics.  
• 
All AEs will be summarised 
and listed by using System 
Organ Class (SOC) and 
Preferred Term (PT) assigned 
to the event using Medical 
Dictionary for Regulatory 
Activities (MedDRA). 
Furthermore, these events 
will be summarised by the 
maximum intensity. The 
number of participants who 
experienced drug-related 
AEs will also be summarised. 
Any SAEs, AESIs and/or AEs 
that led to withdrawal will be 
summarised and listed.  


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Objectives 
Endpoints 
Statistical analyses 
Secondary  
• 
To determine the 
pharmacokinetics (PK) 
of PYR and PQP when 
administered alone and 
in combination for three 
days. 
• 
PK parameters derived by 
non-compartmental 
methods including 
maximum observed 
plasma concentration 
(Cmax), time to reach 
maximum plasma 
concentration (tmax), 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 
extrapolated to infinite 
(AUC0-), apparent total 
plasma clearance (CL/F), 
apparent volume of 
distribution during the 
terminal phase (Vz/F), 
terminal elimination rate 
constant (λz), and 
terminal elimination half-
life (t1/2). 
• 
Non-compartmental analysis 
will be used for estimation of 
pharmacokinetic parameters.  
• 
For individual plasma 
concentration data, the 
actual time of investigational 
medical product (IMP) 
administration and actual 
blood sampling time 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.  
• 
Area under the 
concentration-time curve 
(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 Limit 
of Quantification (LOQ) prior 
to the first quantifiable 
concentration will be set to 
zero. Samples with 
concentrations below LOQ 
after the first quantifiable 
concentration will be set to 
‘missing’ and omitted from 
the analysis. Other 
pharmacokinetic parameters 
will be calculated according 
to standard equations.  
• 
To determine the 
relationship between 
PQP and ECG 
parameters (QTc, QRS 
and PR), between PYR 
and ECG parameters, 
and to evaluate any 
impact of the 
combination of PYR and 
PQP on ECG parameters. 
• 
Difference between 
baseline corrected QTc 
following placebo and 
baseline corrected QTc 
following PQP alone, and 
with PYR. 
• 
Two complementary sets of 
analyses will be performed: 
a per timepoint analysis and 
a concentration-QTc analysis.  
• 
For all quantitative ECG 
parameters, descriptive 
statistics will be given for the 
change from baseline. In 
addition, for QTc, a linear 
model will be fitted for each 
timepoint and the difference 
between each of the active 
treatments and placebo will 


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be estimated based on this 
model and two-sided 90 % 
confidence intervals be 
given.  
This analysis will be based 
on the change of QTc from 
baseline and will use 
baseline QTc and the 
concentrations of PYR and 
PQP as covariates. 
Treatment and time will be 
used as discrete fixed 
effects. A significant 
treatment effect (based on 
an F-test) will be considered 
an indication for model 
misfit. For the best fitting 
linear model, predictions of 
the effect on QTc will be 
made at the mean 
concentrations of the 
moieties involved at the tmax 
for each of these moieties. 
Exploratory 
Objectives 
Endpoints 
Statistical analyses 
• 
To investigate the 
exposures to PQP 
metabolites (e.g. N-
oxidated metabolite, 
provided a future 
bioanalytical method is 
available). 
• 
PK parameters of PQP 
metabolites (e.g. N-
oxidated metabolite) and 
metabolites to parent 
drug ratios. 
• 
PQP metabolites PK 
parameters including 
metabolite to parent drug PK 
parameters will be calculated 
using non-compartmental 
methods from plasma 
concentration-time data and 
will be summarised by dose 
group using descriptive 
statistics. 
• 
To determine if CYP 
genetic polymorphism 
influences drug PK and 
safety & tolerability. 
• 
The relationship between 
CYP genetic 
polymorphism, PK 
parameters, and safety & 
tolerability. 
• 
The relationship between 
CYP genetic polymorphism, 
PK parameters, and safety & 
tolerability will be 
summarised as 
applicable/appropriate. 
Trial design  
The trial is a single-centre, randomised, double-blind, placebo controlled, parallel group study to 
determine the safety, tolerability and PK of the registered dose for treatment of acute 
uncomplicated malaria of PYR + PQP, PYR + PQP placebo, PYR placebo + PQP, as well as PYR 
placebo + PQP placebo when administered orally once daily for three days to healthy adult male 
and female participants.   
Forty (40) participants are planned to be enrolled and randomised to one of the four treatments 
in a 2:1:1:1 ratio, as described below: 
• 
Treatment 1 (N=16): PYR + PQP  


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• 
Treatment 2 (N = 8):  PYR + placebo for PQP 
• 
Treatment 3 (N = 8):  placebo for PYR + PQP  
• 
Treatment 4 (N = 8):  placebo for PYR + placebo for PQP.  
All participants will receive a single dose of PYR or placebo, as well as a single dose of PQP or 
placebo, on the morning of Day 1, Day 2 and Day 3. Participants will fast for at least three hours 
prior to dosing and four hours after dosing. Within each treatment arm, fasted participants will 
take PYR/placebo tablets, followed by PQP/placebo tablets, at the following weight-dependent 
doses (Table 1). 
 
Table 1: Planned treatment arms and IMP administration  
Number 
of 
Participants  
IMPs 
Planned Dose (depending on Body 
Weight) 
Number 
of 
Doses/ 
Dose Interval  
16 
 
PYR 
540 mg (BW 50 kg - <65 kg); OR 
720 mg (BW 65 kg or greater) 
 
Single morning doses on 
D1, D2 and D3 
 
PQP 
960 mg (BW 50 kg - <75 kg); OR 
1280 mg (BW 75 kg or greater) 
8 
 
PYR 
540 mg (BW 50 kg - <65 kg); OR 
720 mg (BW 65 kg or greater) 
Placebo 
for PQP 
N/A 
8 
Placebo 
for PYR 
N/A 
PQP 
960 mg (BW 50 kg - <75 kg); OR 
1280 mg (BW 75 kg or greater) 
8 
 
Placebo 
for PYR 
N/A 
Placebo 
for PQP 
N/A 
Abbreviations: BW: body weight; D: day; kg: kilograms; mg: milligrams; PQP: piperaquine; PYR: 
pyronaridine. 
 
Participant screening will take place between Day -22 and Day -2 (Figure 1). Each participant will 
receive verbal and written information, then sign the Informed Consent Form (ICF), before any 
screening procedures take place. Participants will be admitted on Day -1 and dosed once in the 
mornings of Day 1, Day 2 and Day 3. Participants in the sentinel group will be discharged on Day 
7 and will return to the unit for outpatient assessments on Days 8, 15 and 22. If safety and 
tolerability data allow, and if agreed by the Safety Review Committee (SRC), the remaining (non-
sentinel) participants will be discharged on Day 5 and will return to the unit for outpatient 
assessments on Days 6, 8, 15, 22. Final assessments will be carried out at the follow-up visit on 
Day 30 (+/-1 day). The trial Schedule of Assessments (Table 5 and Table 6) details all 
assessments that will take place during the trial. The trial design features as well as the number 
of participants may be adapted according to the Adaptive Features (Table 7). This trial will use a 
sentinel dosing strategy. For full details see Section 3.4.4. 
 
 
 


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Figure 1: Trial flow chart 
 
Abbreviations: N: number of participants; PQP: Piperaquine; PYR: Pyronaridine.  
Participants in the sentinel group will remain in-house until Day 7. Participants in the main group 
may be discharged on Day 5, based on the available safety and tolerability data from the sentinel 
group and as decided by the Safety Review Committee (SRC). The Day 6 OP visit will apply to the 
non-sentinel group only.  
Number of participants 
40 healthy male or female participants will be recruited onto the trial. Sufficient reserve 
participants will be identified to ensure that 40 participants complete the trial. For an individual 
participant: A participant is considered to have reached the end of the study if the participant has 
completed the last visit (Day 30 for this protocol). In each cohort, if more than two discontinuations 
due to non-safety related reasons occur, additional participants may be recruited to replace the 
discontinued participants. This would require prior agreement with the trial Sponsor. 
Main criteria for admission 
Healthy black male or female participants, of Sub-Saharan African origin (defined as participants 
whose parents are both black and are of Sub-Saharan African origin) will be included if they are 
aged between 18 and 45 years (inclusive), weigh 50 kg or greater and have a Body Mass Index 
(BMI) between 18 kg/m2 and 28 kg/m2 (inclusive). Participants of childbearing potential must use 
highly effective methods of birth control. All efforts will be made to ensure a balanced male: female 
ratio throughout the trial. Every effort will be made to recruit participants in order to stratify 
randomisation according to weight, so that a minimum of two participants receive each of the 
seven treatment options (see Table 12 for details). 
Main exclusion criteria are: Any female participant detected to be pregnant, breastfeeding, or who 
is likely to become pregnant during the trial or any male participant with a female partner(s) who 
is (are) pregnant or lactating from the time of the administration of trial medication. Current or 
recurrent disease (or condition) which, in the opinion of the Investigator, may either put the 
participant at risk because of participation in the trial, may influence the result of the trial, or the 
participant’s ability to participate in the trial. 


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Anticipated test treatment(s) and mode of administration 
Oral recommended malaria treatment doses of PYR and PQP administered once daily on Day 1, 
Day 2 and Day 3, in the fasted state. See Section 6.1.2 for details. 
Reference treatment(s) and mode of administration 
Oral matched placebo tablets for PYR and PQP. 


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1. 
INTRODUCTION  
In 2019, an estimated 229 million cases of malaria occurred worldwide, with 
approximately 94 % occurring in WHO African Region, leading to 409 000 deaths, 
of which about two thirds were in children under five years of age [1]. In addition, 
there were an estimated 33 million pregnancies in the moderate to high 
transmission countries of the WHO African Region, of which 35 % (12 million) were 
exposed to malaria infection during pregnancy [1]. 
Case management with highly effective antimalarial drugs has contributed to the 
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 or cure undetected malarial illness with the goal to achieve 
therapeutic drug levels in the blood throughout the period of greatest risk [1]. 
WHO strongly recommends with a high-certainty evidence the following malaria 
chemopreventive 
therapies: 
seasonal 
malaria 
chemoprevention 
(SMC), 
intermittent preventive treatment in infants (IPTi), and intermittent preventive 
treatment of malaria in pregnancy (IPTp) [1,2]. 
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 [2]. In this context, SPAQ 
demonstrated a protective efficacy of >80 % in Burkina Faso [3]. 
Despite the strong public health evidence of chemoprevention, only SP and SPAQ 
are currently recommended by WHO for chemoprevention, which use is currently 
threatened by increasing resistance to SP [4,5]. MMV’s strategy is to re-combine 
existing and approved antimalarials used individually 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 products has been 
conducted, with a view to identify a new combination of two registered products 
that may be suitable for malaria chemoprevention. 
A combination of pyronaridine  (PYR) and piperaquine (PQP) was considered to 
have potential for this purpose. In the European Union and in many African 
countries, PQP is marketed in a fixed dose combination with the short acting 
antimalarial dihydroartemisinin (DHA) as Eurartesim® for treatment of acute 
uncomplicated malaria. PYR in a fixed dose combination with artesunate (AS) 
received positive scientific opinion from EMA through Article 58 and is registered  
in many malaria endemic countries in Africa and South-East Asia as Pyramax® for 
treatment of acute uncomplicated malaria for both adults and children. The efficacy 
of both PYR and PQP combined to artemisinin derivatives have been demonstrated 
in the treatment of uncomplicated malaria in various clinical trials in different 
regions and these combinations have been in clinical use for at least 20 and 40 
years, respectively [4,6].  
Based on efficacy data provided to support registration for malaria treatment, PYR 
and PQP are long-acting antimalarials, which extended half-lives shall confer a 


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protection for one month with the standard three-day regimen. Additionally, DHA-
PQP was associated with a protective effect of over 75 % in children three to 59 
months old [3]. It is therefore assumed that a monthly based treatment of the 
three-day regimen of both PQP and PYR (for three to four consecutive months 
during the malaria season) shall achieve adequate efficacy for malaria prophylaxis. 
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 show a good safety profile and 
be well tolerated. In an internal thorough MMV evaluation of multiple candidates, 
the safety and tolerability profile of these two compounds did not show any 
prohibitive overlap [7,8]. In addition, until today, neither PYR nor PQP showed any 
teratogenic liabilities and they are 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. 
Finally, the combination of these two compounds with distinct mechanisms of 
action is expected to be at low risk of rapid emergence of resistance [4,6].  
 
Mechanism of action, clearance and pharmacokinetics 
PYR inhibits the formation of β-haematin and thus prevents the malarial parasite 
from neutralizing haem, which is toxic to the parasite. Additionally, by forming a 
drug-haematin complex pyronaridine inhibits glutathione-dependent degradation 
of haematin and enhances haematin-induced lysis of red blood cells. Both of these 
actions lead to parasite death [6]. In healthy participants and patients with 
malaria, peak plasma concentrations of PYR are generally reached between two 
hours and eight hours post-dose. Pyronaridine appears to have many potential 
metabolites, with several metabolic pathways involved (including CYP3A4 and 
CYP2D6). Pyronaridine elimination half-life in adults is between 14 days and 
18 days. 
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 [4]. In humans, PQP has a tmax of approximately five 
hours. PQP is mainly metabolized by CYP3A4 and to a lesser extent by CYP2C9 and 
CYP2C19. PQP is a CYP3A4 inhibitor, and a clinical study of Eurartesim® with 
midazolam showed a modest increase in the exposure of midazolam (<two-fold) 
[4]. The terminal elimination half-life of PQP is around 22 days for adult patients.  
 
Safety and tolerability 
Through their extensive use in many African and South-East Asian countries, the 
safety and tolerability of PYR and PQP for the treatment of uncomplicated malaria 
when combined to AS and DHA respectively, are well established. Safety data from 
a European registry have also been recently published for DHA-PQP [9]. 
The main safety signal observed with PYR in healthy participants and malaria 
patients consists of transient asymptomatic AST/ALT elevations which are not 
associated with bilirubin changes. The most frequently reported AEs (>1/100 to 
<1/10) are headache, eosinophilia, neutropenia, anaemia, increased platelet 
count, vomiting (2.2 % to 2.5 %), abdominal pain, bradycardia, transaminase 


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increases and hypoglycaemia. Additionally, analyses performed in malaria patients 
suggest that no clinically concerning QTc prolongation is expected at therapeutic 
concentrations of PYR [10]. 
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 [11,12]. Although transient 
asymptomatic ALT/AST elevations have also 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 [13,14]. Despite 
significant 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 [15]. 
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 are appropriately controlled [16].  
Based on the reported clinical safety profile of the two drugs, the three major 
toxicities of focus with combination over three days will be: 
1) gastrointestinal toxicity (reported with both drugs) 
2) liver toxicity (primarily expected with PYR) and 
3) QTc prolongation (primarily expected with PQP). 
 
Potential for interaction between PQP and PYR 
The potential for pharmacokinetic interaction between PQP and PYR, leading to 
increased exposure and subsequent risk of toxicities has been assessed as follows. 
Based on in vitro data, PQP is a CYP3A4 time-dependent inhibitor, and pyronaridine 
a CYP3A4 substrate (estimated fm = 0.6). A clinical study evaluating the PK of PYR 
in the presence of ritonavir, a typical CYP3A4 time-dependent inhibitor, showed no 
drug-drug interaction [17]. Therefore, the risk of possible drug-drug interaction 
between PYR and CYP3A4 inhibitors is considered to be low.  
The potential CYP3A4-mediated drug-drug interaction between PQP (as a 
perpetrator) and PYR (as a substrate) was simulated using Simcyp PBPK modelling, 
which confirmed its low likelihood (less than 25 % increase in AUC) [18]. 
Consequently and since the two drugs will be administered in a fasting state, if an 
increase in PQP exposure is observed in the presence of PYR, the potential impact 
on the PQP-induced QTc prolongation should be less than the one documented in 
the presence of a high fat meal. There is however a risk of accumulation in the 
liver with PYR as seen in preclinical dog studies where more than 10 % of the dose 
remained in the liver eight months after a single oral administration [19]. 
In addition to the risk of accumulation there is risk of potentiation and summation 
of the overlapping gastrointestinal, CNS (dizziness), liver and cardiac toxicity  seen 
with PQP and PYR. The following aspects of the pharmacokinetic and Adverse Event 
profiles of PQP and PYR were considered to determine the inclusion and exclusion 
criteria and to design the tolerability and safety monitoring of this trial: 


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• 
the overlapping Adverse Events profiles of PQP and PYR in healthy 
participants and/or malaria patients (e.g. nausea, vomiting, diarrhoea, 
dizziness and increases of liver AST and ALT) indicate a potential for 
additive Adverse Events 
• 
PQP is known to prolong QTc in humans and this effect is concentration-
related [7] 
• 
Based on a study with reduced number of digitalized ECGs, there is no 
evidence of clinically significant QTc prolongation with PYR in malaria 
patients [18], however one cannot formally exclude that PYR may 
influence the expected QTc prolongation with PQP in healthy participants 
with a maximal effect expected on the last day of administration 
• 
PQP has a Terminal Elimination Half-life of approximately 22 days. 
However, approximately 1 % of the Cmax is predicted on 672 hours (i.e. 
28 days) after the administration of 1280 mg in healthy adults [22]. 
Therefore, a follow-up of 30 days (i.e. 28 days after last dose) is 
considered acceptable to ensure that possible delayed effects on safety 
laboratory tests are appropriately documented.  
Close clinical monitoring will include LFT measurements (including AST, ALT, 
bilirubin and alkaline phosphatase [ALP]) and ECG measurements in triplicate. 
Participants will remain in the unit under medical supervision until at least 48 hours 
following the final dose (i.e. at least 120 hours [h] inpatient) and will be followed 
up to Day 30 (+/-1 day). 
 
1.1 
Rationale for conducting trial 
This study in healthy adults will be the first one to evaluate combined 
administration of PYR and PQP in humans, with a view for potential use in the 
future as seasonal malarial chemoprevention for populations at risk based in 
endemic areas. A parallel group design (n=40) including a placebo cohort will be 
used to evaluate safety/tolerability and PK of the two investigational medicines 
either as monotherapy or in combination. To our knowledge, this study will be the 
first human study with this new combination. The approved adult malaria 
treatment doses of PYR and PQP have been chosen for this trial.  
The trial will involve four treatment arms:  
• 
Treatment 1 (N=16):  PYR + PQP 
• 
Treatment 2 (N=8):    PYR + placebo for PQP 
• 
Treatment 3 (N=8):    placebo for PYR + PQP 
• 
Treatment 4 (N=8):    placebo for PYR + placebo for PQP. 
This will facilitate discrimination of the contribution of the investigational medicines 
to any safety/tolerability signal and determine the pharmacokinetic of PYR and PQP 
when administered alone and in combination. 
Given the ultimate target population, the study will be carried out in healthy black 
participants of sub-Saharan African origin (defined as participants whose parents 
are both black and are of Sub-Saharan African origin). 


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1.2 
Risk-benefit evaluation 
1.2.1 
Potential benefits 
Healthy participants will take PYR and PQP for research purposes only. It is not 
anticipated that participants will receive any medical benefit apart from a general 
health examination. 
 
1.2.2 
Potential risks 
1.2.2.1 Piperaquine (PQP) 
The risks of PQP are described in detail above in the Safety and Tolerability section. 
Further SOC specific risks and mitigation strategies are described below in the Risk 
Management table.  
The risk of PQP-induced QTc prolongation will be reduced appropriately by 
controlling for other clinical risk factors for QTc prolongation [20]. 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 ECGs be obtained 
• 
recent exposure to concomitant drugs known to induce QTc prolongation 
be avoided [4,14]. 
Therefore, during this trial, healthy participants with risk factors for QTc 
prolongation will be excluded and enrolled participants will receive PQP under 
fasting conditions and will be monitored for QTc effects. 
 
1.2.2.2 Pyronaridine (PYR) 
Transient ALT/AST elevations above 3 x ULN are commonly reported in clinical 
trials investigating the three-day regimen of PYR-AS (pyronaridine-artesunate, 
Pyramax®). These elevations have been reported in both patients treated for acute 
uncomplicated malaria and healthy participants enrolled in clinical pharmacology 
studies. The overall pattern seems consistent across studies with a transient 
asymptomatic elevation in ALT/AST without bilirubin elevation which for most of 
the episodes occurred after the three-day treatment, within three and seven days 
after the initial dose and resolved within 21 days after reaching a peak value 
between eight and fifteen days after the first day of treatment. Higher elevations 
of >10 x ULN in patients and >5 x ULN in healthy have also been reported but are 
less common. 
Concomitant elevation in bilirubin and possible Hy’s Law cases have not been 
reported in healthy participants. In a retrospective pooled analysis of completed 
trials in patients, a total of 16 cases defined as concomitant elevations in ALT or 
AST >3 x ULN and total bilirubin >2xULN (i.e. Hy’s Law cases) were reported in 
the clinical development program for PYR-AS. Ten cases were reported in malaria 
patients receiving PYR-AS and six were also reported in patients receiving one of 
the comparator malaria drugs which could possibly suggest a confounding 
background effect of the disease. Of these 16 cases, the Independent Safety 


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Monitoring Board adjudicated six possible Hy’s Law cases in the PYR-AS group and 
four in the comparator drugs group.  
A total of four Phase 1 studies were conducted with PYR-AS in healthy participants. 
A SAD-MAD-Food Effect study was conducted in healthy South Korean participants 
[21] and three subsequent clinical pharmacology studies including a human C14 
study were performed in Switzerland [22,23,24]. With the exception of the human 
ADME study where PYR was administered as a single oral dose, all these Phase1 
studies have evaluated the three-day therapeutic regimen of PYR-AS for acute 
uncomplicated malaria. Of note, the safety laboratory tests monitoring in the Asian 
study was limited to two post-dose time-points (72h and Day 11) while the two 
other studies (both DDI studies) used a very intensive monitoring with almost daily 
for one week and then weekly ALT/AST/bilirubin evaluations up to study end which 
covered a full month of observation. In the two DDI studies with ritonavir and 
metoprolol the LFT monitoring obtained for the control arm (i.e. PYR-AS alone) 
showed ALT/AST elevations with normal bilirubin consistent with the pattern 
described in malaria patients [22,23]. For example, in the Metoprolol DDI study, 
the control group of Caucasian participants dosed with PYR-AS alone over three 
days in Period 1 showed the following incidence of asymptomatic ALT elevations: 
37 % (1-3 x ULN), 3 % (3-5 x ULN) and 10 % (>5 x ULN, including one case >20 
x ULN). Similar incidences were observed for AST with 3 % of the study 
participants reaching values in the range 10-20 x ULN [23]. In the MAD study 
conducted in South Korea with four incremental doses of PYR-AS, only one case of 
ALT/AST elevations (>2 x ULN) was reported. However, these results should be 
interpreted with caution due to the very limited number of timepoints for safety 
laboratory tests: the study schedule did not include ALT/AST/bilirubin evaluation 
between Day 4 and Day 11. Additionally, a statistical comparison conducted on 
ALT/AST changes from baseline to Day 4 or to Day 11 in this Phase 1 study showed 
a statistically significant increase in ALT/AST suggesting a trend for elevation 
versus placebo particularly at the two highest doses of PYR 12 and 15 mg/kg [21]. 
Other most frequently reported AEs (>1/100 to <1/10) are headache, eosinophilia, 
neutropenia, anaemia, increased platelet count, vomiting (2.2 to 2.5 %), 
abdominal pain, bradycardia, transaminase increases and hypoglycaemia [18]. 
Additionally, analyses performed in malaria patients suggest that no clinically 
concerning QTc prolongation is expected at therapeutic concentrations of PYR [10]. 
 
1.2.2.3 Risk management 
This trial will be conducted at an accredited Phase 1 clinical trial unit by an 
experienced Investigator and well-trained medical staff and technical staff with 
ample experience in the conduct of early phase clinical trials. The trial has been 
designed to safely include suitable participants, monitor, treat and communicate 
potential expected Adverse Reactions as well as potential unexpected Adverse 
Events. Additionally, a sentinel dosing strategy will be used; please refer to 
protocol Section 3.4.4. 
Although not expected, participants will be closely monitored for potential Serious 
Adverse Events. There are also special AR rules (both individual and group) that 
apply to the most significant risks (see Section 4.4). 
In applying the above risk management strategies, the overall risk to participants 
in this trial is considered low. 


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There is currently no clinical experience with PYR and PQP given in combination. 
Potential risks will be closely monitored for as part of the safety evaluations being 
performed in this trial. The risk mitigation measures are summarised in Table 2 
and Table 3 below. 
 
Table 2: Class effect risk and risk mitigation features 
Area 
Other factors 
Risk Mitigation 
 Class Effect 
Falls in haemoglobin are common 
after effective treatment with a 
variety of anti-malarial drugs and 
have been reported in patients 
with Pyramax® (PYR-artesunate) 
and 
Eurartesim® 
(PQP-DHA) 
[4,19]. 
1) Standard monitoring as with all early 
phase studies.  
2) Close monitoring of full blood count 
(including haemoglobin and white 
blood cell/ neutrophil count) will be 
conducted at regular intervals 
throughout the trial.  
 
