Comparative Efficacy and Safety of Pyronaridine-Artesunate Versus Artemether-Lumefantrine in The Treatment of Acute Uncomplicated Malaria Among Children In South-West Nigeria
Phase: PHASE2
Conditions: Malaria Fever, Plasmodium Falciparum Malaria, Uncomplicated Malaria
Sponsor: University of Ibadan

COMPARATIVE EFFICACY AND SAFETY OF PYRONARIDINE-ARTESUNATE 
VERSUS ARTEMETHER-LUMEFANTRINE IN THE TREATMENT OF ACUTE 
UNCOMPLICATED MALARIA AMONG CHILDREN IN SOUTH-WEST NIGERIA. 
1 
 
 
 
 
 
Principal Investigator - Professor Catherine Olufunke FALADE 
 
University of Ibadan, Ibadan 
 
Institute for Advanced Medical Research and Training, University of Ibadan, Ibadan 
 
 
Telephone no: +234-8033264593, +234-8023609151 
 
E-mail Address: lillyfunke@yahoo.com; lillyfunke2012@gmail.com 
 
 
 
 
 
 
 
Date last updated: 
25 March 2019 

COMPARATIVE EFFICACY AND SAFETY OF PYRONARIDINE-ARTESUNATE 
VERSUS ARTEMETHER-LUMEFANTRINE IN THE TREATMENT OF ACUTE 
UNCOMPLICATED MALARIA AMONG CHILDREN IN SOUTH-WEST NIGERIA. 
2 
 
 
 
SUMMARY 
 
Malaria is a common protozoan infection that poses a serious health problem in the world today 
especially in tropical Africa where morbidity and mortality is high among pregnant women and 
children under five years of age. In Nigeria, malaria is the commonest reason for outpatient 
clinic attendance in childhood and is responsible for about 20 % of childhood deaths. The 
emergence of strains of P. falciparum resistant to chloroquine and sulfadoxine-pyrimethamine 
led to severe worsening of the morbidity and mortality from malaria. As a result of resistance 
to previously used monotherapy, the World Health Organization (WHO) in 2001, 
recommended that malaria endemic countries experiencing drug resistant malaria infection 
adopt combination therapy. Artemisinin-based combination therapy (ACT) is preferred to non- 
ACT combination 
 
This study is a randomized open label clinical trial that will compare the safety and efficacy 
of pyronaridine-artesunate and artemether-lumefantrine in the treatment of malaria among 
children aged 3 to 144 months who have microscopically confirmed symptomatic 
Plasmodium falciparum malaria. The study will be carried out at the Oni Memorial 
Children’s Hospital, Ring Road Ibadan. One hundred and sixty-two children between 3 and 
144 months who meet the inclusion criteria will be enrolled after obtaining written or 
witnessed signed informed consent from the parents or guardian. Details obtained from the 
enrolee will be entered into a case record form specifically designed for the purpose of 
accurate documentation. A detailed history and physical examination  will  be  carried  out  
on each enrolee.  Finger  prick  blood samples will be taken from each enrolee for thick 
blood smear for malaria parasite, haematocrit and blood spots on filter paper. Five millilitres 
of venous blood will be taken from an arm vein for baseline liver function tests, creatinine 
and random blood glucose on days 0, 3, 7 and 28. 
 
Enrolees will be randomized into one of two groups. Group one will receive pyronaridine- 
artesunate while group two will receive  artemether-lumefantrine  at  standard  doses. 
Enrolees will be seen daily from days 0-3, and on days 7, 14, 21 and 28. Study drugs will be 
administered supervised at standard dosage on days 0, 1, and 2. History taking, physical 
examination and blood smears will be done at each contact time. Special attention will be 
paid to adverse effects. 
 
Parasite clearance time, fever clearance time and cure rates will be compared between the  
two groups. The data collected from  the  participants  will  be  entered  into  Epi  info 
version 6 databases and then transferred to SPSS Statistics Software version 20 for statistical 
analysis. 