 
 


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Table 3: Clinical and non-clinical known risks and mitigation features 
Target System Effect 
Risk Mitigation 
 Renal System 
PQP: hepatorenal function and 
urinalysis did not change in study 
of 
PQP 
administration 
(500mg 
single dose in healthy adults) [25]. 
No trials have been conducted with 
Eurartesim® 
or 
PQP 
alone 
in 
patients with renal impairment. 
1) Standard monitoring as with all 
early phase studies.  
2) Urinalysis and safety bloods 
including urea, creatinine and 
glomerular filtration rate will be 
taken at regular intervals 
highlighted in the Schedule of 
Assessments (Table 5 and 
Table 6).  
3) Additional assessments may be 
completed if required 
(including renal ultrasound, 
unscheduled microscopy or 24-
hour urine collection). 
PYR: Contraindicated in Severe 
renal failure. 
Blood, protein or white cells in the 
urine have been seen uncommonly 
with Pyramax®. 
Pre-clinical study in rats: 
Pyronaridine 
decreased 
urine 
volume 
with 
a 
concomitant 
increase in density and electrolyte 
concentration at 500 mg/kg in the 
rat 
(no 
effect 
at 
33 
and 
100 mg/kg). See Table 4-1 in PYR 
IB. 
 Hepatic System 
PQP: Overall considered as not 
commonly associated with LFT 
derangements [25]. 
LFT elevations have been seen 
uncommonly in healthy 
participants and malaria patients. 
1) Specific Inclusion and Exclusion 
Criteria will be used to select 
potential participants (Sections 
5.3 and 5.4). 
2) Extensive liver function testing 
will be completed including 
ALP, AST, ALT, bilirubin, GGT, 
Total protein as well as 
Albumin and Globulin, and 
Coagulation will be measured 
as per the clinical Schedule of 
Assessments (Table 5). 
3) Previous exposure to Hepatitis 
B (+/- D) and C will be 
assessed (excluding 
participants who have previous 
exposure).  
4) Specific AR rules will be 
implemented. 
5) Additional assessments could 
be added depending on clinical 
requirements, including a 
FibroScan of the liver.  
PYR: is associated with transient 
asymptomatic increases in liver 
enzymes without bilirubin 
elevation in both healthy 
participants and patients [8].  
 
Please see Risk Section 1.2.2.2 
above for further details. 
Cardiovascular  
system 
PQP: alone known to induce QTc 
prolongation in human participants 
with a well-documented 
exacerbation when the drug is 
taken with food [12,13]; also 
associated with tachycardia. 
 
Please see Risk Management text 
above for further details. 
 
1) Comprehensive monitoring and 
intensive cardiac assessments 
(including screening Holter and 
Telemetry D1-D3 with intensive 
time matched 12-Lead ECGs on 
D1 and D3).  
2) Three hour fasted state dosing 
to reduce Cmax of PQP and QTcF 
risk. Four hour post dose fast 
also.  
3) Exclusion of participants on 
QTcF prolonging medications 
(Section 5.4) 
4) Strict Exclusion Criteria 
surrounding history of 
PYR: not known to induce 
clinically concerning QTc 
prolongation in human 
participants but no formal 
concentration/QTc modelling in 
healthy participants is available. 


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Target System Effect 
Risk Mitigation 
Phase I CYP3A4 DDI study of 
Pyronaridine-DHA with ritonavir, 
there was no relationship between 
QTcF change and plasma 
concentrations of pyronaridine or 
DHA [23]. 
PYR: more commonly associated 
with bradycardia in patients. 
Decrease in heart rate correspond 
to reduction in fever of malarial 
infection. 
PYR use associated with 
palpitations and ventricular 
extrasystoles albeit uncommon 
(≥1/1000 to <1/100). 
predisposing cardiac conditions 
(Section 5.4). 
Respiratory  
System  
PQP: No effects noted in human 
studies. 
1) Standard monitoring as with all 
early phase studies. 
PYR:  
Pre-Clinical Study: 
A transient increase in respiratory 
rate was observed at a dose of 500 
mg/kg two hours post- dose in a 
pre-clinical study in guinea pigs. No 
effects noted at doses of 33 and 
100 
mg/kg 
or 
at 
any 
other 
timepoint [19]. 
Human Malarial Studies:  
Bronchitis, rhinitis and cough have 
uncommonly been seen in PYR-AS 
combination 
treatment 
of 
uncomplicated malaria. 
Central nervous 
system 
PQP: 
headache 
(common), 
dizziness 
(uncommon) 
and 
convulsion (rare/very rare) has 
been seen in DHA-PQP combination 
clinical trials. 
Asthenia commonly seen in DHA-
PQP combination. 
1) Standard monitoring as with all 
early phase studies. 
2) Warning regarding driving or 
operating machinery upon 
discharge if dizziness or 
fatigue/asthenia occurs.  
PYR: Headache commonly seen 
with PYR use. Paraesthesia and 
insomnia less commonly seen. 
Insomnia or fatigue/asthenia has 
been seen in PYR-AS combination 
clinical trials. 
Haematological 
system 
PQP: Haematological indices did 
not change as a result of PQP 
administration [25]. 
Anaemia 
and 
a 
reduction 
of 
haemoglobin commonly seen with 
DHA-PQP use. [25] 
1) Specific inclusion and exclusion 
criteria will be used to select 
potential participants. 
2) Close monitoring of full blood 
count (including haemoglobin, 
white blood cell/neutrophil and 
platelet count) will be 
conducted at regular intervals 
throughout the trial.  
3) Specific AR rules related to 
haematology.  
PYR: 
eosinophilia, 
neutropenia, 
anaemia, 
reduced 
haemoglobin 
and increased platelet count [19].  


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Target System Effect 
Risk Mitigation 
Gastrointestinal 
system  
PQP: gastrointestinal disturbances 
such 
as 
nausea/vomiting, 
abdominal 
pain 
and 
diarrhoea 
[9,10]. 
1) Standard monitoring as with all 
early phase studies. 
2) Regular biochemistry blood 
samples 
PYR: nausea/vomiting (2.2 % to 
2.5 %), abdominal pain, diarrhoea 
and constipation [8]. 
Reproductive 
system 
PQP: no specific data relating to the 
effects of PQP on human fertility; 
however, to date no AEs have been 
reported during clinical use [25]. 
Animal studies: In reproductive 
studies, 
PQP 
did 
not 
induce 
malformation in rats or rabbits 
[25].  
 
1) Specific contraceptive 
requirements will be in place 
for participants. 
2) Contraceptive guidance will be 
used in Inclusion Criteria 
(Section 5.3). 
3) Female participants will need 
evidence of negative pregnancy 
tests prior to dosing. 
PYR: no adequate data on the use 
of pyronaridine alone in human 
pregnancy or lactation.  
Animal studies: pyronaridine did 
not show any teratogenic effects 
nor 
effects 
on 
fertility 
or 
reproductive 
performance 
were 
observed 
at 
doses 
three-fold 
higher than the proposed human 
exposure [19]. 
 
2. 
TRIAL OBJECTIVES AND OUTCOMES  
2.1 
Objectives 
2.1.1 
Primary 
• 
To determine the safety and tolerability of the registered dose for 
treatment of acute uncomplicated malaria of PYR (once daily for three 
days) and the registered dose for the treatment of acute uncomplicated 
malaria of PQP (once daily for three days) when administered alone and 
in combination, in comparison with placebo. 
  
2.1.2 
Secondary 
• 
To determine the pharmacokinetics (PK) of PYR and PQP when 
administered alone, and in combination, for three days. 
• 
To determine the relationship between PQP and ECG parameters (QTc, 
QRS and PR), between PYR and ECG parameters, and to evaluate any 
impact of the combination of PYR and PQP on ECG parameters. 
 
2.1.3 
Exploratory 
• 
To investigate the exposures to PQP metabolites (e.g. N-oxidated 
metabolite, provided a future bioanalytical method is available). 


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• 
To determine if CYP genetic polymorphism influences drug PK and safety 
& tolerability. 
 
2.2 
Endpoints 
2.2.1 
Primary 
• 
The incidence, severity and relationship of Treatment-Emergent Adverse 
Events (TEAEs). 
• 
Proportion of participants with clinically significant changes in laboratory 
safety tests (haematology, biochemistry, coagulation and urinalysis). 
• 
Proportion of participants with morphological and/or rhythm abnormalities 
on electrocardiogram (ECG). 
• 
Proportion of participants with clinically significant changes in ECG time 
intervals (PR, QRS, QT and QTc intervals) and clinically significant changes 
against baseline Holter. 
• 
Proportion of participants with clinically significant changes in vital signs 
(systolic blood pressure, diastolic blood pressure and pulse rate). 
 
2.2.2 
Secondary 
• 
PK parameters derived by non-compartmental methods including 
maximum observed plasma concentration (Cmax), time to reach maximum 
plasma concentration (tmax), 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 
extrapolated to infinite (AUC0-), apparent total plasma clearance (CL/F), 
apparent volume of distribution during the terminal phase (Vz/F), terminal 
elimination rate constant (λz), and terminal elimination half-life (t1/2). 
Difference between baseline corrected QTc following placebo and baseline 
corrected QTc following PQP alone, and with PYR. 
 
2.2.3 
Exploratory 
• 
PK parameters of PQP metabolites (e.g. N-oxidated metabolite) and 
metabolites to parent drug ratios. 
• 
The relationship between CYP genetic polymorphism, PK parameters, and 
safety & tolerability. 
 
3. 
TRIAL DESIGN 
3.1 
Overall trial design  
This will be a single-centre, randomised, double-blind, placebo-controlled, parallel 
group study to determine the safety, tolerability and PK of the registered dose to 
treat acute uncomplicated malaria of PYR + PQP, PYR + PQP placebo, PYR placebo 


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+ PQP, as well as PYR placebo + PQP placebo when administered orally once daily 
for three days to healthy adult male and female participants. 
Forty (40) participants are planned to be enrolled and randomised to one of the 
four treatments in a 2:1:1:1 ratio as described below: 
• 
Treatment 1 (N=16):  PYR + PQP  
• 
Treatment 2 (N=8):    PYR + placebo for PQP 
• 
Treatment 3 (N=8):    placebo for PYR + PQP  
• 
Treatment 4 (N=8):    placebo for PYR + placebo for PQP. 
All participants will receive a single dose of PYR or placebo, as well as a single dose 
of PQP or placebo, on the morning of Day 1, Day 2 and Day 3. Participants will fast 
for at least three hours prior to dosing and four hours after dosing. Within each 
treatment arm, fasted participants will take PYR/placebo tablets, followed by 
PQP/placebo tablets, at the following weight-dependent doses (Table 4). 
 
Table 4: Planned treatment arms and IMP administration 
Number 
of 
Participants  
IMPs 
Planned Dose (which depends 
on Body Weight [BW]) 
Number of 
Doses/ Dose 
Interval  
16 
 
PYR 
540 mg (BW 50 kg - <65 kg); OR 
720 mg (BW 65 kg or greater) 
 
Single morning 
doses 
(fasted 
state) on D1, 
D2 and D3 
 
PQP 
960 mg (BW 50 kg - <75 kg); OR 
1280 mg (BW 75 kg or greater) 
8 
 
PYR 
540 mg (BW 50 kg - <65 kg); OR 
720 mg (BW 65 kg or greater) 
Placebo for PQP 
N/A 
8 Placebo for PYR 
N/A 
PQP 
960 mg (BW 50 kg - <75 kg); OR 
1280 mg (BW 75 kg or greater) 
8 
 
Placebo for PYR 
N/A 
Placebo for PQP 
N/A 
Abbreviations: BW: body weight; D: day; IMP: investigational medicinal product; kg: kilograms;  
mg: milligrams; PQP: piperaquine; PYR: pyronaridine. 
 
Participant screening will take place between Day -22 and Day -2. Each participant 
will receive verbal and written information, then sign the Informed Consent Form 
(ICF), before any screening procedures take place. Participants will be admitted 
on Day -1 and dosed once in the mornings of Day 1, Day 2 and Day 3. Participants 
in the sentinel group will be discharged on Day 7 and will return to the unit for 
outpatient assessments on Days 8, 15, 22. Non-sentinel group participants may 
be discharged on Day 5 and return for outpatient assessments on Days 6, 8, 15 


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and 22, provided there are no clinically significant safety and tolerability signals 
and the SRC are in agreement. 
Final assessments will be carried out at the follow-up visit on Day 30 (+/-1 day). 
The trial Schedule of Assessments (Table 5 and Table 6) details all assessments 
that will take place during the trial. The study design features as well as the 
number of participants may be adapted according to the Adaptive Features (Table 
7). This trial will use a sentinel dosing strategy. For full details see Section 3.4.4. 
 
Figure 2: Trial flow chart 
 
 
Abbreviations: N: number of participants in corresponding treatment arm; PQP: Piperaquine; PYR: 
Pyronaridine.  
As long as the data from the sentinel group demonstrate acceptable safety and tolerability, the 
participants in the non-sentinel group will be discharged on Day 5, but this decision will be made by 
the Safety Review Committee (SRC) (See  Table 7). The Day 6 OP visit will apply to the non-sentinel 
group only.


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Table 5: Schedule of Assessments 
Procedure 
Screening 
(D-22 to 
D-2) 
D-1 
D1 
D2 
D3 
D4 
D5 
D6 
D711 
Sentinel 
Group 
only 
D8 
D15 
D22 
Last 
visit 
D30 
(±1) 
In-house stay 
 
X 
X 
X 
X 
X 
X11 
X 
X 
 
 
 
 
Outpatient visit 
 
 
 
 
 
 
 
 X 
  
X 
X 
X 
X 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility check 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history/ 
demographics 
X 
X7 
 
 
 
 
 
 
 
 
 
 
 
Prior & concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Smoking history and 
current 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Beck depression 
inventory 
questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drugs of abuse 
screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Serology HIV 1&2, 
Hepatitis B&C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
(females) 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
FSH (post-
menopausal females) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Trial drug 
administration10 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Meals9 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Safety and tolerability: 
Vital signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
24-hour Holter ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Telemetry6 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
BMI calculation 
X 
X8 
 
 
 
 
 
 
 
 
 
 
 
Physical examination3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 


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Procedure 
Screening 
(D-22 to 
D-2) 
D-1 
D1 
D2 
D3 
D4 
D5 
D6 
D711 
Sentinel 
Group 
only 
D8 
D15 
D22 
Last 
visit 
D30 
(±1) 
Biochemistry, 
Haematology, 
Coagulation4 
X 
X 
X 
X12 
X12 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
Pharmacokinetics: 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sampling – PYR5 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
PK sampling – PQP5 
(including e.g. N-
oxidated metabolite) 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
Pharmacogenomics: 
CYP polymorphism 
 
 
X 
 
 
 
 
 
 
 
 
 
 
1. Vital signs (supine blood pressure, heart rate and respiratory rate) will be measured after rest of at least five minutes in supine position. Tympanic 
body temperature will be taken at each time-point (resting in supine position is not required for body temperature). Standing blood pressure and 
heart rate will be performed one minute after standing to assess for orthostatic change at screening and on Day -1, Day 1 and Day 3. See Table 6 for 
Time-points.  
2. 12-lead ECG will be measured in triplicate after a rest period of at least ten minutes in supine position. See Table 6 for time-points. 
3. Full physical examination at screening and last visit only. Symptom-directed physical examinations at other time-points. 
4. See Table 13 for details of laboratory parameters to be measured. 
5. Plasma samples for PQP and blood samples for PYR. See Table 6 for time-points. 
6. Continuous 12-lead telemetry will be recorded from at least one hour pre-dose on Day 1 to 24 hours post-dose on Day 3. 
7. Update only on Medical History at admission. 
8. On Day -1, only weight will be collected and height from screening will be used for BMI calculation. 
9. Standard meals will be served at standard unit times. On Days 1, 2 and 3 the first meal will be lunch given four hours post-dose. Meals will be optional 
on the discharge day. 
10. Dosing will be carried out in fasted state on the morning of each dosing day (Days 1, 2 and 3), firstly with PYR/ placebo tablets, followed by PQP/ 
placebo tablets. 
11. Participants in the sentinel group will remain in-house until Day 7. If there are no clinically concerning safety signals, the remaining participants 
subsequently dosed (from the main group) will remain in-house until Day 5. 
12. On Day 2 and Day 3, only the following safety blood tests will be measured: AST, ALT, bilirubin. 
 
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 RPL COVID-
19 Infection Control Guidelines and pre-entry algorithms. 
 
Abbreviations: AE: Adverse Event; BMI: body mass index; D: Day (where Day 1 is the first day that IMPs are administered); ECG: electrocardiogram; 
FSH: Follicular Stimulating Hormone; PK: pharmacokinetic; PQP: piperaquine; PYR: pyronaridine.


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Table 6 Schedule of Assessments (continued) 
1. Plasma samples for PQP and blood samples for PYR. 
2. 12-lead ECG will be measured in triplicate after a rest period of at least ten minutes in supine 
position. 
3. Vital signs will be measured after rest of at least five minutes in supine position. Standing vitals 
will be performed after one minute in the upright standing position, to assess for orthostatic 
change, on Screening, Day -1, and on Day 1 and Day 3 at pre-dose (-30 min) and post dose at 
5h. 
4. On dosing days, participants will fast from all food and drink (excluding water) at least 
three hours pre-dose and four hours post-dose. Participants may drink water until one hour 
before dosing and may re-commence water one hour subsequent to dosing. 
5. Four-hour procedures to be completed prior to lunch being given 
Abbreviations: D: day; ECG: electrocardiogram; h: hours (where hour 0 is the time at which the first 
IMP is administered); mins: minutes; PK: pharmacokinetic. 
 
 
 
 
 
 
 
 
Trial 
Day 
Time (h) 
PK sampling1 
12-lead ECG2 
Vitals3 
Meals4,5 
D1 
-1.5 
 
X 
 
 
-1 
 
X 
 
 
 
-30 mins 
X 
X 
X 
 
 
1 
X 
X 
X 
 
 
2 
X 
X 
X 
 
 
3 
X 
X 
 
 
 
4 
X 
X 
 
X 
 
5 
X 
X 
X 
 
 
6 
X 
X 
 
 
 
7 
X 
X 
 
 
 
8 
X 
X 
X 
 
 
10 
 
 
 
X 
 
12 
X 
X 
 
X 
D2 
-1.5 
 
X  
 
 
-1 
 
X 
 
 
-30 mins 
X 
X 
X 
 
4 
X 
X 
X 
X 
6 
X 
X 
X 
 
10 
 
 
 
X 
12 
X 
X 
X 
X 
D3 
-1.5 
 
X  
 
 
-1 
 
X 
 
 
-30 mins 
X 
X 
X 
 
-5 mins 
 
X 
 
 
1 
X 
X 
X 
 
2 
X 
X 
X 
 
3 
X 
X 
 
 
4 
X 
X 
 
X 
5 
X 
X 
X 
 
6 
X 
X 
 
 
7 
X 
X 
 
 
8 
X 
X 
X 
 
10 
 
 
 
X 
12 
X 
X 
 
X 


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3.2 
Order of procedures, scheduling time windows and protocol 
deviations 
 
Scheduling time windows:  
Priorities, order of procedures, scheduling time windows, and deviations from 
scheduled time and scheduling time windows. 
Priorities:  
When the protocol’s Schedule of Assessments requires that multiple procedures 
occur at the same timepoint, PK blood sampling takes priority and is to be 
scheduled at the exact time point defined in the schedule of assessments.  
Furthermore, the trial design also incorporates intensive ECGs as part of the 
analysis planned to determine the effect of the study drug(s) (either alone or in 
combination) on ECG parameters. Therefore, scheduled ECGs are also important 
for this trial and should take priority after PK sample. 
 
Order of procedures: 
When the Schedule of Assessments requires that multiple procedures occur at the 
same timepoint, the order of the procedures is as specified below. 
 
Screening:  
Screening can occur over several days if required. There is no set order of 
procedures required if this occurs. If all procedures are performed on the same 
day and where timepoints collide, then blood samples must be taken after vital 
signs (including standing vitals) and ECGs, to avoid the process of venepuncture 
affecting the vital sign readings and the ECG measurements.  
 
Order of procedures for D-1: 
1. ECGs (measured after rest of at least 10 minutes in supine position) 
2. Vital Signs (measured after rest of at least 5 minutes in supine position and 
after rest of at least 1 minute in standing position). 
 
Order of procedures pre-dose, during in-house period:  
1. ECGs (measured after rest of at least 10 minutes in supine position) 
2. Vital Signs (measured after rest of at least 5 minutes in supine position and 
after rest of at least 1 minute in standing position) 
3. Blood Samples (PK [exactly on time] > Biochemistry, Haematology and 
Coagulation) 
4. PGx sample. 
 
Order of procedures post-dose, during in-house period:  
1. ECGs (measured after rest of at least 10 minutes in supine position) 
2. Vital Signs (measured after rest of at least 5 minutes in supine position and 
after rest of at least 1 minute in standing position) 
3. Blood Samples (PK [exactly on time] > Biochemistry, Haematology and 
Coagulation) 


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4. Food (first meal to be served a minimum of four hours post-dose on Days 
1, 2 and 3). 
 
Order of procedures during outpatient visits: 
1. ECGs (measured after rest of at least 10 minutes in supine position) 
2. Vital Signs (measured after rest of at least 5 minutes in supine position and 
after rest of at least 1 minute in standing position) 
3. Blood Samples (PK [exactly on time] > Biochemistry, Haematology and 
Coagulation). 
 
Meals will be provided in the order below on each dosing day (Days 1, 2 and 3), 
following the standard timings of the research unit: 
1. Lunch (at least 4 hours post dose) 
2. Dinner (10 hours post dose) 
3. Snack (12 hours post dose). 
 
Meals for the non-dosing residential days will be served as below, following the 
standard timings of the research unit:  
1. Breakfast (following the morning procedures) 
2. Lunch  
3. Dinner  
4. Snack. 
 
Scheduling time windows: 
Considering priorities and order of procedures, the design of the master treatment 
schedule (MTS) requires scheduling time windows for those tasks that occur at the 
same protocol time point but need to be performed before or after the priority 
task. The permitted time windows are set out in the Data Handling Protocol for 
scheduling time windows (DHP STW). 
 
Clinical assessments should be performed exactly at the time prescribed in the 
MTS. 
 
Deviations: 
• 
Deviation from scheduled time in MTS: If the time of clinical assessment 
deviates from the time prescribed in the MTS, a clinical comment should be 
made in the appropriate source data/CRF space that a deviation from the 
MTS occurred. The following deviations from the MTS do not require a 
comment: 
 
All Procedures ± 2 mins 
 
• 
Deviation from scheduling time window in DHP STW: If the time of clinical 
assessment deviates from the scheduling time window in the DHP STW, this 
will be considered a protocol deviation. These deviations will be identified, 
classified (minor, major, critical), and managed in accordance with the DHP 
STW. 
 


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3.3 
Adaptive design 
This trial incorporates the use of an adaptive design. Trial specific adaptive features 
and their limits are described in Table 7. 
Adaptive features may be implemented only with the approval of the sponsor. 
Implementation of adaptive features affecting whole dose groups or cohorts, or 
the entire trial, will be documented in a non-substantial amendment.  
The exceptions to this are those adaptive features in Table 7 that relate to 
individual participant safety. These may be implemented at the discretion of the 
Investigator and recorded in that participant’s source data. 
 
Table 7: Adaptive protocol features 
Adaptive 
Study Design 
Areas 
Features 
Limits 
Sentinel/ 
subgroup 
dosing  
1. Cohorts may be split into sub-
groups. 
 
I. 
A mandatory sentinel dosing 
strategy 
of 
dosing 
four 
participants from treatment 
arm 1, and two participants 
from each of treatment arms 
2, 3 and 4, will be used. There 
will 
be 
a 
total 
of 
ten 
participants in the sentinel 
dosing. 
The 
remaining 
participants can be dosed if 
safety and tolerability data up 
to 15 days post first dose is 
acceptable. 
II. 
The 
participants 
in 
the 
sentinel group will all be 
dosed in parallel. If they are 
successfully dosed (i.e. it is 
deemed safe to dose the other 
participants), the remaining 
30 participants may all be 
dosed at the same time, in 
parallel, or they may be 
divided into two or more 
dosing 
groups, 
with 
the 
groups 
being 
dosed 
on 
different days. Each dosing 
group 
would 
contain 
a 
minimum of two participants 
from 
each 
of 
the 
four 
treatment arms, to maintain 
blinding and avoid bias (See 
Table 12). 
Flexible 
Cohort Sizes 
2. Withdrawn participants can be 
replaced at the discretion of the 
sponsor and PI. 
3. Replacement participants may be 
enrolled in an ongoing treatment 
group or dosed together as a group 
or dosed separately, except for 
I. 
The maximum extension is 
100 
% 
of 
the 
original 
treatment group. 
II. 
Trial specific AR rules (Section 
4.4) apply. 


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Adaptive 
Study Design 
Areas 
Features 
Limits 
those participants in the sentinel 
group. 
4. The number of participants in a 
treatment group can be extended 
to gather further information. 
In-house 
duration and 
visit numbers 
 
5. Participants in the sentinel group 
will remain in-house until Day 7. 
Participants in the main group may 
be discharged on Day 5, based on 
the available safety and tolerability 
data from the sentinel group and 
as decided by the SRC. 
6. The in-house stay or follow-up 
period 
may 
be 
prolonged 
or 
shortened if: 
a. it 
is 
considered 
clinically 
necessary to prolong the in-
house stay by the PI/delegate 
for individuals on a case-by-
case basis 
b. the SRC considers it necessary 
from a safety/tolerability point  
 
I. 
A maximum extended in-
house or follow-up period 
cannot be pre-defined as the 
extension will be as long as 
necessary 
to 
ensure 
the 
safety 
of 
the 
individual 
participant(s). 
II. 
The maximum extended in-
house or follow-up period for 
trial will be based on evolving 
safety and tolerability data.   
III. 
Alterations in duration of in-
house stay or follow-up need 
to ensure that sufficient data 
are obtained to fulfil the trial 
objectives and be a reflection 
of the established safety and 
tolerability PK profile up to the 
decision-making time-point. 
Samples and 
Assessments 
(safety) 
 
7. Additional safety assessments may 
be performed on an individual 
participant 
if 
it 
is 
considered 
clinically necessary by the PI for 
individuals on a case-by-case basis. 
8. Additional 
safety 
assessments 
(including 
but 
not 
limited 
to 
laboratory safety samples, vital 
signs and ECGs) may be added to 
the Schedule of Assessments at 
additional 
time-points 
for 
an 
upcoming treatment arm if the SRC 
considers 
it 
necessary 
from 
a 
safety/tolerability perspective, on 
the basis of evolving data. 
9. Additional safety assessments may 
refer to either: 
a. an increased number of the 
same 
safety 
assessments 
planned in the existing Schedule 
of Assessments. 
b. additional parameters (specific 
tests) on assessments already 
scheduled e.g. troponin tests on 
safety blood samples. 
c. 
additional safety tests requiring 
additional blood/urine sample 
collections 
or 
other 
clinical 
I. 
Trial specific maximum blood 
volume (470 ml) will not be 
exceeded (Section 7.12).  
II. 
A maximum for individuals will 
be determined on a case-by-
case basis and cannot be pre-
defined, 
because 
investigations 
will 
be 
performed as necessary to 
ensure the safety of the 
individual participants. 
III. 
If 
additional 
safety 
assessments or parameters 
are required for upcoming 
treatment arms/cohorts and 
have a similar risk profile to 
those planned in this trial 
protocol, 
they 
will 
be 
documented 
in 
a 
non-
substantial 
amendment. 
Additional safety assessments 
required 
for 
upcoming 
treatment arms/cohorts that 
are more invasive or have a 
different risk profile to those 
in this current protocol must 
be detailed in a substantial 
amendment. 
 


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Adaptive 
Study Design 
Areas 
Features 
Limits 
procedures 
e.g. 
ultrasound 
scans. 
10. Specialist 
referrals 
(e.g. 
to 
a 
cardiologist) may be made (and 
may 
include 
all 
relevant 
assessments and investigations) if it 
is considered clinically necessary by 
the PI or Sponsor or SRC for 
individuals on a case-by-case basis. 
11. The timing of safety assessments 
including 
but 
not 
limited 
to 
laboratory safety samples, vital 
signs and ECGs may be adjusted in 
accordance with evolving data and 
dosing schedule. 
IV. 
Alterations in timing of the 
safety assessments need to 
be 
a 
reflection 
of 
the 
established safety/tolerability 
and PK profile up to the 
decision-making time-point. 
Samples and 
Assessments 
(PK) 
 
12. Additional blood PK assessments 
may be taken in accordance with 
evolving data and dosing schedule. 
This includes those for the analysis 
of metabolites. 
13. Additional PK samples may be 
taken to get a better understanding 
of PK profile related to safety e.g. 
in the event of LFT changes for an 
individual participant during the 
trial it may be necessary to take 
additional PK samples. 
I. 
Study 
specific 
maximum 
blood volume will not be 
exceeded (Section 7.12). 
Samples and 
Assessments 
(ECG 
assessments) 
 
14. Additional PK samples paired with 
ECGs may be taken in the case of 
QT/QTc interval or LFT changes in an 
individual participant.  
15. If the meal-times need to be 
changed, ECG times may also be 
changed to maintain the sampling 
schedule required to capture the 
food effect for the confirmation of 
assay sensitivity. 
15. Telemetry data gathered during the 
trial may be used in the exploratory 
analysis of drug-related QT/QTc 
interval changes. 
I. 
To confirm assay sensitivity, a 
minimum of four postprandial 
time points will be recorded in 
triplicate between 1-4h after 
the start of the meal. 
 
Screening 
16. Screening assessments, including 
Holter ECG recordings performed at 
Richmond Pharmacology Ltd on 
participants 
screened 
(but 
not 
randomised) for another study can 
be used for this study to avoid 
unnecessary tests. 
I. 
The assessments must meet 
protocol 
criteria 
(e.g. 
the 
method to be used). 
II. 
The assessments must be 
performed within the protocol 
defined screening window. 
III. 
The Holter ECG recordings are 
valid for a period of three 
months. 


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Adaptive 
Study Design 
Areas 
Features 
Limits 
Optional 
analysis 
17. Exploratory analysis of CYP isoforms 
and transporters may be performed 
in individual participants, selected 
or all treatment groups. 
18. The CYP isoforms and transporters 
can 
be 
adjusted 
according 
to 
emerging data. 
19. Exploratory 
analysis 
of 
PK 
parameters of PQP metabolites (e.g. 
N-oxidated 
metabolite) 
and 
metabolites to parent drug ratios 
may be performed in individual 
participants, 
selected 
or 
all 
treatment groups. This may be 
reported separately from the CSR. 
20. ECG analysis for the purpose of 
intensive cardiac assessments may 
be 
performed. 
Telemetry 
data 
gathered during the study may be 
used in the optional analysis. 
IV. 
Any 
results 
of 
optional 
analysis 
will 
be 
reported; 
however, 
they 
may 
be 
reported separately and not in 
the Clinical Study Report. 
Abbreviations: AR: Adverse Reaction; ECG: Electrocardiogram; h: hour; PK: pharmacokinetic. 
 
3.4 
Rationale for trial design, doses and control groups 
This trial will evaluate the safety and tolerability profile of the approved regimen 
of PYR and PQP for the treatment of uncomplicated malaria when co-administered 
once daily for three days. It is anticipated that these same doses will be used in 
the future, when used for seasonal malarial chemoprevention. The trial is 
randomised and double blinded in order to minimise bias and includes matched 
placebo for both IMPs to facilitate identification of effects related to treatment, 
rather than situational- or procedure-related effects. 
 
3.4.1 Justification for the selected dose level 
Based on efficacy data provided to support registration for malaria treatment, PYR 
and PQP are long acting antimalarials, which extended half-lives shall confer a 
protection from re-infection for one month with the standard three-day regimen. 
Additionally, DHA-PQP was associated with a protective effect of over 75 %. It is 
therefore assumed that a monthly treatment (for three to four consecutive months 
during the malaria season)  based on the registered doses should achieve adequate 
protective efficacy (i.e. in people who are either parasite-free or have circulating 
parasites but are asymptomatic). 
The approved adult malaria treatment doses of PYR and PQP have therefore been 
chosen for this trial because these are the adult equivalent doses of the doses that 
would be used in the treatment of children. The dosage chosen corresponds to the 
dosages of PYR and PQP used in current combination antimalarials which are 
already licenced and known to be well tolerated. 
PYR will be given at a total daily dose of 540 mg for participants with a body weight 
between 50 and <65 kg and a total daily dose of 720 mg for participants with a 


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body weight superior or equal to 65 kg. PQP will be given at a total daily dose 
960 mg for participants with a BW between 50 and <75 kg and a total daily dose 
of 1280 mg for participants with a BW equal or superior to 75 kg. See Table 1 
above for weight-based dose calculations. 
 
3.4.2 
Choice of participants for trial 
Male and female participants aged between 18 and 45 years inclusive considered 
healthy for their age are planned to be recruited in the trial. The selection criteria 
are defined such that participants selected for participation in the trial are known 
to be free from any significant illness which potentially could confound the trial 
results or put the participant at risk. Healthy participants are also unlikely to 
require concomitant treatments which could interfere with the trial drugs. All 
efforts will be made to ensure a reasonable male:female gender balance 
throughout the trial. 
Considering that the African population is at considerably higher risk of contracting 
malaria and will be the target population for future prophylaxis trials with this new 
combination, the current trial will only recruit black participants of Sub-Saharan 
African origin (defined as participants whose parents are both black and are of 
Sub-Saharan African origin). 
  
3.4.3 
Route and rate of administration 
PYR, PQP and matched placebo tablets will be administered via the oral route in 
the fasted condition. Fasting is required for PQP administration in order to minimize 
the QTc prolongation induced by the medicine. As no clinically relevant food effect 
has been observed with PYR, the drug can also be given in a fasted state in order 
to achieve efficacious exposures. Initially, PYR or matched PYR placebo will be 
administered. Immediately subsequently, PQP or matched PQP placebo will be 
administered. Participants will fast of all food and drink (except water) for 
three hours pre-dose and four hours post-dose. Water may be consumed up to 
one hour prior to dosing and re-starting one hour subsequent to dosing. 
 
3.4.4 
Precautions to be applied for dosing between participants in 
sentinel group and participants in the main group 
A mandatory sentinel dosing strategy of dosing ten participants will be used to 
provide safety assessment. The sentinel group will consist of four participants from 
treatment arm 1 and two participants from each of treatment arms 2, 3 and 4. 
Blinded safety data up to Day 15 in the sentinel group will be reviewed by a Safety 
Review Committee (SRC) prior to dosing the 30 remaining participants. If safety 
and tolerability is acceptable from participants within the sentinel group, the 
remaining participants of each treatment arm may be dosed.  
 
3.4.5 
Monitoring and communication of Adverse Events/Reactions  
AEs will be continuously monitored throughout the trial from the signing of the ICF 
until the last follow-up assessment. Each AE reported will be assessed by a trained 
Research Physician (RP) who will ensure that the event is dealt with as appropriate 
based on clinical need, trial protocol, study operations manual and Richmond 


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Pharmacology Standard Operating Procedures (SOPs). AEs will be documented in 
the participants’ source Case Report Forms (CRFs) and reviewed regularly by the 
RPs and the Investigator.  
If any information relating to the IMPs in this trial becomes available after the 
submission of a final protocol to the Competent Authority which may impact on 
the conduct of the trial, including but not limited to the risk and benefit evaluations 
underpinning approvals and participant’s consent, MMV shall notify RPL in writing 
as soon as practically possible and the parties will agree, in writing, what steps 
need to be taken if any. 
 
3.4.6 
Investigator site facilities and personnel 
This trial will be conducted in a specialised early phase Clinical Pharmacology Unit 
with onsite resuscitation equipment and medication, in addition to access to an 
acute hospital with Critical Care facilities, thus ensuring direct access to equipment 
and staff for resuscitating and stabilising participants in acute medical conditions 
and emergencies. The trial is conducted by an experienced PI and well trained 
medical and technical staff with ample experience in the conduct of early phase 
clinical trials. 
The trial is designed to closely monitor, treat and communicate potential expected 
Adverse Reactions as well as potential unexpected adverse events. 
 
4. 
DECISION-MAKING, RULES AND LIMITS 
4.1 
Definitions  
‘Continuation’ in the context of this protocol refers to either (1) continuing dosing 
in an individual participant or (2) continuing dosing in the trial. 
 
4.2 
Rules and limits governing decision-making 
The criteria and rules that will govern PI/SRC decisions are: 
1. minimum data requirements (Table 8) 
2. Adverse Reaction rules (Section 4.4) 
3. Adaptive features and their limits (Table 7).  
The dose continuation decision requirement for the trial is outlined in Table 8 
below. 
 
 


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Table 8: Minimum data requirements to proceed from sentinel dosing to 
dosing remaining participants 
Decision-
making 
time point 
Person 
or body 
making 
the 
decision 
Minimum data to be looked at 
(in accordance with the CSP) 
Method of documentation 
of decision and/or 
communication to sponsor 
(if applicable) 
Continuation 
from the 
sentinel 
group to the 
remainder of 
the 
participants 
in all 
treatment 
arms.  
SRC 
The SRC will review all available 
safety and tolerability data collected 
up to Day 15. All clinically significant 
findings will be taken into account 
by the SRC when determining 
whether the remaining participants 
can be dosed as planned. 
Safety data from minimum of three 
participants in the combination PYR-
PQP sentinel arm is required. Safety 
data from a minimum of one 
participant in each of the sentinel 
IMP-placebo arms is required for 
SRC. 
The SRC will document the 
decision on the dose 
continuation approval form. 
Abbreviations: CSP: Clinical Study Protocol; SRC: Safety Review Committee 
 
4.3 
Safety Review Committee 
The SRC will consist of, as a minimum: 
• 
Principal Investigator (RPL) or delegate 
• 
MMV, Study Medical Director or delegate 
• 
Study Medical Monitor or delegate. 
Further internal or external experts such as a pharmacokineticist and/or a 
statistician, may be consulted by the SRC as necessary. Any additional information, 
if required, will be included in the SOM and the SRC Charter. 
 
4.3.1 
SRC Meeting  
The SRC will meet to review sentinel group data up to and including Day 15 of the 
final participant in the sentinel group (Table 8).  
There is an option to have ad-hoc SRC meetings to discuss urgent issues should 
the need arise. 
Prior to each SRC meeting, an interim safety report will be prepared, presenting 
the relevant safety and tolerability data. These will be signed by the investigator.  
Initially the data will be reviewed blinded. If the SRC consider it necessary due to 
a safety concern, either individual participants or the entire cohort may be 
unblinded to enable their decision-making. For non-emergency unblinding, before 
breaking the code, the potential decisions and actions should be determined and 
documented. 


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These decisions will be signed by one of the sponsor’s representatives and by the 
investigator. For logistical reasons, the signature of the sponsor or investigator 
may be communicated via email. 
The decision of the SRC will be taken in consensus between the members of the 
SRC. If consensus cannot be reached, then the most cautious approach will 
proceed. 
 
4.4 
Adverse Reaction (AR) rules 
An AR is any AE where there is a reasonable possibility of it being related to the 
IMP(s). ARs will be classified in accordance with Sections 8.1 and 8.2 to support 
standardised recording and reporting. 
• 
Seriousness will be assessed using the criteria in Section 8.1. 
• 
Severity and causality will be assessed using the criteria in Section 8.2. 
Seriousness and severity are assessed independently. ‘Severity’ characterises the 
intensity of an AE. ‘Serious’ is a regulatory definition and serves to define and 
trigger regulatory reporting obligations. 
Seriousness and severity grade both have consequences when applying AR rules. 
Seriousness of an AR always overrides the severity grade and the rules for Serious 
AR should be applied, irrespective of severity grade. 
These rules will only apply to AEs/SAEs where there is a reasonable 
possibility of relationship to the IMP (i.e. ARs and SARs). Every AE will be 
assessed in the following order: 
1) the impact on the individual participant, e.g. whether IMP administration 
can be continued 
2) whether blinding can continue for the individual 
3) a) (if the participant is unblinded) the impact on the treatment arm the 
individual participant is part of, e.g. in the following circumstances: 
o if a treatment arm is due to receive further doses (i.e. a dose on the 
following day), whether that treatment arm can receive further doses 
as per the dosing schedule 
o if the individual(s) is/are part of the sentinel group, the impact on 
the successive participants of that treatment arm – i.e. whether the 
remaining subjects can be dosed or not. 
3) b) (if the participant remains blinded) the impact on all remaining 
participants in the study, e.g. in the following circumstances: 
o if participants are due to receive further doses (i.e. a dose on the 
following day), whether the remaining participants can receive 
further doses as per the dosing schedule 
o if the individual(s) is/are part of the sentinel group, the impact on all 
successive participants – i.e. whether the remaining cohort can 
proceed or not. 
4) the impact on continuation or suspension of the overall study. 
The individual (decision 2), within-cohort (decision 3) and the trial progression 
(decision 4) rules are shown in Table 9 and Table 10 below. 


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Table 9: Individual rules (decision 1) 
Adverse Events Related to Trial Drug 
Actiona 
Moderate (Table 14) except QT interval 
prolongation, haematology, and liver 
function, for which rules are specified 
below) 
Trial drug administration may be continued, 
delayed, temporarily suspended or discontinued in 
accordance with Investigator’s clinical judgment  
 
Moderate LFT increases: ALT or AST value 
>3 x and <5 x ULN  
QT interval prolongation: 
A prolongation of the uncorrected QT 
interval of greater than 500 ms, using 
consistent, technically valid triplicate ECG 
Trial drug administration will be discontinued. 
Haematology: 
a) Hb drop of >25 % from baseline 
on Day-1 (only for values below 
the laboratory reference range), 
or to an absolute value of 
<100 g/L 
b) Platelet count drop of > 25% from 
baseline on Day-1 (only for values 
outside the laboratory reference 
range), or absolute value of <80 x 
109/L 
c) Clinically significant neutrophil 
dropb 
Severe (Table 14) except liver function, 
for which rules are specified below. 
ALT or AST value >3 x and <5 × ULN, 
and symptomatic or ALT or AST value >5 
× ULN +/- symptoms b  
Serious (fatal or life-threatening) 
Serious LFT increase: ALT or AST value 
>3 × ULN together with bilirubin >1.5 x 
ULN, without other evidence of cholestasis 
aActions are only relevant for dosing regimens where additional doses are planned for administration. 
bSymptoms include fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash 
and/or eosinophilia (eosinophil percent or count above the ULN). Abbreviations: ALT: alanine 
aminotransferase; AST: aspartate aminotransferase; ECG: Electrocardiogram; Hb: Haemoglobin; 
ms: milliseconds; QT: QT interval; ULN: upper limit of normal. 
*Investigator judgement will be used to determine which of the pre-dose measurements are 
considered the baseline Where possible, the baseline value should be the one that was taken at the 
closest time of day to the samples being assessed for change, to account for diurnal variation (for 
example, the D-1 morning blood samples) 
 
 


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Table 10: Cohort and trial rules (decisions 3 and 4) 
Adverse Events Related 
to Trial Drug 
Reversibility 
Number of 
Participants 
Actiona 
Moderate LFT increases:  
ALT or AST value >3 x ULN 
and <5 x ULN 
 
ALT/AST 
improves to 
<3 x ULN in all 
participants 
≥50 % of 
sentinel group  
≥50 % of a 
treatment arm 
(if unblinded) 
≤5 participants 
of the remaining 
main cohort 
after sentinel 
dosing 
Trial drug administration 
may continue 
Moderate LFT increases:  
ALT or AST value >3 x ULN 
and <5 x ULN 
ALT/AST does 
not improve to 
<3 x ULN in all 
participants 
≥50 % of 
sentinel group 
≥50 % of a 
treatment arm 
(if unblinded) 
≤5 participants 
of the remaining 
main cohort 
after sentinel 
dosing 
Further dosing of the 
remaining participants of 
the relevant treatment arm 
(if unblinded) or trial (if 
blinded) will be suspended. 
Re-commencement of 
dosing requires regulatory 
approval via a substantial 
amendmentaFurther dosing 
of the remaining 
participants of the relevant 
treatment arm (if 
unblinded) or trial (if 
blinded) will be suspended. 
Re-commencement of 
dosing requires regulatory 
approval via a substantial 
amendmenta 
 
QT interval prolongation:  
A prolongation of the 
uncorrected QT interval of 
greater than 500 msec, 
using consistent, 
technically valid triplicate 
ECG 
N/A 
≥2 
Haematology: 
a) Hb drop of >25 % from 
baseline on Day -1 (only 
for values below the 
laboratory reference 
range), or to an absolute 
value of <100 g/L 
b) Platelet count drop of 
>25 % from baseline on 
Day -1 (only for values 
below the laboratory 
reference range), or 
absolute value of 
<80 x 109/L 
Clinically significant 
neutrophil dropb 
 
 
 
 
 
≥2 
Severe Adverse Reaction 
(Table 14) 
 
≥2 


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Adverse Events Related 
to Trial Drug 
Reversibility 
Number of 
Participants 
Actiona 
Severe LFT increase: ALT 
or AST value >3 × ULN 
and symptomatic/ ALT or 
AST value >5 × ULN +/- 
symptomsb 
 
 
≥2 
Serious Adverse Reaction 
(fatal or life-threatening) 
 
 
≥1 
Serious LFT increase: ALT 
or AST value >3 × ULN, 
together with Bilirubin 
>1.5 ULN without other 
evidence of cholestasis 
 
≥1 
aA substantial amendment may include an amendment to the protocol, the ICF, or other trial related 
documents as appropriate.  
bSymptoms include fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash 
and/or eosinophilia (eosinophil percent or count above the ULN).  
Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit 
of normal; QT: QT interval; ms: milliseconds; ECG: electrocardiogram; Hb: haemoglobin; SOC:  
System Organ Class; WCC: white cell count. 
The investigators judgement will be used to determine which of the pre-dose measurements are 
considered the baseline Where possible, the baseline value should be the one that was taken at the 
closest time of day to the samples being assessed for change, to account for diurnal variation (for 
example, the D-1 morning blood samples). 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
5.1 
Number and Source of participants 
Forty (40) participants will be recruited to this trial and will be randomised to one 
of the four treatment arms in a 2:1:1:1 ratio as described below: 
• 
Treatment 1 (N=16):  PYR + PQP  
• 
Treatment 2 (N=8):    PYR + placebo for PQP 
• 
Treatment 3 (N=8):    placebo for PYR + PQP  
• 
Treatment 4 (N=8):    placebo for PYR + placebo for PQP. 
Participants enrolled in this trial will be members of the community at large. The 
recruitment advertisements may use various media types (e.g. radio, newspaper, 
the clinical site website and participant database). 
 
5.2 
Replacement participants 
Additional participants may be recruited to replace any discontinued participants, 
in order to ensure that 40 participants complete the trial. This will require 
agreement with the trial sponsor. 
 
5.3 
Inclusion Criteria  
Participants must meet all of the following criteria to be eligible for enrolment in 
this trial: 
1. Black male or female, of Sub-Saharan African origin (defined as participants 
whose parents are both black and are of Sub-Saharan African origin) aged ≥18 
years to ≤45 years at the date of signing informed consent. This inclusion 
criterion will only be assessed at the screening visit 
2. Healthy as defined by: 
• 
the absence of clinically significant illness and surgery within four weeks 
prior to dosing. Participants vomiting within 24 hours pre-dose will be 
carefully evaluated for upcoming illness/disease. Inclusion pre-dosing is 
at the discretion of the Investigator 
• 
the absence of clinically significant history of neurological, endocrine, 
cardiovascular, respiratory, haematological, immunological, psychiatric, 
gastrointestinal, renal, hepatic and metabolic disease 
3. Participants must agree to use the following contraceptive requirements for the 
applicable duration:  
• 
Female participants of non-childbearing potential (WNCBP): 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)  
CONTRACEPTION REQUIRED: None 
• 
Female participants of childbearing potential (WOCBP) who anticipate 
being sexually active with a male during the trial (from one complete 


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menstrual cycle prior to the first IMP administration until 110 days (slightly 
less than 16 weeks) after the last IMP administration):  
CONTRACEPTION REQUIRED: Highly effective contraception must start 
one complete menstrual cycle prior to the first day of dosing and continue 
until 110 days (slightly less than 16 weeks) after the last IMP 
administration. Highly effective contraception methods for WOCBP 
include:  
• combined (i.e. oestrogen- and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation: 
▪ 
oral  
▪ 
intravaginal 
▪ 
transdermal 
• progestogen-only hormonal contraception associated with inhibition 
of ovulation: 
▪ 
oral  
▪ 
injectable  
▪ 
implantable 
o intrauterine hormone-releasing system (IUS) 
o intrauterine device (IUD)  
o bilateral tubal occlusion 
o infertile male partner (e.g. vasectomised, permanently sterile 
following bilateral orchidectomy, or any other documented cause of 
infertility) 
• 
Female participants of childbearing potential (WOCBP) who agree to 
remain abstinent for the duration of the trial (from one complete 
menstrual cycle prior to the first IMP administration until 110 days (slightly 
less than 16 weeks) after the last IMP administration): 
CONTRACEPTION 
REQUIRED: 
Abstinence 
(sexual 
abstinence 
is 
considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with 
the trial treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the participant. Calendar, symptothermal and post-
ovulation methods of contraception are not considered to be equivalent 
to abstinence) 
• 
Male participants, who agree to remain abstinent for the duration of the 
trial (from first IMP administration until 110 days (slightly less than 16 
weeks) after the last IMP administration): 
CONTRACEPTION 
REQUIRED: 
Abstinence 
(sexual 
abstinence 
is 
considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with 
the trial treatments. The reliability of sexual abstinence needs to be 


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evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the participant)  
If the situation changes post-dose during the trial, participants must use 
a condom with or without spermicide. 
• 
Male participants, who anticipate being sexually active during the trial 
period (from first IMP administration until 110 days (slightly less than 16 
weeks) after the last IMP administration) with a woman who is either a 
WOCBP, a woman who is pregnant and/or breast feeding:  
CONTRACEPTION REQUIRED: From the first day of dosing until the end 
of the systemic exposure of the trial drug. Acceptable methods are: 
o male condom with or without spermicide  
o infertile male (e.g. vasectomised, permanently sterile following 
bilateral orchidectomy, or any other documented cause of infertility) 
4. Participants must agree not to donate sperm or ova from the time of the first 
administration of trial medication until three months after the end of the 
systemic exposure of the trial drug 
5. Participants must have a body weight of 50 kg or greater and a BMI between 
18.0 kg/m² - 28.0 kg/m² (inclusive) at screening  
6. Satisfactory medical assessment with no clinically significant or relevant 
abnormalities as determined by medical history, physical examination, vital 
signs, 12-lead ECG and clinical laboratory evaluation (haematology, 
biochemistry, coagulation, and urinalysis) that is reasonably likely to interfere 
with the participant's participation in or ability to complete the trial as assessed 
by the Investigator 
7. Ability to provide written, personally signed, and dated informed consent to 
participate in the trial, in accordance with the ICH Good Clinical Practice (GCP) 
Guideline E6 (R2) (2016) and applicable regulations, before completing any 
trial-related procedures 
8. An understanding, ability, and willingness to fully comply with trial procedures 
and restrictions. 
 