INTRODUCTION 
3 
 
 
 
Background of the study 
 
Malaria is an important protozoan infection which poses a major health problem in the world 
today.[1] The infection is endemic in most parts of the tropics, including Nigeria with a greater 
percentage of malaria incidence and deaths occurring amongst pregnant women and children 
under five years of age.[2] In Nigeria, malaria is the commonest reason for outpatient clinic 
attendance in childhood and is responsible for about 20 % of childhood deaths.[3] Malaria is 
the only vector borne disease placed on the World Health Organization’s disability adjusted 
life years (DALYS) list.[4] Of the approximately 3.4 billion people worldwide who are exposed 
to malaria yearly, the World Health Organization (WHO) states that there were about 219 
million cases of symptomatic malaria in 2016.[5] 
 
Although, mortality rates from malaria seem to have fallen globally and in the Africa region 
due to effective control measures, the disease continues to be a major threat to childhood health 
and development. In 2016 there were 445000 deaths with 80% of these occurring in children 
under 5years and pregnant women.[5] Chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) 
which were once very effective against the malaria parasite, have been replaced in many 
malaria-endemic countries by artemisinin-based combination therapies as first line drugs due 
to the emergence of resistance to these monotherapies in the malaria parasite following WHO 
recommendations[6]. Increasing parasite resistance to these old drugs and failure of malaria 
treatment with these single agents in many endemic countries of Africa led to a widespread 
promotion of artemisinin-based combination therapy (ACT) as a strategy for effective 
management of Plasmodium falciparum malaria. The World Health Organization (WHO) in 
2001 recommended that malaria endemic countries change their treatment policies and adopt 
combination therapy, and in particular artemisinin-based combination therapy as the first-line 
antimalarial treatment.[1] 
 
The artemisinins act by inhibiting Plasmodium falciparum encoded sarcoplasmic endoplasmic 
reticulum calcium ATPase. They inhibit development of gametocytes thus reducing 
transmission.[7] Gametocytes, the sexual stages of the malaria parasite, do not cause clinical 
disease but are vital to the maintenance of malaria transmission cycle. These gametocytes are 
present in symptomatic and asymptomatic parasitemic individuals.[7] The WHO defines 
artemisinin-based combination therapy for malaria as the simultaneous use of at least two 
efficacious schizonticidal drugs one of which is an artemisinin derivative. The two or more 
drugs must have different mechanisms of action and thus different biochemical targets in the 
parasite.[8] It is important that the two or more constituent drugs are efficacious and are used 
at individual full dosages. Artemisinin-based combination therapies (ACTs) are now the first- 
line treatment for acute uncomplicated malaria globally. They are more effective than the non- 
artemisinin–based combination or monotherapies, as they lead to rapid parasite clearance, 
hasten clinical recovery and reduce the chances of development of drug resistance in the 
parasite.[1] 

4 
 
 
Artemether-lumefantrine (AL) is the first fixed - dose ACT to be pre-qualified by the WHO 
and the most commonly used ACT as first-line drug for the treatment of uncomplicated 
falciparum malaria in sub-Sahara Africa.[6, 8]. It has also been extensively studied in 
Nigeria.[9-11] Artesunate-amodiaquine (ASAQ) the second most widely used ACT globally 
after artemether-lumefantrine is also currently used as a first line treatment in some countries 
in sub-Saharan Africa.[12-14] However, ASAQ is disadvantaged by the variability in dosing 
regimens between the different formulations of ASAQ.[15, 16] Dihydroartemisinin- 
piperaquine (DP) is another ACT that has been recommended by the WHO for use in the 
treatment of acute uncomplicated malaria.[17] However, DP is not widely used in sub-Saharan 
Africa compared to AL as its recommendation by the WHO is more recent.[1] 
Dihydroartemisinin-piperaquine has the advantage of daily dosing and does not require taking 
it with meal. The long half-life of piperaquine confers on DP a longer post treatment 
chemoprophylaxis when compared with AL.[18] 
 