5.4 
Exclusion Criteria 
Participants will be excluded from enrolment in this trial if they meet any of the 
following criteria:  
1. 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 PYR or PQP or 
could affect clinical assessments or clinical laboratory evaluations 
2. Any history of seizures or epilepsy 
3. Any history of photosensitivity 
4. Any documented retinopathy 
5. History of malaria in the previous two years 


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6. A score of 20 or more on the Beck Depression Inventory, and/or a response 
of 1, 2 or 3 for item 9 of this inventory (related to suicidal ideation) [26]. 
7. 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 
8. 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 
9. 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 
10. 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 >220 msecs (PQ) interval prolongation 
• 
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 
(males and females) 
• 
any other ECG abnormalities in the standard 12-lead ECG and 24-hour 12 
lead Holter ECG or an equivalent assessment which in the opinion of the 
Investigator will interfere with the ECG analysis 
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. 
11.Has vital signs consistently outside of normal range at screening or Day -1. 
Acceptable normal range is as follows:  
• 
supine HR 40 - 100 bpm (after at least five minutes of supine rest) 
• 
supine blood pressure (after at least five minutes of supine rest):  
o systolic blood pressure: 90 - 140 mmHg  
o diastolic blood pressure: 40 - 90 mmHg 
12.Has a positive test for Hepatitis B surface Antigen (HBsAg), Hepatitis C 
Antibody (HCV Ab), or Human Immunodeficiency Virus Antibody (HIV Ab) at 
screening 


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13.Has total bilirubin, ALT or AST consistently >ULN at screening (up to  
two repeats may be taken during the screening period; participant may be 
included if two out of the three total results are ≤ULN), or has total bilirubin, 
ALT or AST>ULN on Day -1 (mild variations from baseline may be allowed if 
considered not clinically significant by the Investigator) 
14.Has a haemoglobin, platelet count, total white blood cell count, lymphocyte or 
monocyte count less than 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 
15.Any other abnormal findings on vital signs, ECG, physical examination or 
laboratory evaluation of blood and urine samples that the Investigator judges 
as likely to interfere with the trial or pose an additional risk in participating 
16.Positive test results for alcohol or drugs of abuse at screening or Day -1 
17.Female participants who are pregnant (including a positive serum pregnancy 
test at screening or on Day -1) or breastfeeding 
18.Male participants with a female partner(s) who is (are) pregnant or lactating 
at screening or on Day -1, or is (are) expected to be during the trial period 
19.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), using the following National 
Health Service (NHS) alcohol tracker https://www.nhs.uk/oneyou/for-your-
body/drink-less/know-your-alcohol-units/ 
20.Treatment with an investigational drug within 90 days or five half-lives 
preceding the first dose of trial medication (whichever is the longer) 
21.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) within 
six months prior to the planned first day of dosing 
22.Has 
used 
any 
medication 
(see 
list 
for 
reference: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-
and-drug-interactions-table-substrates-inhibitors-and-inducers#transporter) 
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 first day 
of dosing 
23.Additionally, participants must have not consumed other substances known 
to be potent inhibitors or inducers of CYP3A4 system such as grapefruit or 
cranberry juice-containing products in the 30 days before the planned first 
IMP administration 
24.Has 
used 
any 
other 
prescription 
medication 
(excluding 
hormonal 
contraception and hormone replacement therapy) within 14 days or five half-
lives (whichever is longer) prior to Day 1 of the dosing period that the 
Investigator judges is likely to interfere with the trial or pose an additional 
risk in participating 


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25.Has used any over-the-counter medication (including multivitamin, herbal, or 
homeopathic preparations;) during the seven days or five half-lives of the 
medication (whichever is longer) prior to Day 1 of the dosing period, that the 
Investigator judges is likely to interfere with the trial or pose an additional 
risk in participating 
26.Consumption of any herbal remedies or dietary supplements containing a 
herbal remedy in the 30 days before the planned Day 1 of the dosing period 
27.Ingestion of any poppy seeds within the 24 hours prior to screening and 
admission 
28.Known or suspected intolerance or hypersensitivity to the investigational 
products, any closely related compound, or any of the stated ingredients 
29.History of significant allergic reaction (e.g. anaphylaxis, angioedema, but 
excluding untreated, asymptomatic, seasonal allergies) to any product (food, 
pharmaceutical, etc) 
30.Donation of blood or blood products (excluding plasma) within 90 days prior 
to trial medication administration 
31.Has a mental incapacity or language barriers precluding adequate 
understanding, co-operation, or compliance with the trial requirements 
32.An inability to follow a standardised diet and meal schedule or inability to fast, 
as required during the trial 
33.Inability to swallow up to eight tablets in short succession 
34.Participants with 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) 
35.Prior screen failure (where the cause of the screen failure is not deemed to be 
temporary), randomisation, participation, or enrolment in this trial. 
Participants who initially failed due to temporary non-medically significant 
issues are eligible for re-screening once the cause has resolved 
36.Participants who have received or are planning on receiving a COVID-19 
vaccination four weeks before first dose administration, or within one week 
after trial completion 
37.Any conditions which in the opinion of the Investigator would make the 
participant unsuitable for enrolment or could interfere with the participants’ 
participation in or completion of the trial. 
 
5.5 
Participant restrictions  
Participants will have to comply with the restrictions described in Table 11. 
Participants must also comply with the latest COVID-19 safety measures/ testing 
applicable at the site at that time, for entry into the unit and during in-house stays. 
 
 


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Table 11: 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).  
From six months prior to the 
planned first day of dosing. 
After trial completion/last 
visit. 
Meals/snacks/water. 
 
Whenever participants are 
confined in the ward, only the 
drinks and meals provided by 
the trial personnel will be 
allowed. 
Standard meals will be 
provided at the standard unit 
times as stated in the trial 
plan, and meals should be 
completed each time. 
On each dosing day, 
participants will be required to 
fast from all food and drink 
except water a minimum of 
three hours before and four 
hours after dosing. 
Water will be provided until 
one hour pre-dose and from 
one hour post-dose. 
Standard meals will be given 
at regular intervals 
throughout the in-house stay. 
 
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. 
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 
 


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Items participants must 
not consume or do 
When participants must 
stop 
When participants can re-
start 
ten minutes prior to ECG 
measurement. 
Any prescription medication. 
For details, including 
exceptions see Section 5.4 
Exclusion Criteria 21 and 23, 
and Section 6.3 Concomitant 
Medications. 
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. For details, 
including exceptions, see 
Section 5.4 Exclusion 
Criterion 24. 
Seven days or five half-lives 
(whichever is longer) before 
the planned first trial drug 
administration. 
Any herbal remedy or dietary 
supplement containing a 
herbal remedy. 
30 days before the planned 
first trial drug administration. 
After trial completion/last 
visit. 
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.  
Blood and plasma donation. 
90 days before the planned 
first trial drug administration. 
Three months after trial 
completion/last visit. 
Excessive UV radiation 
exposure. Participants should 
use sun protective measures 
and limit exposure to natural 
sunlight (including 
occupational exposure to the 
sun or sunbathing) and avoid 
artificial sunlight (tanning 
beds or phototherapy). 
Ideally, outdoor activities 
should be scheduled outside 
the hours that ultraviolet 
radiation is most intense or 
should be performed in the 
shade. Participants should be 
advised to use sun protective 
measures (such as a hat, 
sunglasses, protective 
clothing, and sunscreen SPF 
≥30). 
Excessive sun exposure 
should be avoided from 
Admission (Day -1). 
Participants can resume usual 
sun exposure 110 days 
(slightly less than 16 weeks) 
after the last dose of the IMP. 


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Items participants must 
not consume or do 
When participants must 
stop 
When participants can re-
start 
Contraception: Participants 
must follow the contraceptive 
requirements as stated in 
Section 5.3. 
Start times for contraceptives 
vary according to method 
used - see applicable 
contraceptive method in 
Section 5.3. 
110 days (slightly less than 16 
weeks) after the last dose of 
IMP.  
COVID-19 vaccination. 
Four weeks before the 
planned first trial drug 
administration. 
Seven days after trial 
completion/last visit. 
 
5.6 
Criteria for withdrawal  
The Investigator or designee may withdraw a participant from the trial if the 
participant: 
• 
is in violation of the protocol, which may jeopardise the trial results or 
represent a risk to the participant 
• 
has an AE warranting withdrawal 
• 
becomes pregnant 
• 
meets individual rules criteria 
• 
use of/need for a prohibited medication which in the opinion of the 
Sponsor or Investigator may jeopardise the trial results or represent a risk 
to the participant 
• 
requests to be withdrawn from the trial (participant withdrawal of consent) 
• 
is found to be considerably non-compliant with the protocol-required 
dosing visits 
• 
in the Investigator’s opinion, is unable to continue trial participation 
• 
is withdrawn from the trial upon the request of Sponsor or the SRC, 
including if the Sponsor terminates the trial. 
 
5.6.1 
Handling of withdrawals 
If a participant withdraws or is withdrawn from the trial, the Investigator will 
inform the Sponsor immediately. If there is a medical reason for withdrawal, the 
participant will remain under the supervision of the Investigator for protocol-
specified safety follow up procedures.  
Should any of the participants be withdrawn from the trial (by the Investigator 
and/or Sponsor) after being dosed, all the relevant assessments in relation to last 
dose should be completed as per protocol. 
Should a participant withdraw themselves from the trial, every effort should be 
made to conduct a complete Early Termination (ET) visit at an appropriate time-
point. The procedures required for the ‘last visit’ should be performed at this visit.  
A participant who fails to return for final evaluations will be contacted by the site 
in an attempt to have the participant comply with the protocol, in accordance with 
the site SOPs.  


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When a participant withdraws from the trial, the primary reason for discontinuation 
must be recorded in the appropriate section of the Case Report Form (CRF). 
 
6. 
TRIAL AND CONCOMITANT TREATMENTS  
The trial treatments and concomitant therapies are categorised as described below 
and are shown in Figure 3 below. 
An ‘Investigational Medicinal Product (IMP)’ is defined as a pharmaceutical 
form of an active substance or placebo being tested or used as a reference in a 
clinical trial, including products already with a marketing authorisation but used or 
assembled (formulated or packaged) in a way different from the authorised form, 
or when used for an unauthorised indication, or when used to gain further 
information about the authorised form. 
• 
The term ‘test IMP’ is used to indicate only the experimental product 
under trial or development. Note: This term is more specific than ‘IMP’ 
which includes comparators and placebos.  
• 
The term ‘reference IMP’ is used to indicate any medicinal product 
being used as a comparator or reference substance (including placebo). 
Note: This term is more specific than ‘IMP’ which includes the 
experimental product and placebos. 
• 
The ‘non-IMP (NIMP)’ is defined as any medicinal product(s) intended 
for research and development trials, which does not fall within the 
definition of an IMP. NIMPs include: 
o 
the rescue medication (for ineffective treatment, anticipated ARs, or 
anticipated emergency situations): e.g. analgesic rescue medication 
or laxative in opioid studies, naltrexone 
o 
challenge agents, e.g. skin prick tests 
o 
medicinal products used to assess end-points in the clinical trial, e.g. 
any diagnostic agents used to assess the disease under trial 
o 
concomitant medicinal products systematically prescribed to the trial 
participants, e.g. cancer treatment in an opioid trial with cancer 
patients who all get the same cancer treatment according to the 
protocol 
o 
background treatment, standard care that all patients receive in 
addition to the IMP and for the same indication, e.g. standard 
chemotherapy in addition to a new oncological product to be tested. 
 


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Figure 3: Trial treatments and concomitant therapies 
 
 
Abbreviations: IMP: Investigational medicinal product; PQP: piperaquine; PYR: pyronaridine. 
 
6.1 
Investigational Medicinal Products (IMPs)  
The following IMPs will be used in this trial: 
• 
piperaquine tetraphosphate – the test IMP 
• 
pyronaridine tetraphosphate – the test IMP 
• 
piperaquine matched placebo – the reference IMP 
• 
pyronaridine matched placebo – the reference IMP. 
The following IMP strengths will be used in this trial: 
• 
PYR – 180 mg tablets 
• 
PQP – 320 mg tablets 
• 
PQP matched placebo tablets 
• 
PYR matched placebo tablets. 
Bulk IMPs will be supplied and QP certified by MMV or their contractor. Prior to 
being used on the clinical trial, the IMPs will be prepared by Richmond 
Pharmacology’s clinical trials pharmacy. The prepared individual participant doses 
will be QP certified and dispensed by the site’s pharmacy staff. 
PQP is uncoated and bitter to taste, the effect may be persistent for some time 
after administration.  This effect cannot be masked and may provide an indication 
of the treatment received.  As the key safety and tolerability endpoints are 
objective assessments and parameters, it is anticipated that there will be no 
impact on the primary trial objective to determine the safety and tolerability of the 
registered doses of IMP.    
 


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6.1.1 
Packaging and labelling of IMPs  
The labelling of the trial drugs will be in compliance with Good Manufacturing 
Practice (GMP) specifications, as described in The Rules Governing Medicinal 
Products in the European Union, Volume 4, Annex 13, Investigational Medicinal 
Products, and any other or local applicable regulations. 
Sample label(s) will be submitted to the UK health authorities according to the 
submission requirements. 
 
6.1.2 
Drug administration 
PYR, PQP and matched placebos will be administered orally as detailed in Table 12. 
Doses of IMP will depend on the participant’s body weight. The weight taken on 
Day -1 should be compared to the weight taken at screening to ensure there is no 
more than 5 % variation. More details will be provided in the SOM. 
 
 
 


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Table 12: IMP or placebo for each anticipated dose level 
Treatment 
group 
Weight 
(kg) 
Treatment: 
IMP/Placebo Dispensed: 
Administration 
1 
 
50 - 
<65 
*PYR 540 mg +  
PQP 960 mg 
Three PYR tablets of 180 mg 
+ three PQP tablets of 320 mg 
Participants will fast 
from all food and 
drink (except for 
water) for a minimum 
of three hours prior to 
dosing.  
Participants may 
drink water until 
one hour prior to 
dosing, and from one 
hour after dosing. 
IMPs will be 
administered to each 
participant with 
approximately 
240 mL of water. 
65 - 
<75 
*PYR 720 mg +  
PQP 960 mg 
Four PYR tablets of 180 mg + 
three PQP tablets of 320 mg 
≥75 
*PYR 720 mg +  
PQP 1280 mg 
Four PYR tablets of 180 mg + 
four PQP tablets of 320 mg 
2 
50 - 
<65 
*PYR 540 mg + 
placebo for PQP 
Three PYR tablets of 180 mg 
+ three placebo PQP tablets 
65 - 
<75 
*PYR 720 mg + 
placebo for PQP   
Four PYR tablets of 180 mg + 
three placebo PQP tablets 
≥75 
PYR 720 mg + 
placebo for PQP  
Four PYR tablets of 180 mg + 
four placebo PQP tablets 
3 
50 - 
<65 
*placebo for PYR 
+ PQP 960 mg 
Three placebo PYR tablets +  
three PQP tablets of 320 mg 
65 - 
<75 
placebo for PYR 
+ PQP 960 mg 
Four placebo PYR tablets +   
three PQP tablets of 320 mg 
≥75 
*placebo for PYR 
+ PQP 1280 mg 
Four placebo PYR tablets +   
four PQP tablets of 320 mg 
4 
50 - 
<65 
placebo for PYR 
+ placebo for 
PQP 
Three placebo PYR tablets +   
three placebo PQP tablets 
65 - 
<75 
placebo for PYR 
+ placebo for 
PQP 
Four placebo PYR tablets +   
three placebo PQP tablets 
≥75 
placebo for PYR 
+ placebo for 
PQP 
Four placebo PYR tablets +   
four placebo PQP tablets 
Abbreviations: IMP: investigational medicinal product; mL: millilitres; PQP: piperaquine; PYR: 
pyronaridine. 
*Efforts will be made to recruit participants in order to stratify randomisation according to weight, 
so that a minimum of two participants receive each of the seven treatment options, i.e. ≥ two 
participants will be administered with each of the following treatment options: 
• 
PYR 540 mg + PQP 960 mg 
• 
PYR 720 mg + PQP 960 mg 
• 
PYR 720 mg + PQP 1280 mg 
• 
PYR 540 mg + placebo for PQP 
• 
PYR 720 mg + placebo for PQP 
• 
placebo for PYR + PQP 960 mg 
• 
placebo for PYR + PQP 1280 mg. 
 
An RP will verify doses of PYR, PQP or matched placebo(s) and the details of dosing 
will be recorded in the CRF. The dosing will be verified by another member of the 
Investigator’s staff. Detailed instructions for dose administration will be included 
in the SOM. 


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In the event that a participant vomits following IMP administration on a particular 
dosing day, that participant will not be re-dosed on that same day, however they 
will receive IMP on the subsequent days as planned (as per Table 5: Schedule of 
Assessments). The exact time of vomiting will be documented in the source 
document and eCRF for PK analysis purposes (i.e. to refine sub-populations 
depending on the time of vomiting). 
 
6.1.3 
Storage of IMPs 
PYR, PQP and matched placebos will be stored in accordance with the labelling 
instructions as defined in the IMPD. The IMPs will be stored securely in a 
temperature-controlled pharmacy with authorised access only. 
 
6.1.4 
Drug accountability  
The designated pharmacy staff at the clinical trial site will maintain accurate 
records of the receipt and the condition of all trial IMP including dates of receipt. 
In addition, accurate records will be kept by the pharmacy staff of when and how 
much trial IMP is dispensed and used by each participant in the trial. Any reason 
for departure from the protocol dispensing regimen must also be recorded.  
IMP accountability records and inventory will be available for verification by the 
Sponsor or designee. At the completion of the trial, there will be a final 
reconciliation of all trial IMPs. 
A trial IMP must not be used for any purpose other than the present trial. The 
destruction of remaining trial IMP will be arranged by the clinical trial site according 
to applicable regulations and only after receipt of written authorisation from the 
Sponsor. 
 
6.2 
Treatment allocation and blinding  
6.2.1 
Participant randomisation  
All participants in this trial will be assigned to a treatment regimen according to a 
randomisation schedule generated by a statistician using PROC Plan. Details 
regarding the unique screening and participant number will be included in the SOM. 
Eligible participants will be randomly assigned in a 2:1:1:1 ratio to one of four 
treatment arms on Day 1, at the point of dosing. Treatment arms are outlined 
below: 
• 
Treatment 1 (N=16):  PYR + PQP 
• 
Treatment 2 (N=8)  :  PYR + placebo for PQP 
• 
Treatment 3 (N=8)  :  placebo for PYR + PQP 
• 
Treatment 4 (N=8)  :  placebo for PYR + placebo for PQP. 
Sentinel dosing (N=10) will occur: four participants for treatment arm 1, and two 
participants from each of treatment arms 2, 3 and 4, will be dosed before the 
remaining participants of each treatment arm are dosed together (see Section 
3.4.4). 
 


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6.2.2 
Methods for ensuring blinding 
The trial will take place in a double-blind fashion whereby participants and clinical 
trial site staff are blinded to the active or placebo trial drug assignment. 
PQP is uncoated and bitter to taste, the effect may be persistent for some time 
after administration. This effect can not be masked and may provide an indication 
of the treatment received. As the key safety and tolerability endpoints are 
objective assessments and parameters, it is anticipated that there will be no 
impact on the primary trial objective to determine the safety and tolerability of the 
registered doses of IMP.    
The pharmacy staff preparing the investigational products will not be blinded to 
trial drug assignment. During the trial, the individual randomisation codes will be 
kept in the site's clinical trials pharmacy, accessible to the pharmacy personnel 
only. Upon completion of the trial, after the database lock and after the blind is 
revealed, the randomisation list will be filed in the Trial Master File (TMF). 
Sponsor staff involved in clinical decision-making (such as those involved in SRC 
decisions) will be blinded to trial drug assignment (see AR rules section above). 
 
6.2.3 
Methods for unblinding the trial 
In the event of an emergency, an envelope for each participant containing his/her 
trial drug assignment will be available in the pharmacy at the clinical trial site. 
Unblinding should only be considered for the safety of the participant. If unblinding 
is deemed necessary by the Investigator, the Investigator or designee can unblind 
the participant’s treatment allocation using the envelope available from the 
pharmacy. The Investigator or designee must note the date, time and reason for 
unblinding and inform the sponsor of unblinding as soon as practicably possible. 
If there is an unblinding, the randomisation schedule should be revised and this 
should be communicated to the RPL pharmacy team. Unblinding if required will be 
done in accordance with RPL SOP. SRC can decided whether to unblind a 
participant in either an emergency or non-emergency fashion.  
 
 
6.3 
Concomitant medications/permitted medications  
The use of hormonal contraception and hormone replacement therapy is 
permitted. During the trial, other prescription or over-the-counter medications 
may be permitted at the discretion of the Investigator. The need for other 
medication may lead to participant’s withdrawal from the trial. In any case, the 
Investigator will inform the sponsor about the concurrent medication given. 
Ibuprofen/NSAIDS should be used for rescue pain relief only, at the discretion of 
the PI. The dose and reason for ibuprofen/NSAID use in AEs other than as rescue 
medication must be recorded in the CRF and source record.  
Details of all other prior and concomitant medications should be recorded by the 
Investigator on the CRF and source record. 
 


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6.4 
COVID-19 vaccinations 
Given the current COVID-19 pandemic, consideration has been made regarding 
participants who have had the vaccination or may be offered the vaccination during 
trial participation (see Section 5.4). 
To optimise the data collected from this trial, the following rules will apply. 
Participants may not be considered for participation if they: 
• 
have received a COVID-19 vaccination within the four weeks prior to Day 1 
of the trial 
• 
plan to receive a vaccination from one week after trial completion/last 
visit. 
 
7. 
TRIAL METHODOLOGY 
7.1 
Medical history 
All clinically significant medical history (including any significant surgical 
procedures) must be recorded on the CRF for each participant. Each participant’s 
full medical history will be obtained through direct questioning and the medical 
assessment at screening and will be updated at the day of admission (Day -1). If 
any clinically relevant observations or investigation results are detected prior to 
dosing, they will be recorded as medical history. 
 
7.2 
Eligibility check 
The RP will perform a trial eligibility check for all trial participants during the 
screening period and on Day -1, as described in the Schedule of Assessments 
(Table 5 and Table 6). Further details will be provided in the SOM. 
 
7.3 
Prior and concomitant medication check 
Each participant will have a prior and concomitant medication check as described 
in the Schedule of Assessments (Table 5 and Table 6) and in Section 0. 
 
7.4 
Beck depression inventory 
Each participant will undergo a Beck Depression Inventory questionnaire [26], as 
described in the Schedule of Assessments (Table 5 and Table 6). A participant will 
be excluded from the trial if they have a score of 20 or more on the Beck 
Depression Inventory, and/or a response of 1, 2 or 3 for item 9 of this inventory 
(related to suicidal ideation) [26]. 
 
7.5 
Meals 
Standardised meals will be provided during the trial period according to the timings 
described in the Schedule of Assessments (Table 5 and Table 6). 
On dosing days, participants will fast of all food and drink (except water) for at 
least three hours prior to IMP administration and for at least four hours post-dose. 


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Participants can drink water until one hour pre-dose and from one hour post-dose. 
Meals on the discharge day are optional. 
 