There are limitations to the use of AL which is the commonly used ACT in Nigeria. These 
include high number of dosing (six) which is not convenient and the need to give the drug with 
fatty food for optimal absorption of lumefantrine because of its high lipophilic property.[19] 
Pyronaridine, a Mannich base 1-aza-acridine structurally related to mepacrine and 
amopyroquine, one of the earliest synthetic antimalarial drugs, was first developed in China 
over 30 years ago. It has been used as monotherapy in parts of Asia and China.[20] 
Pyronaridine, is a benzonaphthyridine derivative that is active against Plasmodium falciparum 
and Plasmodium vivax.[21, 22] 14 
 
Pyronaridine-Artesunate (PA) is a novel fixed dose ACT drug that received a Positive Opinion 
through Article 58 from the European Medicine Agency1 (EMA). This Positive Opinion is a 
stringent regulatory review and approval granted for a specific group of drugs that will not be 
marketed in Europe. This rigorous review process is performed in conjunction with the WHO. 
At the time of the Positive Opinion (registration) PA also obtained WHO prequalification 
status. Pyramax received approval with EMA for the treatment of acute uncomplicated P. 
falciparum and P. vivax malaria. Subsequent EMA approvals have been granted for repeated 
dosing and for the paediatric formulation of granules in sachets. pyronaridine-artesunate has 
been found to have good efficacy and tolerability and is cost effective.[23-26] Like DP, 
pyronaridine-artesunate has a daily dosing regimen and can be taken with or without meals.[23] 
The studies conducted so far on the efficacy and tolerability of PA showed that other ACTs 
were not superior to it and there were strong recommendations that PA should be included as 
a standard antimalarial treatment.[27] The most commonly reported adverse effects were 
headache, eosinophilia, neutropenia, anaemia, increased platelet count, vomiting, abdominal 
pain, bradycardia, short lasting transaminase increases and hypoglycaemia.16 Other studies 
reported vomiting which may be due to it bitter taste, nausea, loss of appetite and cough.[27] 
More recent studies provide increasing evidence on the safety of Pyramax.[28, 29] 
 
 
 
 
 

5 
 
 
1 
RATIONALE FOR THE STUDY 
 
The World Health Organization currently recommends the use of one of five different 
artemisinin-based combination therapies (ACTs) for the treatment of acute uncomplicated 
falciparum malaria [1]. Studies conducted on pyronaridine-artesunate (Pyramax™ Shin 
Poong) showed that it compared well in terms of efficacy and safety with other ACTs. EMA 
granted positive opinion through Article 58 to Pyramax tablet in 2013 and to Pyramax granules 
in 2015, this stringent regulatory authority recognition confirms that Pyramax can be used in 
malaria patients and, in particular, in African children. However, additional studies are needed 
to confirm, in parallel to the launch of Pyramax, the good safety and efficacy observed in the 
Phase III program and in the peri-approval (WANECAM) study. The WHO is however yet to 
make a statement on the unconditional inclusion of pyronaridine-artesunate in the treatment 
guidelines, which may not be unconnected with limited amount of data available for a new 
product. Hence the more the observations recorded across different malaria endemic countries 
and in real life scenarios the greater the degree of confidence on the safety of the drug. This 
will enhance the possibility of having a greater role in the management of uncomplicated 
malaria. 
 
The need for a cost effective and user friendly antimalarial with good efficacy and tolerability 
is highly desirable to expand the number of ACTs in Nigeria and the need to continue efforts 
to optimize efficacy, tolerability, costs, and treatment regimens has led to this clinical trial. 
Whereas the therapeutic and efficacy studies are often used to select ACTs for programmatic 
deployment, the National Malaria Elimination Programme (NMEP) in Nigeria has restructured 
and streamlined the conduct of Therapeutic Efficacy Studies (TES) restricting each cycle to 
just about 3-4 sentinel cites per year. Under the current arrangement, Pyronaridine-artesunate 
will not be included in the country’s 2018 TES. A TES efficacy study conducted that is well 
aligned with the national TES protocol will provide important opportunity for expanding the 
use of pyronaridine-artesunate in Nigeria. 
 
It is also important to continue to assess the efficacy of AL, the ACT of choice in Nigeria in 
order to detect early loss of efficacy as the country is an endemic region for malaria. In the 
results of the WANECAM study, the efficacy PCR corrected (recrudescence of the initial 
infection) is the same between Pyramax and AL, while PCR uncorrected (new infection) is 
different and Pyramax is better than AL. In addition, the safety and efficacy of pyronaridine- 
artesunate in children less than 20kg shall be studied, especially in children under 1year of age 
which this study intends to cover. 
 
2 
OBJECTIVES 
 
The aim of the study is to compare the safety and efficacy of Pyronaridine-Artesunate (PA) 
and Artemether-Lumefantrine (AL) in children aged between 3 months and 12 years with acute 
uncomplicated malaria in south-west Nigeria. 

6 
 
 
2.1 
SPECIFIC OBJECTIVES 
1. Primary: 
 
To determine the comparative efficacy of pyronaridine-artesunate and artemether- 
lumefantrine in the treatment of acute uncomplicated malaria in children in south-west 
Nigeria. 
2. Secondary: 
 
i. To compare the efficacy and safety (crude – ACPR) of pyronaridine-artesunate and 
artemether-lumefantrine in the treatment of acute uncomplicated malaria in children in 
south-west Nigeria 
ii. To determine and compare the parasite clearance time and the fever clearance time of 
pyronaridine-artesunate and artemether-lumefantrine in the treatment of acute 
uncomplicated malaria in children in south-west Nigeria 
iii. To determine and compare gametocyte carriage between pyronaridine-artesunate and 
artemether-lumefantrine during treatment of acute uncomplicated malaria in children 
in south-west Nigeria 
iv. To compare the PCR Corrected cure rates of pyronaridine-artesunate and artemether- 
lumefantrine in the treatment of acute uncomplicated malaria in children in south-west 
Nigeria 
 
3 
INVESTIGATION PLAN 
3.1 
Study Design 
3.2 
This is a randomized open label trial that will compare the safety and efficacy of PA and 
AL in patients of both sexes between the ages of 3 months and 10 years who have 
symptomatic microscopically confirmed acute uncomplicated Plasmodium falciparum 
malaria. Patients will be randomized following a pre-generated randomization code. On 
the basis of the results of these assessments, the patients will be classified as having 
therapeutic failure (early or late) or adequate clinical and parasitological response 
(ACPR). The proportion of patients experiencing therapeutic failure during the follow- 
up period will be used to estimate the efficacy of the study drug(s). The primary outcome 
will be PCR-adjusted adequate clinical and parasitological response (ACPR) i.e., absence 
of patent parasitaemia, regardless of axillary temperature and without evidence of 
previous treatment failure up to day 28. Secondary outcomes will be adequate clinical 
and parasitological response without correction for reinfection, parasite clearance time, 
fever clearance time and the proportions of patients who are aparasitaemic or apyretic on 
days1, 2, and 3. 
3.3 
Study Site 
The study will be conducted in Oni Memorial Children’s Hospital, Ring Road, Ibadan. Ibadan, 
the capital of Oyo state is a highly populated city located in the rain forest belt of south-western 
Nigeria. Malaria transmission is intense and occurs all year round in the study area. The total 
population of Oyo state is estimated to be about 5.5 million with about 3.8 million people in 

7 
 
 
Ibadan alone. Ibadan has a land mass of 28,245.26 km. Oni Memorial Hospital serves a mix 
of urban and rural populations as rural patients are referred to it, though more of its patients are 
from the urban populations. 
 
3.4 
Timing and Duration of Study 
The study will be conducted during the high malaria transmission season, from April 2019 to 
September 2019. 
 
3.5 
Study Population 
The study population will consist of patients with uncomplicated P. falciparum malaria 
attending the study hospital who are aged between 3 and 144 months of age. 
 