 
7.6 
Clinical laboratory assessments 
Laboratory parameters to be measured are presented in Table 13. 
 
Table 13: Laboratory parameters 
Haematology 
Biochemistry 
Urinalysis 
• 
Platelets  
• 
Hb 
• 
Haematocrit 
• 
White blood cells 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Red blood cells 
• 
Mean cell haemoglobin (MCH) 
• 
Mean corpuscular haemoglobin 
concentration (MCHC) 
• 
Mean corpuscular volume 
(MCV) 
• 
HbA1c*** 
• 
Aspartate aminotransferase 
(AST) 
• 
Alanine aminotransferase 
(ALT) 
• 
Alkaline phosphatase (ALP) 
• 
BUN 
• 
Gamma GT 
• 
Total bilirubin 
• 
Direct bilirubin 
• 
Indirect bilirubin 
• 
Creatinine 
• 
Urea 
• 
Total Serum Proteins 
• 
Albumin 
• 
Alpha1 Glycoprotein# 
• 
Sodium 
• 
Potassium 
• 
Calcium 
• 
Corrected calcium 
• 
Magnesium 
• 
Chloride 
• 
Bicarbonate 
• 
Amylase 
• 
Total cholesterol 
• 
Triglycerides 
• 
Serum pregnancy test* 
• 
FSH* 
 
• 
Leukocytes 
• 
Nitrite 
• 
Urobilinogen 
• 
Protein 
• 
pH 
• 
Blood 
• 
Specific gravity 
• 
Ketones 
• 
Bilirubin 
• 
Glucose 
• 
Urine microscopy** 
 
 
 
 
Coagulation 
Urine Screen for Drugs of Abuse 
• 
aPTT 
• 
PT  
• 
Fibrinogen 
• 
INR 
• 
Benzodiazepines 
• 
Opiates 
• 
Amphetamines 
• 
Methamphetamines 
• 
Methadone 
• 
Cocaine 
• 
Cannabinoids 
• 
Barbiturates 
• 
Phencyclidine 
• 
Tricyclic antidepressants 
 
Serology 
• 
Hepatitis B surface Antigen 
(HBsAg) 
• 
Hepatitis B core Antibody (anti-
HBC IgG + IgM, if IgG positive) 
• 
Hepatitis C Antibody (anti-HCV) 
• 
HIV I and II Antibodies 
* Measured at the times presented in the Schedule of Assessments (Table 5 and Table 6). Serum 
pregnancy test for pre-menopausal women only; FSH for post-menopausal women only. ** Only if 
urinalysis is abnormal. *** Measured at screening only. # On admission day only. 
 
 


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7.6.1 Haematology, biochemistry and coagulation 
Blood samples to determine biochemistry, haematology and coagulation 
parameters will be taken at the times given in the Schedule of Assessments (Table 
5 and Table 6). The date and time of collection will be recorded on the appropriate 
CRF pages. Further details will be described in the SOM. 
 
7.6.2 
Serology 
Serology will take place at screening as detailed in the Schedule of Assessments 
(Table 5 and Table 6). At the screening visit all participants will be tested for the 
parameters listed in Table 13. This is for the safety of the trial personnel and the 
result from the tests will not be entered into the trial database. 
If a participant is found to be confirmed positive in any of these tests, they will be 
referred for further examination/treatment and will not be included in the trial, 
with the exception of a participant with a confirmed positive Anti-HBc IgG and 
negative Anti-HBc IgM and negative HBsAg, indicative of natural immunity due to 
a past infection without active chronic or acute infection. 
The serology tests will be analysed in the same blood sample used for 
biochemistry. 
 
7.6.3 
Pregnancy testing  
Serum β-hCG pregnancy tests will be performed for females of child-bearing 
potential, as per the Schedule of Assessments (Table 5 and Table 6); as well as 
any time a pregnancy is suspected. The results of the pregnancy test must be 
known before IMP administration. Participants who are pregnant will not be eligible 
for trial participation. Any woman with a positive pregnancy test will not receive 
any further IMP but will continue to be followed up for safety until the pregnancy 
outcome is known. See Section 8.5 for follow-up instructions.  
 
7.6.4 
Urinalysis 
Urine samples for determination of urinalysis parameters will be taken at the times 
given in the Schedule of Assessments (Table 5 and Table 6). If deemed necessary, 
based on a clinically significant positive test, microscopic examination of urine will 
be performed. 
 
7.6.5 
Drugs of abuse 
Urine will be tested for the drugs of abuse as described in the Schedule of 
Assessments (Table 5 and Table 6). If a participant fails the drug abuse screen, 
they will be excluded from the trial. A repeat drug screen can be performed where 
methodological reasons are believed to have led to a false positive. If participants 
are suspected to be positive due to medication e.g. flu/cold remedies, they may 
undergo a repeat drug screen. 
 


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7.6.6 
FSH assessment 
The postmenopausal status of women will be confirmed by: 
1) a positive medical history of at least one year of amenorrhoea and  
2) an increased blood FSH level (>30 IU/L).  
FSH will be measured in postmenopausal female participants at the time of 
screening (Table 5). 
 
7.7 
Alcohol breath test 
An alcohol breath test will be done using an alcometer as described in the Schedule 
of Assessments (Table 5 and Table 6). If a participant tests positive to the test 
they will be excluded from the trial. 
 
7.8 
Vital Signs (blood pressure, pulse rate, respiratory rate and 
tympanic temperature) 
Vital signs will be measured at the time points as detailed in the Schedule of 
Assessments (Table 5 and Table 6). Blood pressure and pulse rate will be measured 
in supine position after the participant has rested comfortably for at least 
five minutes, using automated blood pressure monitors. Respiratory rate will be 
measured by manual counting for one minute. Temperature will be measured using 
tympanic thermometers. Standing vitals where described in the Schedule of 
Assessments (Table 5 and Table 6) will occur after standing for one minute.   
 
7.9 
Electrocardiographic (ECG) measurements 
7.9.1 
Recording of 12-lead ECGs 
12-lead ECGs will be recorded at the time-points described in the Schedule of 
Assessments (Table 5 and Table 6) using a GE ECG recorder connected via a fixed 
network connection to the MUSE® Cardiology Information System (MUSE®). ECGs 
recorded during screening will be stored electronically on the MUSE® information 
system. Only ECG recorded electronically will be valid ECG for any purpose other 
than safety assessment. ECG printouts may be filed in the participant’s CRF for 
medical safety reviews. 
Each ECG recorder will be set up to the required technical specifications and will 
contain the information required to identify the records. Each ECG recording will 
be clearly identified (with participant ID, visit date, and the actual times of ECG 
recordings).  
12-lead ECG recordings will be made after the participants have been resting in a 
supine position for at least ten minutes. The participants will avoid postural 
changes during the ECG recordings and clinical staff will ensure that participants 
are awake during the ECG recording.  
At each time point, the ECG will be recorded in triplicate, to reduce variance and 
to improve the precision of measurement. The triplicates will be performed at 
approximately one-minute intervals. Each ECG recording (trace) will last ten 
seconds. Repeat ECG will be performed until at least three ten-second ECG records 
per scheduled time-point meet the quality criteria set out in the SOM and the 


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applicable SOP to enable the reading and analysing of at least five complexes per 
derivation. 
 
7.9.2 
Safety review of 12-lead ECGs 
All recorded ECGs will be reviewed by an RP and the review will be documented in 
the CRF. If a participant shows an abnormal ECG, additional safety recordings 
(including the use of 5-lead or 12-lead Holter equipment) may be made and the 
abnormality be followed to resolution if required. 
 
7.9.3 
24-hour Holter ECG 
Holter recording will be performed at screening as described in Table 5. Each 
electronic Holter ECG file will be downloaded onto the GE Gatemed Holter Analysis 
system.  
 
7.9.4 
Real Time ECG Telemetry 
A 12-lead real time ECG will be recorded as described in the Schedule of 
Assessments (Table 5 and Table 6). ECG telemetry will be monitored by the 
investigator or qualified member of clinical staff. The system will be managed 
according to local working practices. The ECG telemetry reports will be archived 
with study documents. 
 
7.9.5 
Analysing and over-reading 12-lead ECG for the purpose of 
intensive cardiac assessments 
Each electronic ECG will contain the ECG data as well as the result of the automated 
ECG analysis performed by the Marquette® 12SL™ ECG Analysis Program, a 
program resident in each of the ECG machines. All of the ECG and its associated 
automated interval measurements will subsequently be reviewed by qualified 
cardiologists in accordance with the ICH E14 Guidance for Industry document and 
ICH E14 Implementation Working Group Questions and Answers document, before 
any of the ECG is used for the thorough ECG analysis. The manual adjudication 
process applied in this trial is also referred to in the ICH guidance and relevant 
literature as ‘manual over-read’, ‘computer-assisted’ or ‘semi-automated’ ECG 
measurements. The following parameters on each ECG will be assessed by a 
cardiologist using the commercially available MUSE® in its latest version. The 
intention is to also measure sub-intervals: 
• 
QT interval and sub intervals 
• 
RR interval 
• 
heart rate (HR) 
• 
PR interval 
• 
presence or absence of U-wave 
• 
quantitative and qualitative ECG variations. 
Manual on-screen over-reading using electronic callipers in MUSE® will be 
performed by a small and select group of cardiologists with extensive experience 


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with manual QT measurement (including on-screen measurement with electronic 
callipers). For all trial ECG the over-reading cardiologists will be blinded to time, 
date, treatment and any data that identify the participant. All ECGs of a given 
participant will be over-read by the same cardiologist (or cardiologists in case 
manual adjustments of the automated measurement are necessary). 
 
7.10 
Physical examination, height, weight and BMI 
The physical examination performed at screening and at the post-trial visit will 
include an assessment of the following: general appearance, skin, eyes, ears, 
nose, neck, lymph nodes, throat, heart, lungs, abdomen, musculoskeletal system 
and extremities. The timings of the physical examinations are described in the 
Schedule of Assessments (Table 5 and Table 6). 
Height will be measured in centimetres and weight in kilograms. Measurements 
should be taken with participants wearing light clothing and without shoes, using 
calibrated scales for all measurements. BMI will be calculated from the height and 
weight. Full details will be described in the SOM. 
 
7.11 
Pharmacokinetic assessments 
7.11.1 PK blood samples 
For the timing of individual samples refer to the Schedule of Assessments (Table 
5 and Table 6). The date and time of collection will be recorded on the appropriate 
CRF. 
Plasma samples to determine PQP (and N-oxidated metabolite of PQP, provided a 
future bioanalytical method is available) and blood samples to determine PYR will 
be analysed by Swiss BioQuant AG using a validated method. Full details of the 
analytical methods used will be described in a separate bioanalytical report. All 
sample handling procedures, including the time of each sample collection, the time 
of placement into frozen storage (at the end of the sample workup), and the date 
of transfer or shipment of the samples to the responsible analyst will be 
documented in detail in the SOM. 
 
7.12 
Volume of blood sampling 
The maximum total blood volume collected from participants that take part in this 
trial will not exceed 470 mL overall. The NHS blood donation policy at the time of 
completion of this protocol (https://www.blood.co.uk/who-can-give-blood/) states 
that women can give 470 mL of blood every 16 weeks. Therefore, the 470 mL 
permitted in this trial is consistent with current clinical practice. 
 
7.13 
CYP (polymorphism) sampling 
Blood samples for CYP polymorphism will be collected from all participants as 
indicated in the Schedule of Assessments (Table 5 and Table 6). The sample 
analysis will be optional and may be performed retrospectively, if decided by the 
Sponsor. 


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8. 
ADVERSE EVENTS 
The collection, evaluation and reporting of AEs/ARs arising from this clinical trial 
will be performed in accordance with: 
• 
detailed guidance on the collection, verification and presentation of AE/AR 
reports arising from clinical trials on medicinal products for human use 
(‘CT-3’) (2011/C 172/01) 
• 
International Conference on Harmonization (ICH) harmonised tripartite 
guideline on clinical safety data management: ‘Definitions and standards 
for expedited reporting’ E2A 
• 
ICH harmonised tripartite guideline on Development Safety Update 
Report: E2F 
• 
ICH guideline E2F ‘Note for guidance on Development Safety Update 
Reports (DSUR)’. 
It is the Investigator’s responsibility to document and report all AEs that occur in 
the clinical trial. The period of observation for collection of AEs extends from the 
signing of the ICF until the final visit. Additionally, spontaneously reported Serious 
Adverse Events (SAEs) will be collected until 30 days after the final trial visit. SAEs 
experienced after this 30-day period will only be reported if the Investigator 
suspects a causal relationship with the trial drug.  
 
8.1 
Definitions 
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 considered related to it or not. 
An AE may be: 
• 
a new symptom or medical condition 
• 
a new diagnosis 
• 
an inter-current illness or an accident 
• 
a worsening of a medical condition/disease(s) that existed 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 or other clinical test parameter 
o the criteria to determine whether an abnormal test result should be 
reported as an AE/AR are as follows. The abnormal test result: 
▪ 
is associated with accompanying symptoms, and/or  
▪ 
requires additional diagnostic testing or medical/surgical 
intervention 
• 
an event that 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 


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• 
considered an Adverse Event by the Investigator or Sponsor. 
An AE does not necessarily include the following: 
• 
an abnormal test that needs repeating, in the absence of any of the above 
conditions. 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/AR. 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 and has not worsened. In the latter case, the 
condition should be reported as medical history. 
A ‘Serious Adverse Event (SAE)’ is defined as any Adverse Event that fulfils any 
of the following criteria: 
• 
it results in death 
• 
it is life-threatening (the term ‘life-threatening’ in the definition of ‘serious’ 
refers to an event in which the participant 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 were 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/ARs are to be considered 
serious, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalisation* but may jeopardise 
the participant 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). 
*’Hospitalisation’ qualifying for an SAEs does not include the following: under 24 
hours; admission unrelated to an Adverse Event e.g. for labour and delivery, 
cosmetic surgery, social or administrative for temporary placement (e.g. admission 
due to lack of transport or support at home); admissions for diagnosis or therapy 
of a pre-existing condition that has not increased in severity or frequency; 
protocol-specified admission; pre-planned admission; admission to a rehabilitation 
or nursing facility; hospice; presentation to emergency departments or other 
urgent care centres; admissions to hospital in-patient facilities for logistical 
reasons only that did not result in any therapeutic intervention (e.g. awaiting 
consultation with and decision by senior medical staff or specialists, or for an 
investigation that is not immediately available); admissions to hospital in-patient 
facilities for investigation alone and where no significant abnormality was identified 
and/or no therapeutic intervention was necessary; same-day outpatient surgery. 
An ‘Adverse Reaction (AR)’ is a response to a medicinal product that is noxious 
and unintended, which occurs at any dose (in pre-approval clinical experience) or 


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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 ‘reaction’ means that a causal relationship between a medicinal product and 
an Adverse Event is at least a reasonable possibility. This means that there are 
facts (evidence) or arguments to suggest a causal relationship. 
A ‘Serious Adverse Reaction (SAR)’ is any AR that fulfils the criteria of 
seriousness, as defined above.  
A ‘Suspected Unexpected Serious Adverse Reaction (SUSAR)’ is a Serious 
AR that is unexpected. The ‘expectedness’ of a serious AR is assessed in the light 
of the Reference Safety Information (RSI). 
 
8.2 
Classification 
8.2.1 
Assessment of severity 
The Investigator will assess the severity of AE/ARs using a categorical grading 
(mild, moderate or severe) with grading of individual AE/ARs based on global 
clinical assessment undertaken by an appropriately delegated Research Physician. 
Changes in the severity of an AE/AR should be documented to allow an assessment 
of the AE/AR duration at each level of severity. AE/AR characterised as intermittent 
require documentation of the start and end of each incidence. 
The table on the following page guides categorical grading of AE/ARs. 
 
 


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Table 14: Categorical grading of AE/ARs 
8.2.2 
Assessment of causality 
AEs will be evaluated for whether they meet the criteria for an adverse reaction 
(AR). An AR is a response to IMP which is noxious and unintended, and which 
occurs at any dose. The term "reaction” means that a causal relationship 
between IMP and an adverse event is at least a reasonable possibility. This 
Grade 
Global clinical assessment & application of grading to a diagnosis 
Mild 
Overall clinical condition is asymptomatic, or symptomatic with all the 
following characteristics: 
• 
no or minimal interference with usual social and/or functional 
activities 
• 
no impact, or minimal impact (e.g. of short duration or a return to 
normal status without intervention), upon usual self-care activities 
• 
deviation from reference range for the population and from the 
participant’s clinically determined physiological baseline has no 
clinical impact and does not signal potential safety concern or 
unanticipated clinical risk 
• 
the condition is reversible to baseline within an anticipated timeframe 
• 
intervention or treatment is either not indicated or indicated only to 
increase participant’s sense of wellbeing and comfort, but not due to 
safety concerns or risk. 
Moderate 
Overall clinical condition is asymptomatic or is symptomatic with no or 
minimal impact on usual self-care activities and one or more of the 
following characteristics: 
• 
greater than minimal interference with usual social & functional 
activities 
• 
deviation from reference range for the population and from the 
participant’s baseline has clinical impact, but there is no acute safety 
concern or unanticipated risk. However, should the condition persist 
and/or occur more frequently, it could signal a potential safety 
concern or unanticipated risk and should therefore be monitored 
• 
reversibility of the condition to baseline condition takes longer than 
desirable or anticipated, impacting on the participant’s wellbeing 
beyond the mere severity of the condition 
• 
further medical assessment, intervention or treatment indicated to 
increase participant’s sense of wellbeing and comfort and to 
accelerate recovery and/or to prevent worsening.  
Severe  
Overall clinical condition is asymptomatic or is symptomatic with one or 
more of the following characteristics: 
• 
significant impact on usual self-care activities 
• 
inability to perform usual social & functional activities  
• 
the deviation from reference range for the population and from the 
participant’s baseline has significant clinical impact, it is an acute 
safety concern or unanticipated risk and requires close and continuous 
monitoring 
• 
the reversibility of the condition to baseline condition takes 
significantly longer than desirable or anticipated, with significant 
impact on the participant’s wellbeing 
• 
intervention or treatment essential to treat the acute manifestations 
and to prevent worsening 
• 
life-threatening or actually leads to death. 


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means that there are facts (evidence) or arguments to suggest a causal 
relationship. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, 
and other risk factors, as well as the temporal relationship of the event 
to IMP administration must be assessed. 
• 
The Investigator will also consult the Investigator’s Brochure (IB)/SmPC 
in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes 
that he/she has reviewed the AE/SAE and has provided an assessment of 
causality. 
• 
There may be situations in which an SAE has occurred and the 
Investigator has minimal information to include in the initial report to 
MMV. However, it is important that the Investigator attempts to make an 
assessment of causality before the initial transmission of the SAE data to 
the sponsor or designee. 
• 
This is due to the fact that the causality assessment is one of the criteria 
used when determining regulatory reporting requirements. 
• 
The Investigator may change his/her opinion of causality in light of 
follow-up information and send an SAE follow-up report with the updated 
causality assessment. 
• 
The Investigator should also comment on the source document whether 
an AE is not related to the study treatment but is related to study 
participation (e.g. study procedures, wash-out periods etc.). AEs where 
a causal relationship between study drug and the AE is at least a 
reasonable possibility, are referred to as ARs. 
 
The causality assessment of an AE to the IMP will be rated as follows by the 
Investigator: 
 
‘Related’: An AE for which it can be reasonably explained that the study drug 
caused the AE by available facts (evidence) or arguments. For example, the 
occurrence of the AE cannot be explained by other causative factors, but can be 
explained by pharmacological effect of the study drug such as: 
• 
temporal relationship to IMP exposure 
• 
event is known to be associated with the IMP drug class  
• 
event improved on discontinuation or dose reduction of IMP 
• 
event reoccurred on re-challenge of IMP 
• 
biological plausibility 
• 
other (must be specified). 
 
‘Not Related’: An AE which cannot be reasonably explained by available facts 
(evidence) or arguments that the study drug caused the AE. For example, the 
occurrence of the AE can be explained by other causative factors, such as: 
• 
event attributed to concomitant medication (provide details of the 
concomitant medication) 
• 
event attributed to the concurrent disease(s)/condition(s) (provide 
details of the disease/condition) 


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• 
event attributed to a non-investigational medicinal product (NIMP) 
(specify the NIMP) 
• 
no reasonably temporal relationship associated with IMP administration 
• 
event is expected in the study indication and/or target population 
• 
negative de-challenge and/or negative re-challenge 
• 
other (must be specified). 
 
The Investigator should also comment on the source document whether an AE is 
not related to the study treatment but is related to study participation (e.g. 
study procedures, wash-out periods etc.). 
 
The relationship to the study medication will be classified according to the 
categories described in Table 14. 
 
8.2.3 
Practical application of severity grading and causality 
assessment in relation to AR rules 
Step 1: Confirm diagnosis of the AE/AR (exact term will be decided using the 
MedDRA), once the root cause of the clinical manifestations has been determined 
(rather 
than 
diagnosing 
individual 
signs, 
symptoms, 
assessments, 
and 
measurements). 
Step 2: Distinguish between serious and non-serious AE/ARs using the standard 
definitions of what constitutes a ‘serious’ AE/AR (see Section 8.1).   
Step 3: Assess whether there is a reasonable possibility of a relationship with the 
IMP.  
Step 4: If there is a reasonable possibility that it is related to the IMP, apply the 
correct AR rules (see Section 4.4): 
• 
‘serious AR’: The classification as ‘serious’ (see Sections 8.1 and 8.2) 
overrides the application of the categorical (mild/moderate/severe) 
grading system. The rules for serious AR must be applied. Categorical 
grading (moderate or severe) should also be independently recorded to 
add additional information. 
• 
‘non-serious AR’:  
o some 
individual 
clinical 
manifestations, 
signs, 
symptoms, 
assessments, or measurements (such as QT prolongation, anaemia, 
thrombocytopenia, liver enzyme abnormalities) have pre-defined 
special AR rules, which should be applied if they occur 
o for all other non-serious ARs use the global clinical assessment and 
categorical grading method outlined above to assign the severity 
grade (Section 8.2). Consider: 
▪ 
the clinical significance (including presence or absence of 
clinical symptoms) 
▪ 
participant populations’ specific references ranges and 
degree of deviations thereof 
▪ 
the degree of deviations from baseline 
▪ 
timing, duration, and reversibility 


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▪ 
the nature and intensity of treatment required and the 
responses to the treatment; in addition, the potential to 
worsen or to become defined as serious 
▪ 
apply the general AR rules according to the assigned 
categorical severity grade. 
 
8.2.4 
Expectedness (reference safety information) 
No serious adverse reactions (SARs) are considered expected by the Sponsor for 
the purpose of expedited reporting of suspected, unexpected serious adverse 
reactions (SUSARs). 
 
 
8.2.5 
Adverse Events of Special Interest (AESI) 
An ‘AESI’ is an Adverse Event of scientific or medical concern that is specific to the 
Sponsor or the particular product or program, for which ongoing monitoring and 
rapid communication by the Investigator to the Sponsor may be appropriate. It 
may require further investigation in order to be characterised and understood. It 
could be serious or non-serious and could include events that might be potential 
precursors or prodromes for more serious medical conditions in susceptible 
individuals. If an AESI is serious, reporting procedures for SAE/SUSAR will be used.  
For non-serious AESI, reporting procedures will be described in the SOM.  
The AESIs for this protocol include, but are not limited to, the following: 
• 
hepatic: 
o Moderate: any ALT or AST >3 x and <5 x ULN  
o Severe: any ALT or AST >3 x and <5 x ULN with symptoms/ ALT or AST 
>5 x ULN with or without symptoms* 
o Serious:  ALT or AST >3 x ULN together with an increase in bilirubin to 
>1.5 x ULN 
• 
cardiac: 
o uncorrected QT interval >500 msecs, using consistent, technically valid 
triplicate ECG 
o second- or third-degree atrioventricular (AV) block 
o bundle branch block 
o any arrhythmia 
• 
haematological: 
o Hb drop of >25 % from baseline on Day -1 (only for values below the 
laboratory reference range), or to an absolute value of <100 g/L 
o platelet count drop of >25 % from baseline on Day -1 (only for values 
outside the laboratory reference range) or absolute value of <80 x 109/L.  
o clinically significant drop from baseline in neutrophil count** 
*symptoms include fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash and/or eosinophilia (eosinophil percent or count above the 
ULN). 
**baseline refers to all samples taken prior to dosing on Day 1 (e.g. at screening, 
on Day -1). 


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8.3 
Recording of adverse events and follow-up 
All (serious and non-serious) Adverse Events detected by the Investigator or 
spontaneously notified by the participant at each visit/examination must be 
reported on the particular section of the CRF. 
The following information should be reported for each Adverse Event, whether it 
can be attributed to trial drug or not: 
• 
description of Adverse Event 
• 
date of onset/date of resolution 
• 
characteristics of the event (seriousness, intensity) 
• 
actions taken (required treatment or dose adjustments must be reported 
in the CRF) 
• 
outcome 
• 
relationship 
with 
trial 
drug 
(causality 
assessment) 
and/or 
trial 
participation. 
All Adverse Events must be documented and followed up until the event is either 
resolved or a satisfactory explanation is found, or the Investigator considers it 
medically justifiable to terminate the follow-up. The reason(s) will be recorded in 
the CRF when the AE follow-up is terminated. 
Symptoms and signs that are being recorded as other methods specified in the 
protocol should not be additionally recorded as AEs, unless it leads to the 
participant’s withdrawal from dosing, or it is one symptom of another diagnosis.  
 