 
3.6 
Sample Size Calculation 
(Z 
+ Z 
)
2 P (1 − P ) + P (1 − P ) 
n = 
1− 
1− 
1 
1 
2 
2 
 
 
For Ref – Chow et al, 2008 (see 
 − (P  − P )
2
 
1 
2 
 
attachment) 
 
Where 
 
Z1-α= standard normal deviate for level of significance; at α=0.05, it is 1.96 
Z1-β= standard normal deviate for power (1-β); at β=0.2 (80% power), it is 0.84 but at β=0.1 
(90%), it is 1.28 
P1: 28-day cure rate in AL = 96.4% 
P2: 28-day cure rate in PA = 98.9% 
ε: non-inferiority margin= 5% 
Applying the formula and parameters above, sample size for each group 
90% power: 70 per group [total 140] 
80% power: 51 per group [total 102] 
Assuming a difference of 2.5% in cure rate between PA and AL (98.9% vs 96.4%) [REF- Roth 
et al, 2018], 140 patients are required to be 90% sure that the upper limit of a one-sided 95% 
confidence interval will exclude a difference in favor of the standard group of more than 5% 
 
Total N = 140. Allowing for 20% loss to follow up, the total number of patients required 
would be 168 to give 84 patients per arm. (See sample size calculation attachment) 

8 
 
 
3.6.1 Inclusion criteria 
 
• Individuals of either gender between the ages of 3months (but weight ≥5 kg) and 12 
years who present with symptoms compatible with acute uncomplicated malaria 
• Minimum asexual parasite density of 1000/µl. This will be done at enrolment for all 
study participants. 
• Fever with an axillary temperature≥ 37.5°C or history of fever within 24hours of 
presentation 
• Residence within 15 kilometers to study site 
• Ability to take drugs orally 
• Absence of history of ACT intake in the two weeks prior to enrolment 
• A signed informed consent from parents or guardian of prospective enrollee to 
participate in the study 
 
3.6.2 Exclusion criteria 
 
• History of allergy to study drugs i.e. artemisinins, lumefantrine and pyronaridine 
• Any concurrent illness that could hamper evaluation of response e.g. bacterial 
infections, viral infections, severe gastrointestinal disease, malnutrition (weight for 
height <70%) 
• Presence of clinical evidence of severe malaria such as prostration, inability to drink or 
breast feed, persistent vomiting, convulsion, severe anemia hemoglobin <5 g/dl), 
unarousable coma 
• Patients with known chronic diseases like chronic kidney disease, chronic liver disease, 
malnutrition, cardiac failure, Sickle Cell haemoglobin (HbSS) etc. 
• mixed or mono-infection with another Plasmodium species detected by microscopy; 
• presence of severe malnutrition defined as a child aged between 6-60 months whose 
weight-for-high is below –3 z-score, or has symmetrical edema involving at least the 
feet or has a mid-upper arm circumference < 115 mm) 
• Parent or guardian who in the judgment of the investigator will not comply with 
protocol in the opinion of the investigator 
3.7 
Sample Collection Procedure 
 
Enrollees who have fulfilled the inclusion criteria would have the details of the study explained 
thoroughly to them. The parent or guardian will be required to sign an informed consent form 
once they agree to participate in the study. All enrollees will have a case record form (CRF). 
The CRF will be used to collect the following details. 
1. Socio-demographic, clinical and laboratory details of all enrollees in the study. The CRF 
will also have the contact information of each enrollee as well as the past medical history. 
 
2. Record details of each visit: These will include clinical details that would be assessed at each 
clinic visits, including physical examinations, blood film for malaria parasite, and hematocrit 
values for each enrollee. Any change in contact details or living situation would be noted. 

9 
 
 
For the enrollees, a medical history will be obtained from parent/guardian including presenting 
symptoms and current medications. Physical examination will be performed; weight and 
axillary temperature recorded. A finger prick blood sample will be obtained for thick blood 
smears and blood spots on filter paper for parasite genotyping. Five milliliters of venous blood 
sample will also be obtained for assessment of hematological and biochemical parameters. 
 
Blood film for malaria parasite: Thick blood film will be prepared from finger prick sample 
of each enrollee at each contact time, stained with fresh 10% Giemsa stain at pH 7.2 and read 
under a light microscope at X1000 magnification. Gametocyte carriage will be specifically 
looked out for in the thick film on all contact days. Blood spots on filter paper will be obtained 
at enrollment and at follow up. This will be used for DNA analysis by polymerase chain 
reaction (PCR) to differentiate re-infection from recrudescence 
 
Blood chemistry and hematology: 5mls of venous blood samples would be taken for clinical 
chemistry (electrolytes, urea and creatinine as well as a liver function test) evaluation at day 0 
and on the follow up days. 
 
Hematocrit measurement: This will be done by the micro-hematocrit method and the result 
recorded in percentage. The hematocrit will be done at enrolment and at each clinic visit. 
 
3.7.1 Drug administration 
 
Study participants will then be assigned into one of the two treatment groups according to a 
pre-generated randomization code. Drug treatment will be given in the clinic supervised. 
 
Pyronaridine-artesunate: 
Children randomized to group 1 will receive three doses of pyronaridine-artesunate granules 
or tablets (Pyramax®) manufactured by Shin Poong Pharmaceuticals depending on their body 
weights. Pyramax® granules comes in sachets with each containing 60mg of 
pyronaridine/20mg of artesunate while Pyramax tablets contain180mg pyronaridine/60mg 
artesunate. Pyramax dosing is once daily for three days. Dosing will be according to the chart 
below: 
 
Body weight 
No of sachets or Tablets Regimen 
5 - < 8kg 
1 Sachet 
Daily for 3 days 
8 - < 15Kg 
2 sachets 
Daily for 3 days 
15 - < 20 Kg 
3 Sachets 
Daily for 3 days 
20 - < 24 Kg 
1 Tablet 
Daily for 3 days 
24 - <45 Kg 
2 Tablets 
Daily for 3 days 

10 
 
 
Artemether-lumefantrine: 
 
The study participants randomized to group 2 will receive the standard six-dose regimen of 
artemether-lumefantrine dispersible tablets (Coartem® Novartis pharma) twice daily according 
to body weights. Each dispersible tablet of Coartem® contains 20mg of artemether/120mg of 
lumefantrine) and patient will be dosed as follows 
 
Body weight 
No of dispersible Tablets 
5 -<15 Kg 
1 tablet 
15 - < 25 Kg 
2 tablets 
25 - <35 Kg 
3 Tablets 
≥35 Kg 
4 Tablets 
 
 
 
5 -<15Kg one tablet, 15 - <25 Kg two tablets, 25 - <35 Kg three tablets, and ≥35 Kg four tablets 
at the following dosing intervals 
• 0 hour - 1st dose; 
• 8 hours – 2nd dose; 
• 24 hours – 3rd dose; 
• 36 hours – 4th dose; 
• 48 hours – 5th dose 
• 60 hours – 6th dose. 
 
The first, third and fifth doses will be administered supervised in the clinic with water (very 
young children or a glass of milk while the second, fourth and sixth doses will be given by the 
care-giver at home 8 hours and 12 hours respectively after the first and subsequent morning 
doses. Mothers will be encouraged to breastfeed very young babies still on the breast soon 
after drug administration. Parent/guardian will be provided a sachet of milk after consultation 
on days 0, 1 and 2 for the 2nd, 4th and 6th doses of AL. Parents and care-givers will be also 
advised to give Coartem™ with a fatty meal e.g. fried plantain or bean porridge (local fatty 
meals) for the older children especially those who cannot tolerate milk. 
 
Each enrollee will then be observed in the clinic for 1 hour after drug administration for 
vomiting. If vomiting occurs within 30 minutes of drug administration, the full treatment dose 
(PA or AL) will be re-administered. If vomiting occurred between 30-60 minutes of drug 
administration, half the treatment dose will be re-administered. Any enrollee who vomits the 
repeat dose will be withdrawn from the study and treated with another ACT. 
 