8.4 
Reporting of Serious Adverse Events  
Detailed reporting procedures will be outlined in the pharmacovigilance plan.  
If an SAE occurs, the Investigators will take appropriate action immediately and 
will strive to identify the cause(s) of the events. 


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All SAEs/SUSARs will be notified by the Investigator to the MMV Medical Monitor, 
the MMV Medical Director and to Prime Vigilance within 24 hours of awareness by 
email to: 
Name: Dr Annick Janin MD (MMV Medical Monitor) 
Email: janina-consultants@mmv.org 
Mobile: +33 (0)6 29 54 71 90 
 
Name: Oliver Abschütz (Prime Vigilance) 
Email: oliver.abschuetz@primevigilance.com  
Mobile: +49 (0)1578 3053780 
Head Office: +44 1483 307920 
 
Name: Stephan Chalon (MMV Medical Director) 
Email: chalons@mmv.org 
Mobile: +41 79 962 9244 
 
using the ‘Serious Adverse Event Report Form for Clinical Trials’. The 
pharmacovigilance provider will notify the Sponsor within one working day after 
receipt of the SAE form. 
The SAE follow-up observation period, for the concerned participants, will be jointly 
decided by the Investigator, Sponsor and/or SRC.  
The initial report will be followed up by a full written report within three working 
days or five calendar days, whichever is sooner, unless no further information is 
available. In that case, the follow-up report will be provided as soon as new 
information becomes available. Further follow-up reports will be provided as and 
when new information becomes available. Photocopies of relevant CRF pages, such 
as demography, medical history, concomitant medications, as well as test results, 
consultant report(s), a summary of the outcome of the reaction and the 
Investigator's opinion of IMPs relationship to the SAE/SUSAR will accompany the 
SAE form if and when available.  
The Sponsor will also perform an evaluation of all SAEs.  
SUSARs will be notified to the Competent Authority by MMV and to the relevant 
REC(s) by MMV within seven days (for fatal and life-threatening SUSARs) or 
15 days (all other SUSARs).  
Annual safety reporting to the national Competent Authority and the REC will be 
in agreement with ICH guideline E2F ‘Note for guidance on Development Safety 
Update Reports (DSUR)’. 
 
8.5 
Pregnancy 
Pregnancy in itself is not regarded as an AE, unless there is a suspicion that the 
IMP may have interfered with the effectiveness of a contraceptive medication. 


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However, complications of pregnancy and abnormal outcomes of pregnancy are 
AEs, and many may meet criteria for an SAE. Complications of pregnancy and 
abnormal outcomes of pregnancy, such as ectopic pregnancy, spontaneous 
abortion, intrauterine foetal demise, neonatal death, or congenital anomaly, would 
meet the criteria of an SAE and therefore should be reported as an SAE. Elective 
abortions without complications should not be handled as an AE. 
If a participant becomes or is found to be pregnant while being treated or exposed 
to trial drug, the Investigator must submit the ‘Pregnancy Reporting and 
Outcome/Breast Feeding Form’ to Prime Vigilance and MMV via the same method 
as SAE reporting.  
The participant should be followed until the outcome of the pregnancy is known 
(spontaneous miscarriage, elective termination, normal birth or congenital 
abnormality), When the outcome of the pregnancy becomes known, the form 
should be updated and returned to Prime Vigilance and MMV. If additional follow-
up of the participant is required, the Investigator will be requested to provide the 
information. 
 
8.5.1 
Pregnancy in female partners of male participants 
If a male participant’s female partner becomes or is found to be pregnant while 
the participant was being treated or exposed to trial drug, the Investigator must 
submit the ‘Pregnancy Reporting and Outcome/Breast Feeding Form’ to RPL and 
MMV via the same method as SAE reporting.  
Male participants may continue in the trial if an accidental pregnancy of their 
female partner occurs despite adequate contraception. 
The male participant’s partner should be followed until the outcome of the 
pregnancy is known (spontaneous miscarriage, elective termination, normal birth 
or congenital abnormality), even if the male participant discontinues the trial drug 
or discontinues from the trial. When the outcome of the pregnancy becomes 
known, the form should be updated and returned to RPL and MMV. If additional 
follow-up of the female partner is required, the Investigator will be requested to 
provide the information. 
 
 
9. 
QUALITY ASSURANCE AND QUALITY CONTROL 
9.1 
Quality Assurance and Quality Control 
Regulatory agencies may carry out a Regulatory Inspection of this trial. Such 
audits/inspections can occur at any time during or after completion of the trial. If 
an audit or inspection occurs, the PI and RPL agree to allow the auditor/inspector 
direct access to all relevant documents and to allocate their time and the time of 
their staff to the auditor/inspector to discuss any findings or relevant issues.  
Quality Control (QC) procedures at the RPL will be implemented to ensure data 
recorded into the CRFs are accurate. QC checks will be carried out on an ongoing 
basis and according to the relevant SOPs. Records of QC checks will be documented 
and available for review. 
 


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9.2 
Monitoring 
All aspects of the trial will be carefully monitored by the Sponsor, or designee, for 
compliance with applicable government regulations with respect to Good Clinical 
Practice (GCP) and current Standard Operating Procedures. 
The monitoring of this trial will be performed by the Sponsor’s monitor(s) or a 
designee in accordance with the principles of GCP as laid out in the International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) Good Clinical Practice Guideline E6(R2) (2016). 
The clinical monitor, as a representative of the Sponsor, has an obligation to follow 
the trial closely. In doing so, the monitor will visit the Investigator and site 
periodically and will maintain frequent telephone and email contact. The monitor 
will maintain current personal knowledge of the trial through observation, review 
of trial records and source documentation, and discussion of the conduct of the 
trial with the Investigator and staff. Further details will be described in the SOM. 
 
10. 
STATISTICAL ANALYSIS 
10.1 
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. 
 
10.2 
Analysis sets 
The analysis of data will be based on different analysis sets according to the 
purpose of analysis. Participant eligibility for each analysis set will be finalised 
before the database hard lock. 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. 
 
10.2.1 Safety set 
The safety set will consist of all randomised participants who received at least one 
dose of the IMP. The safety set will be used for the safety analyses. 
 
10.2.2 PK set 
The PK 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 PK 
set will be used for the PK analyses. 
 
10.2.3 ECG set 
The ECG set will consist of those participants in the safety set that have at least 
one valid pre-dose ECG assessment and one valid post-dose assessment. An ECG 


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assessment will be considered valid if it is based on at least two evaluable 
replicates with measurable QTc and RR.  
The analysis set for intensive cardiac assessment will be based on the intersection 
of the PK set and the ECG set. In addition, participants on placebo will be included 
with plasma concentrations of PYR and PQP set to zero. Individual 
QTc/concentration pairs will be excluded from this set if the time of ECG and the 
time of blood sampling are too far apart, based on time window deviations defined 
in DHP. Details will be defined in the SAP. 
 
10.3 
Statistical analysis of safety  
Individual participant demographics (age, gender and race) and body 
measurement data (height, weight and BMI) at screening will be listed. These 
demographic characteristics and body measurements will be summarised by 
treatment group and overall, using the safety analysis set. Other baseline 
characteristics will be listed only. 
AE data will be listed and summarised using descriptive statistics: the number (and 
percentage) of participants who experienced any AEs and the number of AE 
episodes will be summarised for each treatment group. All AEs will be summarised 
and listed by using the System Organ Class (SOC) and Preferred Term (PT) 
assigned to the event using the MedDRA. Furthermore, these events will be 
summarised by their maximum intensity. The number of participants who 
experienced drug-related AEs will also be summarised. Any SAEs and/or AEs that 
led to trial withdrawal will be summarised and listed. 
Vital signs data (SBP, DBP, HR, temperature) will be listed and summarised, along 
with changes from baseline, using descriptive statistics (mean, median, Standard 
Deviation, minimum, maximum). Out-of-reference-range values will be flagged as 
high or low and as being clinically relevant or not. The number of participants 
presenting out-of-range and clinically relevant values will be summarised. 
All safety clinical laboratory data will be listed. Laboratory test results will also be 
compared to laboratory reference ranges. Those values outside of the applicable 
range will be flagged as high or low, and as clinically relevant or not. The number 
of participants that present out-of-range, and clinically relevant values, will be 
summarised. The quantitative laboratory data and changes from baseline will be 
summarised 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. 
ECG analyses will be performed on two sets of ECGs: all ECGs prior to adjudication 
and selected triplicates from each time-point after adjudication. 
All un-adjudicated ECG data (PR, QRS, QT, QTcB, QTcF and HR) and overall ECG 
evaluation will be listed. ECG data and changes from baseline will be summarised 
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 


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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. 
The mean change from baseline value of QTcF will be plotted by treatment group 
and by time-point. Out-of-reference-range values will be flagged as clinically 
relevant or not. The number of participants presenting out-of-range and clinically 
relevant values will be summarised. 
A similar categorical analysis will be presented as follows: 
• 
increase of PR from baseline >25% resulting in PR > 200 ms 
• 
increase of QRS from baseline >25% resulting in QRS > 120 ms 
• 
decrease of HR from baseline >25% resulting in HR < 50 bpm 
• 
increase of HR from baseline >25% resulting in HR > 100 bpm. 
 
10.4 
ECG analysis 
Analysis of drug related QT/QTc interval changes relative to plasma PK 
concentrations will be conducted. The principles of this analysis follow the 
statistical methods described by Garnett et al., 2018 [20]. This analysis will be 
performed on the analysis set for intensive cardiac assessment.  
In addition, a per timepoint analysis will be performed. While this analysis is based 
on minimal assumptions on the nature of the data, it has limited power to show 
the absence of a prolonging effect. On the other hand, the concentration-QTc 
analysis has been shown to have this power, but it is based on more restrictive 
assumptions. Concentration/ QTc modelling may be performed after completion of 
the Clinical Study Report and will be delivered in a separate report. 
 
10.4.1 Baseline 
For all quantitative parameters, baseline will be the average over the values 
obtained at the three pre-dose timepoints of Day 1. 
 
10.4.2 Heart rate correction 
QTcF will be used for ECG analyses unless there is an effect of one of the drugs on 
HR exceeding 10 bpm. Evidence of the absence of such an effect will be considered 
given, if either the absolute mean time matched difference to placebo is bolow 10 
bpm for all timepoints and for both monotherapies and the combination therapy 
or a concentration-effect model similar to the one described below excludes an 
effect exceeding 10 bpm at relecant concentrations. If an effect of the therapy on 
HR cannot be excluded following the criteria above, QTcI will be determined based 
on data extracted from the 24h Holter data and the primary correction method will 
be selected based on the mean squared slope criteria [28] using the Day -1 12-
lead ECG data. Details will be given in the SAP. 


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10.4.3 Per timepoint analysis  
For all quantitative ECG parameters, descriptive statistics will be given for the 
change from baseline. In addition, for QTc, a linear model with the two treatments 
(PYR and PQP) and their interaction as factors and baseline as covariate will be 
fitted for each timepoint; the difference between each of the active treatments and 
placebo will be estimated based on this model; and two-sided 90% confidence 
intervals (CI) will be given.  
 
10.4.4 Hysteresis 
Hysteresis between the effect of each of the monotherapies and its concentration 
will be investigated based on the results of the per timepoint analysis and the 
mean concentrations under these therapies. Details will be given in the SAP. 
 
 
10.4.5 Concentration-QTc analysis  
This analysis will be based on the change of QTc from baseline and will use baseline 
QTc (centred on the mean across participants) and the concentrations of PYR and 
PQP as covariates. Concentrations of relevant metabolites may also be included. 
Treatment with levels Placebo, PYR, PQP and combination (referred to as 
“treatment intercept” in the sequel) and time will be used as discrete fixed effects. 
A series of linear models including one or more of the concentrations will be fitted 
and the most appropriate one will be selected based on the Akaike Information 
Criterion (AIC) and the size of the fixed treatment effect. A significant treatment 
effect (based on an F-test) will be considered an indication for model misfit. For 
the best fitting linear model, predictions of the effect on QTc will be made. For 
these predictions, the Tmax of every moiety included in the model will be determined 
and the mean concentration of all moietis involved at these timepoints will be used. 
Details of the model selection procedure and the concentrations to be included in 
the best fitting model will be given in the SAP. 
Linearity of the concentration-ΔQTc relationship will be explored based on quantile 
plots as described in Garnett et al (2018) [20]. In addition, a significant treatment 
intercept can be interpreted as sign of either hysteresis or nonlinearity. If the best 
fitting linear model has a significant treatment effect, nonlinear e-max models will 
also be considered, and predictions will be made based on the best fitting model. 
In this case, hysteresis between QTc and the concentrations of the relevant 
analytes will be investigated graphically.  
Absence of an effect of concern of the IMP on QTc will be concluded if the 
predictions based on the best-fitting model at the concentrations described above 
exclude an effect exceeding 10 ms, i.e. the upper limit of the two-sided confidence 
interval for these predictions is below 10 ms. 
 
10.4.6 Assay sensitivity 
In a study analysing the effect of a combination of OZ439 and PQP, Darpö et al 
2015 [27] found an effect of PQP concentration on QTc of 0.0475 ms/(ng/mL) with 
a 90 % confidence interval of (0.038, 0.057). If the effect of PQP in the primary 


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linear model of this analysis is similar to this value, assay sensitivity will be deemed 
shown. 
 
10.5 
Pharmacokinetics 
10.5.1 Evaluation of pharmacokinetic parameters  
Non-compartmental analysis will be used for estimation of PK parameters.  
At least the following PK parameters will be calculated for PYR and PQP (and N-
oxidated metabolite of PQP, provided a future bioanalytical method is available): 
 
Table 15: PK parameters 
Cmax 
Maximal plasma concentration 
tmax 
Time to reach maximum plasma concentration  
t1/2 
Terminal Elimination Half-life 
AUC0-inf 
Area under the plasma concentration-time curve from time zero 
extrapolated to infinite time 
AUC0-t 
Area under the plasma concentration curve from time zero up to 
the last quantifiable concentration 
%AUCextrap Percentage of AUC that is due to extrapolation from last to infinity 
CL/F 
Apparent total plasma clearance  
Vz/F 
Apparent volume of distribution during the terminal phase  
 
The individual plasma concentration data, and the actual time for PYR and PQP 
administration and blood sampling will be used in the derivation of the PK 
parameters. If there is any doubt as to the actual time that a sample was taken, 
then the scheduled time will be used. 
AUC0-t and AUC0-inf 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 Limit of Quantification (LOQ) prior to 
the first quantifiable concentration will be set to zero. Samples with concentrations 
below LOQ after the first quantifiable concentration will be set to ‘missing’ and 
omitted from the analysis. Other pharmacokinetic parameters will be calculated 
according to standard equations. Details will be provided in the SAP.  
 
10.5.2 Statistical analysis on PK parameters  
Plasma concentrations will be listed and summarised by time point, including: 
• 
the number of participants (N) 
• 
the number of samples (n) 
• 
the number of samples <LLOQ (nLLOQ) 
• 
arithmetic mean 


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• 
Standard Deviation (SD) 
• 
Coefficient of Variation (CV) 
• 
geometric mean 
• 
median 
• 
minimum 
• 
maximum.  
The PK parameters will be listed for each participant and summarised for each 
treatment group using descriptive statistics, including: 
• 
N 
• 
arithmetic mean 
• 
SD 
• 
CV  
• 
geometric mean 
• 
median 
• 
minimum 
• 
maximum. 
 
10.6 
Handling of missing and incomplete data 
Unrecorded values will be treated as missing. The appropriateness of the 
method(s) for handling missing data may be reassessed at the data review prior 
to database lock.  
 
10.7 
Determination of sample size 
This is an exploratory trial and the sample-size is not based on formal statistical 
considerations. The numbers assigned to each treatment group are considered 
adequate to describe the tolerability, safety and pharmacokinetics. 
Assuming that an event occurs in 10 % of the cases, the probability to see at least 
one case in 16 subjects on combination treatment is 81 %. If the event occurs in 
20 % of the cases, this probability increases to 97 %. 
 
11. 
DATA MANAGEMENT 
The data management department of RPL will perform data management. The 
Data Handling Protocol (DHP) will outline the data management process in detail.  
The RPL data management department will: 
• 
develop and maintain the DHP 
• 
set and validate the clinical trial database 
• 
programme validation checks 
• 
enter data into the clinical trial database 


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• 
review data for accuracy, completeness, and consistency between the CRF 
and the database 
• 
verify adherence to the clinical pharmacology trial protocol and the DHP. 
Clinical data queries will be generated and resolved according to the DHP. RPL 
clinical staff, trial RP/PI will assist to resolve clinical data queries. 
After all clinical data queries are resolved, final error rate is confirmed, and QC 
checks are acceptable, the database will be locked. 
Standard Statistical Analysis System (SAS®) datasets will be generated from the 
final trial database ready for analyses. 
RPL will perform medical coding. AEs, diagnoses from medical history and 
procedures from surgical history will be classified according to MedDRA. 
Concomitant medication will be coded using WHODRUG.  
SAEs in the clinical database will be reconciled with the safety database. 
Final raw SAS® datasets will be transferred to the statistician and the Sponsor (as 
applicable). 
 
11.1 
Case Report Forms 
The Sponsor and the Investigator will sign a source data agreement to define what 
constitutes source data for all types of data captured.  
Case Report Forms will be used to record source data in the trial. Data should be 
recorded legibly onto the CRFs in black ballpoint pen. Correction fluid or covering 
labels must not be used. 
The monitor will check data at the monitoring visits to the trial site. The PI will 
ensure that the data in the CRFs are accurate, complete, and legible.  
The data manager will ensure that data from the completed CRFs are entered into 
RPL’s clinical trial database and validated. Screening failures (participants who 
signed consent to take part in the trial but were not randomised) and admission 
data for reserves will not be entered into the clinical trial database. Any missing, 
impossible (inconsistent with human life), or inconsistent recordings in the CRFs 
will be queried to the PI and be documented for each individual participant before 
clean file status is declared. 
 
12. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES  
12.1 
Sponsor’s responsibilities 
12.1.1 GCP compliance 
MMV and any third party to whom aspects of the trial management or monitoring 
have been delegated will undertake their roles for this trial in compliance with all 
applicable regulations and ICH GCP Guidelines. 
Representatives of MMV will conduct visits to Investigator sites in order to inspect 
trial data, participants’ medical records, and CRFs in accordance with current ICH 
Good Clinical Practice Guideline E6 (R2) (2016) and the respective local and 
national government regulations and guidelines. Additionally, auditors or 
competent authorities may review records and data. 


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12.1.2 Regulatory approval  
MMV (or delegate) will ensure that local competent authority requirements are met 
before the start of the trial.  
 
12.1.3 Indemnity/liability and insurance  
MMV will adhere to the recommendations of the Association of British 
Pharmaceutical Industry (ABPI) Guidelines. The Investigator will receive a copy of 
the indemnity document before trial initiation.  
MMV will ensure that suitable insurance cover is in place prior to the start of the 
trial. RPL will receive an insurance certificate and a statement of insurance. 
 
12.1.4 Protocol management   
MMV and/or RPL will prepare all protocols and amendments. If it becomes 
necessary to issue a protocol amendment during the trial, MMV will notify the 
Investigator and collect a documented Investigator agreement to the amendment.  
 
12.1.5 End of trial notification  
RPL on behalf of MMV will submit an end of trial notification to the MHRA within 
90 days of the end of the trial in accordance with EU Directive 2001/20/EC. The PI 
will be responsible for submitting these to the REC within 90 days of the end of 
the trial. 
For the purposes of this notification, the end of the trial will be defined as database 
lock. 
 
12.1.6 Posting or submission of summary of clinical trial report to 
competent authorities of member states concerned and RECs  
MMV or its delegate will post result-related information on this clinical trial in 
accordance with the UK Statutory Instrument within one year of the end of the 
complete trial, to the competent authority of the Member State concerned, as 
required by the regulatory requirement and to comply with the community 
guideline on Good Clinical Practice. RPL on behalf of MMV will send a short 
confirmatory 
email 
to CT.Submission@mhra.gov.uk once 
the 
result-related 
information has been uploaded to the public register and provide a link. In addition 
RPL on behalf of MMV will submit a summary of the clinical trial report to the 
concerned REC.  
 


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12.2 
Investigator’s responsibilities 
12.2.1 GCP compliance 
The Investigator must undertake to perform the trial in accordance with ICH GCP 
Guidelines, and the applicable MHRA regulatory requirements. 
It is the Investigator’s responsibility to ensure that adequate time and appropriate 
resources are available at the trial site prior to commitment to participate in this 
trial. The Investigator should also be able to estimate or to demonstrate a potential 
for recruiting the required number of suitable participants within the agreed 
recruitment period. 
The Investigator will maintain a record of appropriately qualified persons to whom 
the Investigator has delegated significant trial-related tasks. Before the trial starts, 
MMV (or designee) will receive an up-to-date copy of the curriculum vitaes for the 
Investigator, sub-Investigator(s), and essential trial staff.  
The PI will demonstrate agreement with the final clinical trial by dated signature, 
in compliance with UK Statutory Instrument  and ICH E3. 
 
12.2.2 Protocol adherence and Investigator agreement 
The PI and delegates must adhere to the CSP as detailed in this document. The PI 
will be responsible for including only those participants who have met CSP 
eligibility criteria. The PI must sign an Investigator agreement to confirm 
acceptance and willingness for themselves and delegates to comply with the CSP. 
 
12.2.3 Documentation and retention of records  
After completion of the trial, the PI will keep all documents and data relating to 
the trial in a secure file and/or electronically, in a secure and orderly manner. The 
data will be available for inspection by MMV or their representatives. Essential 
documents must be retained for 25 years after the final marketing approval in an 
ICH region or u n t i l  at least 25 years have elapsed since the formal 
discontinuation of clinical development of PYR and PQP. The PI or delegate must 
contact MMV before destroying any trial-related documentation and it is the 
responsibility of MMV to inform the investigative site of when these documents 
can 
be 
destroyed. In addition, all participant records and other source 
documentation will be kept for a longer period if required by the applicable 
regulatory requirements.  
 
12.3 
Ethical considerations 
This protocol complies with the principles of the World Medical Assembly (Helsinki 
1964) and subsequent amendments. 
 
12.3.1 Informed consent  
The informed consent is a process by which a participant voluntarily confirms 
his/her willingness to participate in a clinical trial. It is the responsibility of the PI 
or delegate to obtain written informed consent from participants. All consent 
documentation must be in accordance with applicable regulations and the ICH 


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Good Clinical Practice Guideline E6 (R2) (2016). Each participant will be requested 
to sign the ICF after they have received and read the written participant 
information and received an explanation of what the trial involves, including but 
not limited to: the objectives, potential benefits and risk, inconveniences, and the 
participant’s rights and responsibilities. Signed ICFs must remain on file and must 
be available for verification by trial monitors at any time. Another signed original 
of the ICF must be given to the participant or the participant’s legally authorised 
representative. The PI or delegate will provide the Sponsor with a copy of the REC 
approved consent forms, and a copy of the REC written approval, prior to the start 
of the trial.  
 
12.3.2 Research Ethics Committee (REC) approval 
It is the responsibility of the PI to submit this CSP, the informed consent document 
(approved by MMV), relevant supporting information, and all types of participant 
recruitment information to the REC for review, and all must be approved prior to 
the start of participant screening. In addition, advertisements must be approved 
by the REC prior to use at the site. Prior to implementing changes in the trial, MMV 
and the REC must also approve any substantial amendments to the CSP and 
corresponding updates to informed consent documents. For non-substantial 
protocol amendments (that do not require REC approval) and subsequent updates 
of the ICF, all changes will be made in agreement with MMV and RPL. 
  
12.4 
Confidentiality 
For the purposes of this Section 12.4, ‘Applicable Data Protection Law’ shall mean 
(a) the Data Protection Act 2018; (b), the UK GDPR (as defined in Section 3(10) 
of the Data Protection Act 2018) and (c) the General Data Protection Regulation 
((EU) 2016/679) as applicable, and any applicable legislation introduced in the UK. 
Data collected during this trial may be used to support the development, 
registration, or marketing of medicinal products. MMV will control all data collected 
during the trial and will abide by the Applicable Data Protection Law. For the 
purpose of the Applicable Data Protection Law, MMV will be the data controller. To 
the extent that RPL processes personal data on behalf of MMV, in relation to such 
data RPL shall only act in accordance with the terms of this protocol and MMV’s 
reasonable written instructions and RPL shall take appropriate technical and 
organisational measures against the unauthorised or unlawful processing of such 
personal data. 
After participants have consented to take part in the trial, MMV and/or its 
representatives will review their medical records and the data collected during the 
trial. These records and data may, in addition, be reviewed by the following: 
independent auditors who validate the data on behalf of MMV, national or local 
regulatory authorities, and the REC which gave its approval for this trial to proceed.   
Although participants will be known by a unique number, their date of birth will 
also be collected by RPL and be used to assist MMV to verify the accuracy of the 
data, for example, that the results of trial assessments are assigned to the correct 
participant. The results of this trial containing the unique number, date of birth, 
and relevant medical information including ethnicity may be recorded and 
transferred to and used in other countries throughout the world. If personal data 


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are transferred outside of the UK, RPL will ensure applicable data transfer 
mechanisms are in place to ensure the data receives essentially equivalent 
protections as are applicable in the UK. The purpose of any such transfer would be 
to support regulatory submissions made by MMV in such countries. The parties 
agree to comply with the relevant provisions of the Applicable Data Protection Law 
and any directions issued by the UK Information Commissioner’s Office in its 
processing of such personal data. All nominative information in the participant’s 
medical record will be kept strictly confidential. Nominative information shall mean 
the name, the address and all other personally identifiable information associated 
with a participant’s name. MMV access to participant’s data shall be performed in 
such a way that no participant could be identified by such data. 
If there are any contradictions in terms of confidentiality requirements, the 
requirements of Applicable Data Protection Law will prevail. 
To the extent that RPL processes personal data on behalf of MMV, the terms of 
Appendix 1 shall also apply. 
 
12.5 
Publication policy 
If the Sponsor and RPL agree that it will be desirable to publish the results of this 
trial; both parties will liaise in good faith to publish the results. RPL agree to obtain 
the Sponsor’s prior written approval of such publications. 
 


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13. 
REFERENCES 
 
1. Geneva: World Health Organization. World malaria report 2020: 20 
years 
of 
global 
progress 
and 
challenges. 
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Published 
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2. Chang C, Lin-Hua T, Jantanavivat C. Studies on a new antimalarial 
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3. Zongo I, Milligan P, Compaore Y, Some A, Greenwood B, Tarning J, 
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product-information-Section. Published 2021. Accessed 8 October 
2021. 
5. Medicines for Malaria Venture. Pyramax® (Artesunate- pyronaridine) 
for the treatment of acute uncomplicated malaria in adults and 
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pyronaridine-artesunate-treatment-acute-uncomplicated-malaria. 
Published 2019. Accessed 7 October 2021. 
6. Bailly C. Pyronaridine: an update on its pharmacological activities and 
mechanisms 
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9. Myint H, Ashley E, Day N, Nosten F, White N. Efficacy and safety of 
dihydroartemisinin-piperaquine. Transactions of The Royal Society of 
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2021. 
10. Ratcliff A, Siswantoro H, Kenangalem E, Maristela R, Wuwung R, Laihad 
F, Ebsworth E, Anstey N, Tijtra E, Price R. Two fixed-dose artemisinin 
combinations for drug-resistant falciparum and vivax malaria in Papua, 
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757-65. 
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2021. 


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11. Internal MMV Material. 
12. Karunajeewa H, Lim C, Hung T, Ilett K, Denis M, Socheat D, Davis T. 
Safety 
evaluation 
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combination 
piperaquine 
plus 
dihydroartemisinin (Artekin) in Cambodian children and adults with 
malaria. British Journal of Clinical Pharmacology. 2007;57(1): 93-9. 
Accessed 8 October 2021. 
13. Mytton O, Ashley E, Peto L, Price R, La Y, Hae R, Singhasivanon P, 
White N, Nosten F. Electrocardiographic safety evaluation of 
dihydroartemisinin piperaquine in the treatment of uncomplicated 
falciparum malaria. American Journal of Tropical Medicine and Hygiene. 
2007; 77(3): 447-50. https://pubmed.ncbi.nlm.nih.gov/17827358/. 
Accessed 8 October 2021. 
14. Wu W, Lu C, Liang Y, Zhang H, Deng C, Wang Q, Xu Q, Tan B, Zhou C, 
Song 
J. 
Electrocardiographic 
effect 
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artemisinin-piperaquine, 
dihydroartemisinin-piperaquine, 
and 
artemether-lumefantrine 
treatment in falciparum malaria patients. The Journal of the Brazilian 
Society 
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2021;54:e05362020. 
https://pubmed.ncbi.nlm.nih.gov/33605379/. Accessed 8 October 
2021. 
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. Funck-Brentano C, Ouologuem N, Duparc S, Felices M, Sirima S, 
Sagara I, Soulama I, Ouedraogo J, Beavogui A, Borghini-Fuhrer I, Khan 
Y, Djimdé A, Voiriot P. Evaluation of the effects on the QT-interval of 4 
artemisinin-based combination therapies with a correction-free and 
heart 
rate-free 
method. 
Scientific 
Reports. 
2019;9(1):883. 
https://pubmed.ncbi.nlm.nih.gov/30696921/. Accessed 8 November 
2021. 
17. Stein C, Fritsch C, Robinson C, Sbruzzi G, Plentz R. Effects of electrical 
stimulation in spastic muscles after stroke: systematic review and 
meta-analysis 
of 
randomised 
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Stroke. 
2015; 
46(8):2197-205. 
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Accessed 12 October 2021. 
18. Unpublished internal MMV Summary Safety Slideset Material. 
19. Pyronaridine Investigator’s Brochure, V2, Section 6.3.2. 
20. Garnett C, Bonate P, Dang Q, Ferber G, Huang D, Liu J, Mehortra D, 
Riley P, Sager P, Tornoe C, Wang Y. Scientific white paper on 
concentration-QTc 
modelling. 
Journal 
of 
Pharmacokinetics 
and 
Pharmacodynamics. 
2018;45, 
383-397. 
https://link.springer.com/article/10.1007%2Fs10928-017-9558-5. 
Accessed on 15 October 2021. 
21. Unpublished internal MMV data; CSR SPC001-03. 
22. Morris C, Lopez-Lazaro L, Jung D, Methaneethorn J, Duparc S, 
Borghini-Fuhrer I, Pokorny R, Shin C, Fleckenstein L. Drug-Drug 
Interaction Analysis of Pyronaridine-artesunate and Ritonavir in 


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Healthy Participants. American Journal of Tropical Medicine and 
Hygiene. 2012;86: 489- 495. Accessed 25 November 2021. 
23. Morris C, Pokorny R, Lopez-Lazaro L, Miller R, Arbe-Barnes S, Duparc 
S, Borghini-Fuhrer I, Shin J, Fleckenstein L. Pharmacokinetic 
Interaction 
between 
Pyronaridine-Artesunate 
and 
Metoprolol. 
Antimicrobial Agents and Chemotherapy. 2014;58: 5900-5908. 
Accessed 25 November 2021. 
24. Morris C, Dueker S, Lohstroh P, Wang LQ, Fang X, Jung D, Lopez-Lazaro 
L, Baker M, Duparc S, Borghini-Fuhrer I, Pokorny R, Shin J, 
Fleckenstein L. Mass balance and metabolism of the antimalarial 
pyronaridine in healthy participants. European Journal of Drug 
Metabolism and Pharmacokinetics. 2015;40: 75-86. Accessed 25 
November 2021. 
25. Sim I, Davis T, Ilett K. Effects of a high-fat meal on the relative oral 
bioavailability of piperaquine. Antimicrobial Agents and Chemotherapy. 
2005;49(6): 
2407-2411. 
https://europepmc.org/article/PMC/1140540. Accessed 10 November 
2021. 
26. Beck A, Ward C, Mendelson M, Mock J, Erbaugh J. An inventory for 
measuring depression. Archives of General Psychiatry. 1961;4:561-71. 
doi: 10.1001/archpsyc.1961.01710120031004. Accessed 26 Nov 
2021. 
27. Darpö B, Ferber G, Siegl P, Laurijssens B, Macintyre F, Toovey S, 
Duparc S. Evaluation of the QT effect of a combination of piperaquine 
and a novel anti-malarial drug candidate OZ439, for the treatment of 
uncomplicated malaria. British Journal of Clinical Pharmacology. 
2015;80(4):706-15. Accessed 29 November 2021. 
28. Tornøe C, Grnett C, Wang Y, Florian J, Li M, Gobburu J. Creation of a 
knowledge management system for QT analyses. The Journal of Clinical 
Pharmacology. 2011;51(7):1035–1042. Accessed 29 November 2021. 
 
 
 
 


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14. 
APPENDIX 1 
 
Where RPL processes personal data on behalf of MMV, RPL shall act as a data 
processor and the Sponsor shall be a data controller. To the extent RPL is the 
data processor on behalf of MMV, RPL shall: 
 
1.1 
process the personal data only in accordance with the documented 
instructions of MMV 
1.2 
implement appropriate technical and organisational measures to protect the 
personal data against unauthorised or unlawful processing and against 
accidental loss, destruction, damage, alteration or disclosure. These 
measures shall be appropriate to the harm and risk which might result from 
any unauthorised or unlawful processing, accidental loss, destruction or 
damage to the personal data and having regard to the nature of the personal 
data which is to be protected and shall include inter alia as appropriate: 
1.2.1 
the pseudonymisation and encryption of personal data 
1.2.2 
the ability to ensure the ongoing confidentiality, integrity, 
availability and resilience of systems and services processing 
personal data 
1.2.3 
the ability to restore the availability and access to personal data in 
a timely manner in the event of a physical or technical incident 
1.2.4 
a process for regular testing, assessing and evaluating the 
effectiveness of technical and organisation measures for ensuring 
the security of processing. 
In order to enable RPL to implement appropriate technical and 
organisational measures, MMV shall provide to RPL any information 
reasonably required by RPL to enable it to assess the appropriateness of 
such measures. 
1.3 
only employ or appoint personnel to process the personal data who have 
given binding undertakings of confidentiality or are under a statutory 
obligation of confidentiality 
1.4 
remain entitled to appoint third party sub-processors. Where RPL appoints 
a third-party sub-processor, it shall: 
1.4.1 
ensure that the third party is subject to, and contractually bound 
by, at least the same obligations as RPL 
1.4.2 
provide to MMV copies of any documentation to demonstrate 
compliance with the obligations under this section  
1.4.3 
remain fully liable to MMV for all acts and omissions of the third 
party 
1.5 
notify MMV without undue delay after becoming aware that it has suffered 
a data breach 
1.6 
at MMV’s cost, permit MMV (subject to reasonable and appropriate 
confidentiality undertakings), to inspect and audit RPL’s data processing 
activities to enable MMV to verify and/or procure that RPL is in full 
compliance with its obligations under the protocol 


Medicines for Malaria Venture 
CONFIDENTIAL 
 
Protocol Ref: MMV_SMC_21_01 
Version 3.0   
 
  
RPL Trial No. C21007 
07-FEB-2022 
 
C21007_MMV_SMC_21_01_Clinical Study Protocol_V3.0_07Feb2022.docx 
SOP-125-TEM-03-07-Clinical Study Protocol Template_13Jul2021  
Page 96 of 96 
1.7 
taking into account the nature of the processing, assist MMV by appropriate 
technical and organisational measures, insofar as this is possible, with the 
fulfilment of MMV’s obligation to respond to requests from data participants 
in connection to this protocol exercising their rights under Applicable Data 
Protection Law 
1.8 
unless applicable law requires otherwise, upon termination of the protocol:  
1.8.1 
at the option of MMV, comply or procure the compliance with the 
following: 
(a) 
return to MMV all personal data and any other information 
provided by MMV to RPL; and/or 
(b) 
permanently delete all personal data provided by MMV to 
RPL; and 
1.8.2 
cease to process the personal data 
Notwithstanding the foregoing, RPL shall be entitled to retain personal data 
to the extent that it is required to do so pursuant to the law of the United 
Kingdom 
1.9 
where the laws of the country where RPL is established require RPL to 
transfer the personal data to a third country or an international organisation, 
inform MMV as soon as reasonably possible of that legal requirement unless 
that law prohibits such communication on important grounds of public 
interest 
1.10 RPL shall only transfer personal data outside the United Kingdom to a 
country or territory that is subject to a UK or European Commission 
adequacy decision, where appropriate safeguards are in place, and on the 
condition that the level of protection offered to the data subject in the third 
country are essentially equivalent to those offered by the Applicable Data 
Protection Law. 
 

SAP_001.pdf: 
Statistical Analysis Plan
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SPONSOR’S REFERENCE NUMBER: MMV_SMC_21_01
EUDRACT NUMBER: 2021-005698-21 
RPL STUDY CODE: C21007 
STATISTICAL ANALYSIS PLAN 
A randomised, double-blind, placebo controlled, parallel group 
study in healthy adult volunteers to determine the tolerability 
and safety of pyronaridine (PYR) co-administered with 
piperaquine (PQP) under fasted conditions 
FINAL VERSION 1.0, 17MAY2022 
Issued by: D. Djumanov 
Signature...................... 
Richmond Pharmacology 
Director of Data Science 
Date............................. 
Approved by: Stephan Chalon 
 Signature...................... 
Medicines for Malaria Venture 
MMV Medical Lead  
Date............................. 
Approved by: Andrea Kuemmerle 
 Signature...................... 
Medicines for Malaria Venture 
Clinical Scientist 
Date.............................  
05/17/2022
05/17/2022
05/18/2022
SignNow e-signature ID: f05d488ef6...
05/17/2022 08:13:01 UTC
Dilshat Djumanov (Signer)
SignNow e-signature ID: 839f95b982...
05/17/2022 08:52:52 UTC
Stephan Chalon (Signer)
SignNow e-signature ID: 59f98aa437...
05/18/2022 16:00:32 UTC
Andrea Kuemmerle (Signer)


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
or Specialist 
Term  
Explanation  
AE  
Adverse Event  
AUC 
Area under the Concentration Time Curve 
AUC0-72 
Area under the Plasma Concentration Curve from Time Zero 
to 72 Hours  
AUC0-168  
Area under the Plasma Concentration Curve from Time Zero 
to 168 Hours – ATV only 
AUC0-inf 
Area under the Plasma Concentration Curve from Time Zero 
Extrapolated to Infinity 
AUC0-t  
Area under the Plasma Concentration Curve from Time Zero 
to the Last Quantifiable Concentration 
BLQ 
Below the Level of Quantification 
CL/F 
Apparent Total Plasma Clearance  
Cmax  
Maximum Observed Plasma Concentration  
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
CYP 
Cytochrome P450  
DRM 
Data Review Meeting 
ECG  
Electrocardiogram  
Frel 
Relative Bioavailability 
H 
High 
HR 
Heart rate 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
λz  
Terminal Elimination Rate Constant  
L 
Low 
LLOQ 
Lower Limit Of Quantification 
LOQ 
Limit Of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMV 
Medicines for Malaria Venture 
PDF 
Portable Document Format 
PK  
Pharmacokinetic(s)  
PQP 
Piperaquine tetraphosphate 
PR 
ECG PR Interval 
PROC 
Procedure in SAS 
PYR 
Pyronaridine tetraphosphate 
QRS 
ECG Ventricular Conductance Time 
QT 
ECG QT interval uncorrected 
QTc 
ECG QT interval corrected  
QTcF  
ECG QT interval corrected using Fridericia’s formula  


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QTcI 
ECG QT interval corrected using a subject specific 
("individual") correction 
QTcS 
ECG QT interval corrected using a study specific correction 
RPL 
Richmond Pharmacology Ltd 
RTF 
Rich Text Format 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOM 
Study Operation Manual 
TEAE 
Treatment-Emergent Adverse Event 
t½ 
Terminal Elimination Half-Life 
TFLs 
Tables, Figures and Listings 
tmax 
Time to Maximum Observed Plasma Concentration 
Vz/F 
Apparent Volume of Distribution during the Terminal Phase 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................... 2
1.
INTRODUCTION .............................................................................. 6
2.
STUDY OBJECTIVES AND ENDPOINTS .............................................. 6
2.1
Study objectives ............................................................................. 6
2.2
Endpoints ...................................................................................... 6
3.
TRIAL DESIGN .................................................................................. 7
3.1 Overall Trial Design ........................................................................... 7
3.2
Sample Size ................................................................................... 9
3.3
Randomisation and Blinding .............................................................. 9
4. STATISTICAL ANALYSES ....................................................................... 10
4.1 General Notes for Statistical Analyses ................................................. 10
4.2
Interim Analysis ........................................................................... 11
4.3
Analysis Sets ............................................................................... 11
4.4
Subject Disposition ....................................................................... 12
4.5
Demographic Characteristics........................................................... 12
4.6
Inclusion and Exclusion Criteria ....................................................... 13
4.7
Protocol Deviations ....................................................................... 13
4.8
Medical and Surgical History ........................................................... 13
4.9
Study Drug Administration ............................................................. 13
4.10
Prior and Concomitant Medications ................................................ 13
4.11
Safety Analysis .......................................................................... 13
4.11.1 Adverse Events ........................................................................ 14
4.11.2 Laboratory Data ....................................................................... 14
4.11.3 Vital Signs ............................................................................... 15
4.11.4 Telemetry and Holter ................................................................ 15
4.11.5 Physical Examination ................................................................ 15
4.11.6 Electrocardiograms ................................................................... 15
4.12 ECGs analyses (adjudicated)............................................................ 16
Presentation of results ........................................................................ 19
4.13 Pharmacokinetic Data Reporting ....................................................... 20
4.13.1 Pharmacokinetic Listings .............................................................. 20
4.13.2 Pharmacokinetic Summary Tables .................................................. 20
4.13.3 Pharmacokinetic Figures ............................................................... 20


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4.13.4 Values Below the Limit of Quantification and Missing Values ............... 20
4.14 Exploratory Analysis ....................................................................... 21
3.
REFERENCES ................................................................................. 21


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1.
INTRODUCTION
The purpose of this Statistical Analysis Plan (SAP) is to define the variables and 
analysis methodology to address the study objectives. 
The protocol dated 07 February 2022, version 3.0, was used to prepare this SAP. 
Pharmacokinetic parameters calculations and statistical analyses of PK data will be 
responsibility of PharmaKinetic (described in a separate PK analyses plan); PK TFLs 
and analyses based on Safety and ECG sets will be the responsibility of Richmond 
Pharmacology Ltd. Concentration-QTc analysis is optional and will be performed in 
future, as required. 
2.
STUDY OBJECTIVES AND ENDPOINTS
2.1 
Study objectives 
The objectives of this study are: 
Primary 
•
To determine the safety and tolerability of the registered dose for
treatment of acute uncomplicated malaria of PYR (once daily for three
days) and the registered dose for the treatment of acute uncomplicated
malaria of PQP (once daily for three days) when administered alone and in
combination, in comparison with placebo.
Secondary 
•
To determine the pharmacokinetics (PK) of PYR and PQP when
administered alone, and in combination, for three days.
•
To determine the relationship between PQP and ECG parameters (QTc,
QRS and PR), between PYR and ECG parameters, and to evaluate any
impact of the combination of PYR and PQP on ECG parameters.
Exploratory 
•
To investigate the exposures to PQP metabolites (e.g. N-oxidated
metabolite, provided a future bioanalytical method is available).
•
To determine if CYP genetic polymorphism influences drug PK and safety
& tolerability.
2.2 
Endpoints
Primary 
•
The incidence, severity and relationship of Treatment-Emergent Adverse
Events (TEAEs).
•
Proportion of participants with clinically significant changes in laboratory
safety tests (haematology, biochemistry, coagulation and urinalysis).


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• 
Proportion of participants with morphological and/or rhythm abnormalities 
on electrocardiogram (ECG). 
• 
Proportion of participants with clinically significant changes in ECG time 
intervals (PR, QRS, QT and QTc intervals) and clinically significant changes 
against baseline Holter. 
• 
 Proportion of participants with clinically significant changes in vital signs 
(systolic blood pressure, diastolic blood pressure and pulse rate). 
Secondary 
• 
PK parameters derived by non-compartmental methods including 
maximum observed plasma concentration (Cmax), time to reach maximum 
plasma concentration (tmax), 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 
extrapolated to infinite (AUC0-), apparent total plasma clearance (CL/F), 
apparent volume of distribution during the terminal phase (Vz/F), terminal 
elimination rate constant (λz), and terminal elimination half-life (t1/2). 
 
Difference between baseline corrected QTc following placebo and baseline 
corrected QTc following PQP alone, and with PYR. 
Exploratory 
• 
PK parameters of PQP metabolites (e.g. N-oxidated metabolite) and 
metabolites to parent drug ratios. 
• 
The relationship between CYP genetic polymorphism, PK parameters, and 
safety & tolerability. 
3. 
TRIAL DESIGN 
3.1 Overall Trial Design 
 
This will be a single-centre, randomised, double-blind, placebo-controlled, parallel 
group study to determine the safety, tolerability and PK of the registered dose to 
treat acute uncomplicated malaria of PYR + PQP, PYR + PQP placebo, PYR placebo 
+ PQP, as well as PYR placebo + PQP placebo when administered orally once daily 
for three days to healthy adult male and female participants. 
Forty (40) participants are planned to be enrolled and randomised to one of the 
four treatments in a 2:1:1:1 ratio as described below: 
 
• 
 Treatment 1 (N=16): PYR + PQP 
• 
 Treatment 2 (N=8): PYR + placebo for PQP 
• 
 Treatment 3 (N=8): placebo for PYR + PQP 
• 
 Treatment 4 (N=8): placebo for PYR + placebo for PQP 
 
All participants will receive a single dose of PYR or placebo, as well as a single 
dose of PQP or placebo, on the morning of Day 1, Day 2 and Day 3. Participants 
will fast for at least three hours prior to dosing and four hours after dosing. Within 


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each treatment arm, fasted participants will take PYR/placebo tablets, followed by 
PQP/placebo tablets, at the following weight-dependent doses (Table 1). 
 
Table 1: Planned treatment arms and IMP administration 
Number 
of 
Participants  
IMPs 
Planned Dose (which depends 
on Body Weight [BW]) 
Number of 
Doses/ Dose 
Interval  
16 
 
PYR 
540 mg (BW 50 kg - <65 kg); OR 
720 mg (BW 65 kg or greater) 
 
Single morning 
doses 
(fasted 
state) on D1, 
D2 and D3 
 
PQP 
960 mg (BW 50 kg - <75 kg); OR 
1280 mg (BW 75 kg or greater) 
8 
 
PYR 
540 mg (BW 50 kg - <65 kg); OR 
720 mg (BW 65 kg or greater) 
Placebo for PQP 
N/A 
8 Placebo for PYR 
N/A 
PQP 
960 mg (BW 50 kg - <75 kg); OR 
1280 mg (BW 75 kg or greater) 
8 
 
Placebo for PYR 
N/A 
Placebo for PQP 
N/A 
Abbreviations: BW: body weight; D: day; IMP: investigational medicinal product; kg: kilograms;  
mg: milligrams; PQP: piperaquine; PYR: pyronaridine. 
 
Participant screening will take place between Day -22 and Day -2. Each participant 
will receive verbal and written information, then sign the Informed Consent Form 
(ICF), before any screening procedures take place. Participants will be admitted on 
Day -1 and dosed once in the mornings of Day 1, Day 2 and Day 3. Participants in 
the sentinel group will be discharged on Day 7 and will return to the unit for 
outpatient assessments on Days 8, 15, 22. Non-sentinel group participants may 
be discharged on Day 5 and return for outpatient assessments on Days 6, 8, 15 
and 22, provided there are no clinically significant safety and tolerability signals 
and the SRC are in agreement. 
 
Final assessments will be carried out at the follow-up visit on Day 30 (+/-1 day). 
The trial Schedule of Assessments in protocol details all assessments that will take 
place during the trial. The study design features as well as the 
number of participants may be adapted according to the Adaptive Features. This 
trial will use a sentinel dosing strategy. 


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Figure 1: Trial flow chart 
Abbreviations: N: number of participants in corresponding treatment arm; PQP: Piperaquine; PYR: 
Pyronaridine.  
 Participants in the sentinel group and the main group remained in-house until Day 7. 
3.2 
Sample Size 
This is an exploratory trial and the sample-size is not based on formal statistical 
considerations. The numbers assigned to each treatment group are considered 
adequate to describe the tolerability, safety and pharmacokinetics. 
Assuming that an event occurs in 10% of the cases, the probability to see at least 
one case in 16 subjects on combination treatment is 81%. If the event occurs in 
20% of the cases, this probability increases to 97%.  
Participants recruitment has stopped at 37. 
3.3 
Randomisation and Blinding 
Subject Randomisation 
All subjects in this trial will be assigned to a treatment regimen according to a 
randomisation schedule generated by a statistician using PROC Plan. Details 
regarding the unique screening and subject number will be included in the SOM. 
Eligible subjects will be randomly assigned in a 2:1:1:1 ratio to one of four 
treatment arms on Day 1, at the point of dosing. Treatment arms are outlined 
below: 
•
Treatment 1 (N=16):  PYR + PQP
•
Treatment 2 (N=8):
 PYR + placebo for PQP 
•
Treatment 3 (N=8):
 placebo for PYR + PQP 
•
Treatment 4 (N=8):
 placebo for PYR + placebo for PQP. 
Sentinel dosing (N=10) will occur: four subjects for treatment arm 1, and two 
subjects from each of treatment arms 2, 3 and 4, will be dosed before the remaining 
subjects of each treatment arm are dosed together (see protocol Section Error! 
Reference source not found.). 


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Methods for ensuring blinding 
The trial will take place in a double-blind fashion whereby subjects and clinical trial 
site staff are blinded to the active or placebo trial drug assignment. 
PQP is uncoated and bitter to taste, the effect may be persistent for some time after 
administration. This effect cannot be masked and may provide an indication of the 
treatment received. As the key safety and tolerability endpoints are objective 
assessments and parameters, it is anticipated that there will be no impact on the 
primary trial objective to determine the safety and tolerability of the registered 
doses of IMP.    
The pharmacy staff preparing the investigational products will not be blinded to trial 
drug assignment. During the trial, the individual randomisation codes will be kept 
in the site's clinical trials pharmacy, accessible to the pharmacy personnel only. 
Upon completion of the trial, after the database lock and after the blind is revealed, 
the randomisation list will be filed in the Trial Master File (TMF). 
Sponsor staff involved in clinical decision-making (such as those involved in SRC 
decisions) will be blinded to trial drug assignment. 
 
4. STATISTICAL ANALYSES 
4.1 General Notes for Statistical Analyses  
In general, descriptive statistics for continuous variables will include number of non-
missing values (n), arithmetic mean, standard deviation (SD), median, minimum, 
and maximum.  
Descriptive statistics for PK parameters will include N - the number of participants, 
n – the number of samples, n(LLOQ) - the number of samples <LLOQ (lower limit 
of quantification), arithmetic mean, SD - standard deviation, CV - coefficient of 
variation, geometric mean, median, minimum, maximum.  
Categorical variables will be summarized using frequency counts and percentages.  
For all tables, except PK parameter tables, descriptive statistics for minimum and 
maximum will be presented with the same decimal digits as the original data, and 
with 1 more decimal place than the original data for mean and median; SD and SE 
will be reported with 2 more decimal places than the original data. Degrees of 
freedom based on the Kenward Roger approximation will be presented with one 
decimal. 
PK parameters will be presented as follows in the listing: Cmax and tmax will be 
presented as given in the raw data; other PK parameters will be presented with 3 
decimal places. Descriptive statistics for PK parameters will be presented with 
decimal places as appropriate for the particular parameter and treatment group.  
The analyses will be presented by treatment group (2 monotherapies, combination 
therapy and placebo), overall as well as stratified by body weight group: 
• 
  < 65 kg 
• 
65 - < 75 kg 
• 
≥ 75 kg.  


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o Treatment arm 1: 
PYR 540 mg + PQP 960 mg 
PYR 720 mg + PQP 960 mg 
PYR 720 mg + PQP 1280 mg 
o Treatment arm 2 
PYR 540 mg 
PYR 720 mg 
o Treatment arm 3 
PQP 960 mg 
PQP 1280 mg 
o Overall (for safety set) 
o Placebo 
 
All collected data will be presented in by-subject listings. Listings will be ordered by 
treatment group, body-weight group and subject number and will include all 
randomized subjects. 
Unless otherwise stated, baseline will be defined as the last non-missing value prior 
to first administration of study drug. Changes from baseline values will be calculated 
as the post-baseline assessment value minus the baseline value. Only observed 
values from scheduled time points will be used to create summary tables. 
Deviations from the planned analyses will be described in the final clinical study 
report (CSR). 
Page layout of the TFLs will be in landscape mode and will be provided as individual 
RTF format. Further details of page layout will be provided in the TFL shell 
document.  
If repeated measurements are made at a time point, the first scheduled value will 
be used for summary analysis, unless otherwise stated in relevant section of this 
SAP. 
  
4.2 
Interim Analysis 
No interim analysis is planned for this study. 
 
4.3 
Analysis Sets  
The analysis of data will be based different analysis sets according to the purpose 
of analysis. Subject eligibility for each analysis set will be finalised before the 


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database hard lock. A subject who withdraws prior to the last planned observation 
in a tail period will be included in analyses up to the time of discontinuation.  
The following data sets will be used for analysis and presentation of the study data: 
Safety Set  
The safety set will consist of all randomised subjects who received at least one dose 
of the IMP. The safety set will be used for the safety analyses. 
 
PK Set 
See PKAP. 
 
ECG Set  
The ECG set will consist of those subjects in the safety set that have at least one 
valid pre-dose ECG assessment and one valid post-dose assessment. An ECG 
assessment will be considered valid if it is based on at least two evaluable replicates 
with measurable QT and RR. 
The analysis set for intensive cardiac assessment will be based on the intersection 
of the PK set and the ECG set. In addition, subjects on placebo will be included with 
plasma concentrations of PYR and PQP set to zero. Individual QTc/concentration 
pairs will be excluded from this set if the time of ECG and the time of blood sampling 
are too far apart: > 15min. 
 
4.4 
Subject Disposition  
All subjects will be included in the summary of subject disposition. This will present 
the overall number of subjects, the frequency and percentage of subjects 
randomized and treated, and who completed or discontinued from the study, along 
with reason for discontinuation.  
Furthermore, the number and percentage of subjects in each analysis set will be 
tabulated. Discontinued subjects will be listed. Subject assignment to analysis sets 
will be listed. Screen Failures will not be listed or included in summary tables. 
 
4.5 
Demographic Characteristics 
Individual subject demographics (including age, sex, race and ethnicity) and body 
measurement data (height, body weight and body mass index and body weight 
group as defined above) at screening will be listed and summarized for the safety 
set. Height will be measured in centimetres and weight in kilograms, body mass 
index will be given in kg/m2.  
Other baseline characteristics with Beck depression inventory questionnaire will be 
listed only. 
 


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4.6 
Inclusion and Exclusion Criteria 
The inclusion and exclusion criteria text will be listed, as well as failed eligibility 
criteria for each randomised subject, if any. 
4.7 
Protocol Deviations 
The final review of protocol deviations will be performed at the DRM prior to 
database lock. The protocol deviations will be listed. 
4.8 
Medical and Surgical History 
Medical and Surgical history data will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary Version 24.0 (or higher) and listed 
individually. Surgical history data will be listed separately. Medical and Surgical 
history data will be summarised using frequency and percentage by SOC and 
preferred term. 
4.9 
Study Drug Administration 
Study drug administration data including treatment received, dose (unit), date and 
time of administration will be listed by subject. 
4.10 Prior and Concomitant Medications 
All prior and concomitant medications will be coded using the World Health 
Organization Drug Dictionary version 2022 (or higher) and will be listed individually. 
The frequency and percentage of prior and concomitant medications will be 
summarized by Anatomical Therapeutic Chemical and Preferred Name. Separate 
tables will be given for prior and concomitant medications. Prior medications are 
defined as those for which the end date and time is prior to the date, and time of 
first study drug administration. Concomitant medications are defined as those with 
start date and time on or after the date and time of first study drug administration 
and those with start date and time prior to the first study drug administration but 
with end date and time on or after the date and time of first study drug 
administration. 
If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant. 
4.11 Safety Analysis 
Safety analyses will be performed on the safety set. 
Safety analyses will include an analysis of all AEs, ECGs, clinical laboratory data, 
vital sign measurements and physical examination results and will be presented 
using descriptive statistics. No formal statistical analysis will be performed. 


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4.11.1 Adverse Events
A Treatment Emergent Adverse Event (TEAE) is any adverse event that commences 
after the start of administration of study drug. 
AEs with unknown start date/time will be assumed to be treatment-emergent unless 
the end date/time is known to be before the first administration of study drug. 
Otherwise missing or partial dates will be listed as such. 
The incidence of TEAEs (after dosing) will be summarized using the safety set. The 
MedDRA dictionary Version 24.0 (or higher) will be used to classify all AEs reported 
during the study by System Organ Class (SOC) and Preferred Term. A summary of 
TEAEs including the incidence of subjects who experienced TEAEs (number and 
percentage of subjects) and incidence of TEAEs (number of events) will be presented 
for each treatment group and overall, by severity and by relationship to study drug. 
Serious TEAEs (after dosing) and AEs leading to withdrawal will be summarized by 
SOC and Preferred Term for each treatment group and overall, and by relationship 
to study drug.  
Subjects having multiple AEs within a category (e.g., overall, SOC and Preferred 
Term) will be counted once in that category. In each table, SOC and Preferred Term 
will be presented in descending order of overall incidence rate (alphabetical order 
will be used in case of equal rates).  
All adverse events will be listed. 
4.11.2 Laboratory Data
Clinical 
laboratory 
parameters 
(including 
blood 
chemistry, 
haematology, 
coagulation, urinalysis and other laboratory results) will be listed and abnormal 
parameters will be flagged and graded as high (H/x) or low (L/x) (where defined) 
according to reference ranges and CTCAE grade. Absolute (observed) values and 
changes from baseline (continuous variables) will be summarized for each 
parameter and scheduled time point by treatment group. The number of volunteers 
presenting out-of-range and clinically relevant values will be summarised by 
treatment group. The scheduled lab value will be used for summary analysis if 
repeated measurements are made at any time point.  
For summary statistics, a lab value with “<” will be replaced with a numeric value 
by removing the “<” sign. In the listings, the values will be displayed as originally
reported by the laboratory. 
The mean and individual change from baseline value of ALT/AST/Bilirubin will be 
plotted by treatment group and by time-point. The number of subjects presenting 
out-of-range and clinically relevant values will be summarised. 
The qualitative urinalysis data will be listed only. 
Test 
Code 
Test 
Unit 
Range 
Low 
Range 
High 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ALT 
IU/L 
10 
50 
>ULN -
3.0 x ULN 
>3.0 - 5.0 x
ULN
>5.0 - 20.0
x ULN
>20.0 x
ULN


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AST 
IU/L 
0 
37 
>ULN - 
3.0 x ULN 
>3.0 - 5.0 x 
ULN 
>5.0 - 20.0 
x ULN 
>20.0 x 
ULN 
Total 
bilirubin 
UMOL/L 
0 
20 
>ULN - 
1.5 x ULN 
>1.5 - 3.0 x 
ULN 
>3.0 - 10.0 
x ULN 
>10.0 x 
ULN 
 
4.11.3 Vital Signs 
Vital signs data (SBP, DBP, Pulse rate, temperature) will be listed for individual 
subjects. Summary statistics of absolute (observed) values and changes from 
baseline will be calculated for each parameter and scheduled timepoint by treatment 
group. 
Out-of-reference-range values will be flagged as high (H) or low (L) and as being 
clinically relevant or not: the number of subjects presenting out-of-range and 
clinically relevant values will be summarised. 
 
Parameter 
Normal Range 
Temperature (tympanic)  
35-37.5°C  
Systolic Blood Pressure (Supine)  
90–140 mmHg  
Diastolic Blood Pressure (Supine)  
40–90 mmHg  
Postural Drop (systolic, symptomatic)  
≤20 mmHg drop  
Pulse Rate (supine)  
40–100 bpm  
Respiratory Rate  
8-20 breaths per min  
 
4.11.4 Telemetry and Holter 
Cardiac telemetry and Holter data (Start / End Date time and evaluation) will be 
listed by subject. 
 
4.11.5 Physical Examination 
The physical examination performed at screening and at the post-trial visit will be 
listed only and include an assessment of the following: general appearance, skin, 
eyes/ears/nose, neck, lymph nodes, throat, heart, lungs, abdomen, musculoskeletal 
system and extremities. 
 
4.11.6 Electrocardiograms 
 
ECG analyses will be performed on two sets of ECGs: all ECGs prior to adjudication 
by a cardiologist and selected triplicates from each time-point after adjudication. 
The latter analyses will be performed as contracted. 
 


Statistical Analysis Plan 
 
 
 
C21007(MMV_SMC_21_01) SAP Final v1.0 17May2022.docx 
Page 16 of 21 
 
All un-adjudicated ECG data (PR, QRS, QT, QTcB, QTcF and HR) including H/L flags 
and overall ECG evaluation will be listed. Out-of-reference-range values will be 
flagged as clinically relevant or not. Reference ranges for ECGs are as follows: 
 
Parameter 
Normal Range 
Heart Rate (Supine)  
40-100 bpm  
PR Interval  
120–220 ms  
QRS duration  
≤120 ms  
QTcF  
≤450 ms (Males & Females) 
 
For summary statistics an arithmetic mean value, of the last 3 evaluable ECGs of 
each timepoint, will be used at each time-point. All below analyses will be 
performed using this set. 
ECG data and changes from baseline will be summarised using descriptive 
statistics. 
The change from baseline will be derived using the arithmetic mean value of each 
time-point triplicate minus baseline value, where baseline is the arithmetic mean 
of the pre-dose QTcF values of Day 1. 
Furthermore, categorical analysis of QTcF data will be presented as follows: 
• 
Absolute QTcF interval prolongation  
o QTcF interval > 450 ms to ≤ 480 ms 
o QTcF interval > 480 ms to ≤ 500 ms 
o QTcF interval > 500 ms 
• 
Change from baseline in QTcF interval 
o QTcF interval increases from baseline > 30 msec to ≤ 60 msec 
o QTcF interval increases from baseline > 60 ms 
 
The mean change from baseline value of QTcF will be plotted by treatment group 
and by time-point. The number of subjects presenting out-of-range and clinically 
relevant values will be summarised. 
 
Additional categorical analysis will be presented as follows: 
• 
 increase of PR from baseline >25% resulting in PR > 200 ms 
• 
 increase of QRS from baseline >25% resulting in QRS > 120 ms 
• 
 decrease of HR from baseline >25% resulting in HR < 50 bpm 
• 
 increase of HR from baseline >25% resulting in HR > 100 bpm. 
 
4.12 ECGs analyses (adjudicated) 
 


Statistical Analysis Plan 
 
 
 
C21007(MMV_SMC_21_01) SAP Final v1.0 17May2022.docx 
Page 17 of 21 
 
Analysis of drug related QT/QTc interval changes relative to plasma PK 
concentrations is optional and will be conducted as required. This analysis will focus 
on the known PQP-induced QTc prolongation and possible impact of PYR on this 
effect. The principles of this analysis follow the statistical methods described by 
Garnett et al., 2018 [1]. This analysis will be performed on the analysis set for 
intensive cardiac assessment. 
 
In addition, a per timepoint analysis will be performed. While this analysis is based 
on minimal assumptions on the nature of the data, it has limited power to show the 
absence of a prolonging effect. On the other hand, the concentration-QTc analysis 
has been shown to have this power, but it is based on more restrictive assumptions. 
Concentration/ QTc modelling may be performed after completion of the Clinical 
Study Report and will be delivered in a separate report. 
 
Baseline 
For all quantitative parameters, baseline will be the average over the values 
obtained at the three pre-dose timepoints of Day 1. 
Heart rate correction 
QTcF will be used for ECG analyses unless there is an effect of one of the drugs on 
HR exceeding 10 bpm. Evidence of the absence of such an effect will be considered 
given, if either the absolute mean time matched difference to placebo is below 10 
bpm for all timepoints and for both monotherapies and the combination therapy or 
a concentration-effect model similar to the one described for QTc below excludes an 
effect exceeding 10 bpm at relevant concentrations. If an effect of the therapy on 
HR cannot be excluded following the criteria above, QTcI and QTcS will be 
determined based on data extracted from the 24h Holter data and the primary 
correction method will be selected based on the mean squared slope criteria. 
More specifically, around 30 ECG snapshots will be extracted from Holters spread 
across the whole recording of Day 1, aiming to capture wide variety of HR values 
and RR and QT values determined. For each subject, these RR/QT pairs will be 
ranked by heart rate and the pairs with odd rank assigned to the training set and 
the remaining ones to the validation set. Based on the data in the training set, a 
regression of the form 
log(QT) ~ log(RR) + 1 
 
will be performed. Let βi be the regression coefficient ("slope") thus obtained for 
subject i, then the individual correction for this subject will be 
 
QTcI i= QT
RR
βi  
The exponent for the study-specific correction (QTcS) will be the median of the 
individual βi across subjects and the correction will be calcualted along the same 
lines. 
For each subject i and each of the three correcton methods QTcF, QTcI and QTcS, 
a linear regression on the pairs of RR and QTc in the validation set of that subject 
will be fitted and the slope bik for the regression of the validation data of subject i 
with method k be obtained. For each method, the mean squared slope across 


Statistical Analysis Plan
C21007(MMV_SMC_21_01) SAP Final v1.0 17May2022.docx 
Page 18 of 21
subjects will be determined and the method with the smallest mean slope will be 
used as primary correction method. 
Per timepoint analysis 
For all quantitative ECG parameters, descriptive statistics will be given for the 
change from baseline. In addition, for QTc, a linear model with the two treatments 
(PYR and PQP) and their interaction as factors and baseline as covariate will be fitted 
for each timepoint; the difference between each of the active treatments and 
placebo will be estimated based on this model; and two-sided 90% confidence 
intervals (CI) will be given. 
Hysteresis 
Hysteresis between the effect of each of the monotherapies and its concentration 
will be investigated based on the results of the per timepoint analysis and the mean 
concentrations under these therapies. These time courses will be displayed in two 
or three panels respectively using the same time axis and, in addition, as hysteresis 
loops, separately for Day 1 and Day 3. Finally the enGRI [4] may also be calculated. 
Concentration-QTc analysis 
Concentration-QTc analysis is optional and will be performed in future, as required. 
It might be based on a separate analysis plan and reported in an addendum to the 
final CSR or a separate report, as appropriate.  
This analysis will be based on the change of QTc from baseline and will use baseline 
QTc (centred on the mean across subjects) and the concentrations of PYR and PQP 
as covariates. Concentrations of relevant metabolites may also be included. 
Interaction between concentrations of PYR and PQP will also be included. Interaction 
terms with metabolites, if any, will not be used. 
Concentrations BLQ will be set to nought. Likewise, concentrations for participants 
under placebo will be set to nought, as well as those for the drug not given to a 
participant. 
Treatment with levels Placebo, PYR, PQP and combination (referred to as 
“treatment intercept” in the sequel) and time will be used as discrete fixed 
effects.(Note that the same timepoint at different days will be considered distinct.) 
A series of linear models including one or more of the concentrations will be fitted. 
The model including both moieties will have the form (in the notation of lmer in R): 
dQTc ~ TP + trt + CPYR*CPQP + Cbl -1 + (1 + CPYR + CPQP|Subj) 
where 
−
dQTc is the change from baseline of QTc
−
TP is the factor describing timepoints
−
trt is the treatment intercept
−
CPYR is the concentration of PYR
−
CPQP is the concentration of PQP
−
Cbl is the centered baseline
−
Subj is the factor describing participants (as unit of observation).
From this model simplified models will be derived by removing one of the 
concentrations variables. 
The most appropriate one will be selected based on the Akaike Information Criterion 
(AIC) and the size of the fixed treatment effect. A significant treatment effect (based 


Statistical Analysis Plan 
 
 
 
C21007(MMV_SMC_21_01) SAP Final v1.0 17May2022.docx 
Page 19 of 21 
 
on an F-test, p < 0.05 two sided) will be considered an indication for model misfit. 
For the best fitting linear model, predictions of the effect on QTc will be made. These 
predictions will be made separately for each treatment group and will be based on 
the mean concentrations of all moieties involved in the respective model. 
For the predictions, the Tmax of every moiety included in the model will be determined 
per participant and the mean concentration of all moieties involved at these 
timepoints will be used. Since a geometric mean will be nought if at least one of its 
components is BLQ, geometric means will only be used for the moiety for which Tmax 
was determined, for concentrations of moiety j at Tmax of moiety i with i ≠ j, 
arithmetic means will be used. 
 
Linearity of the concentration-ΔQTc relationship will be explored based on quantile 
plots as described in Garnett et al (2018) [1]. In addition, a significant treatment 
intercept can be interpreted as sign of either hysteresis or nonlinearity. If the best 
fitting linear model has a significant treatment effect, nonlinear e-max models will 
also be considered, and predictions will be made based on the best fitting model. 
In this case, hysteresis between QTc and the concentrations of the relevant 
analytes will be investigated graphically. 
If the above models fail to converge even after rescaling of the variables included 
to a range between [-30, 30] and [-100, 100], they will be simplified using these 
steps: Removal of random slopes and, if convergence is still not reached, simplifying 
of the covariance structure (originally unrestrained) to compound symmetry. 
 
Absence of an effect of concern of the IMP on QTc will be concluded if the predictions 
based on the best-fitting model at the concentrations described above exclude an 
effect exceeding 10 ms, i.e. the upper limit of the two-sided confidence interval for 
these predictions is below 10 ms. 
Assay sensitivity 
In a study analysing the effect of a combination of OZ439 and PQP, Darpö et al 
2015 [2] found an effect of PQP concentration on QTc of 0.0475 ms/(ng/mL) with a 
90 % confidence interval of (0.038, 0.057). If the effect of PQP in the primary linear 
model of this analysis is similar to this value, assay sensitivity will be deemed 
shown. 
 
Presentation of results 
For each model the parameter estimates with SE, t-value, df and two sided 90 % 
CI will be tabulated. The df and CI will be estimated based on the Kenward-Roger 
approximation. In addition, the following values will be tabulated for each model: 
AIC, residual variance, variance of each of the random effects, F-value for the 
treatment intercept with its corresponding p-value. 
dQTc will be plotted against the concentrations of both moieties, with treatment 
group shown by different symbols. For models based on one concentration only, a 
regression line shifted by the average of the time effects will be added. 
For each model, one or more quantile plots [1] will be presented using concentration 
of each concentration involved as abscissa and the partial residuals with respect to 
this concentration as ordinate. The predicted effect of the respective moiety will be 
given as a regression line with two-sided 90 % confidence range. Note that this 


Statistical Analysis Plan 
 
 
 
C21007(MMV_SMC_21_01) SAP Final v1.0 17May2022.docx 
Page 20 of 21 
 
effect can be obtained from the original dQTc values by subtracting the predictions 
had the same participant taken placebo and the concentrations of all moieties set 
to 0. 
 
4.13 Pharmacokinetic Data Reporting 
 
PK parameters and report will be generated by Pharmakinetic, PK TFLs will be 
generated by RPL. 
4.13.1 Pharmacokinetic Listings  
PK plasma concentration data will be listed for each individual subject by treatment 
and timepoint. In addition, the sum of the moiety data (proguanil and cycloguanil) 
will be listed individually according to treatment.  
PK parameters will be listed for each individual subject by treatment and timepoint. 
The data listings will be generated as defined by the PK population in PKAP. The 
data will be reported to the original decimal points as per source data. 
4.13.2 Pharmacokinetic Summary Tables 
Summary statistics for plasma concentrations (N - the number of participants, n – 
the number of samples, n(LLOQ) - the number of samples <LLOQ, arithmetic mean, 
SD - standard deviation, CV - coefficient of variation, geometric mean, median, 
minimum, maximum) will be calculated at each time point for each treatment.  
Summary statistics for the PK parameters (N - the number of participants, 
arithmetic mean, SD - standard deviation, CV - coefficient of variation, geometric 
mean, median, minimum, maximum) will be presented for each treatment group 
(except Tlag and Tmax). The Tmax and Tlag summary statistics will be provided as 
n, minimum, median and maximum only. 
 
4.13.3 Pharmacokinetic Figures 
Arithmetical mean plasma concentration vs. time curves for each analyte which 
includes all treatments will be produced on both linear/linear and log10/linear 
scales. 
Spaghetti plots of individual plasma concentrations against actual sampling times 
after dosing for each analyte and 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.  
 
4.13.4 Values Below the Limit of Quantification and Missing Values  
When calculating the figures and summary statistics for a concentration at a given 
time point, all BLQ values will be set to zero except when an individual BLQ falls 
between 2 quantifiable values, in which case it will be set to missing. Samples with 
no reportable value due to a bioanalytical issue or missing samples will be set to 
missing. 
 
 


Statistical Analysis Plan
C21007(MMV_SMC_21_01) SAP Final v1.0 17May2022.docx 
Page 21 of 21
4.14 Exploratory Analysis 
Blood samples for CYP polymorphism will be collected and analysis will be optional 
and may be performed retrospectively. SAP addendum will be issued as 
appropriate. 
3.
REFERENCES
1. Garnett C, Bonate P, Dang Q, Ferber G, Huang D, Liu J, Mehortra D,
Riley P, Sager P, Tornoe C, Wang Y. Scientific white paper on
concentration-QTc modelling. Journal of Pharmacokinetics and
Pharmacodynamics. 2018;45, 383-397.
https://link.springer.com/article/10.1007%2Fs10928-017-9558-5.
Accessed on 15 October 2021.
2. Tornøe CW et al (2011) Creation of a knowledge management system
for QT analyses. J Clin Pharmacol 51(7):1035–1042
3. Darpö B, Ferber G, Siegl P, Laurijssens B, Macintyre F, Toovey S,
Duparc S. Evaluation of the QT effect of a combination of piperaquine
and a novel anti-malarial drug candidate OZ439, for the treatment of
uncomplicated malaria. British Journal of Clinical Pharmacology.
2015;80(4):706-15. Accessed 29 November 2021.
4. Ferber, G., Darpo, B., Garnett, C. et al. Detection and impact of
hysteresis when evaluating a drug’s QTc effect using concentration-
QTc analysis. J Pharmacokinet Pharmacodyn 48 (2021) 187 - 202.
https://doi.org/10.1007/s10928-020-09725-w


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