No other antimalarial therapy will be allowed/given throughout the study period (28 days) 
except there is parasite recurrence. Paracetamol – an antipyretic drug will be administered to 
study participants with axillary temperatures ≥38.5°C at standard dosage. 

11 
 
 
3.7.2 Follow-up 
 
Clinical and parasitological evaluation will be done on each day of follow-up or on any other 
day if the patient feels unwell. Patients will be reminded by phone calls 30minutes before the 
next dose of AL and on the day before the follow up visit (all enrollees i.e. PA and AL arms) 
and those who fail to attend follow up will be visited at home. Transportation fare will be given 
as incentives to the parents or care givers to encourage attendance for follow up. During each 
visit, a brief clinical history will be obtained to assess new complaints and possible side effects 
of medications and a physical examination will also be performed. Hematocrit and chemical 
analysis (bilirubin, blood glucose, creatinine and liver enzymes- AST, ALT & Alkaline 
Phosphatase) will be done on at enrolment and follow up on days 3, 7 and 28 to monitor 
possible changes. 
 
Filter paper blood samples for parasite genotyping will be obtained on day 0, 3, 7, 14, 21 and 
28 or earlier if enrollee is symptomatic. A finger prick blood sample will be taken to prepare 
thick blood smears on days 1, 2, 3, 7, 14, 21, 28 and on any other (unscheduled) visit. The 
slides will be air-dried away from direct sunlight, stained with fresh 10% Giemsa at pH 7.2 for 
15 to 20 minutes and read independently by two microscopists. Parasite density (the number 
of asexual parasites per µl) will be calculated by counting parasites against about 200 
leukocytes and assuming a leukocyte count of 8,000/µl of blood 36. A smear will be considered 
negative only after screening at least 200 high power fields. However, a slide will be read 
against 500 leukocytes before it is declared negative. All discordant smears and slides with a 
parasite density difference >10% will be read by an independent microscopist and the PI. For 
quality control 5% of randomly selected slides will be read by an independent microscopist not 
involved in the study. 
 
Paired samples (D0 and Day of recurrence) of blood spots on filter paper collected from 
patients with parasite recurrence on or before D28 will be analyzed using PCR techniques for 
parasite DNA. 
 
Enrollee will be withdrawn from the study if the parent/care giver withdraws consent, enrollee 
develop serious concomitant illness or report taking other unauthorized anti-malarial 
medication apart from the study drugs during the follow-up period. Those who withdraw 
consent will be revolved back to the hospital care while those who develop serious concomitant 
illness would have immediate medical care given to them and thereafter be referred for 
specialist care at Oni memorial children’s hospital or University College Hospital, Ibadan at 
no cost to them. Enrollees who fail treatment with either of the two ACTs being evaluated will 
receive the alternative ACT under supervision. 
 
Daily checks and corrections will be carried out on the CRF of enrollees seen to ensure 
correctness and accuracy. Blood samples collected from study participants will be transported 
to the respective laboratories in the University College Hospital Ibadan for analysis of blood 
chemistry and hematology parameters the same day they are collected. Efficacy parameters 
will be evaluated as follows: 

12 
 
 
• Efficacy evaluation will be based on WHO criteria of treatment outcome as follows; 
(1) Early treatment failure (ETF; danger signs or complicated malaria or failure to 
adequately respond to therapy on days 0–3); (2) Late clinical failure (LCF; danger signs 
or complicated malaria or fever and parasitemia on days 4–28 without previously 
meeting criteria for ETF or LPF); (3) Late parasitological failure (LPF; asymptomatic 
parasitemia on days 7–28 without previously meeting criteria for ETF or LCF); (4) 
Adequate clinical and parasitological response (ACPR; absence of parasitemia on day 
28 without previously meeting criteria for ETF, LCF, or LPF). 
• Recrudescence will be defined as the recurrence of asexual parasitemia within 28 days 
following antimalarial treatment comprising the same genotypes that caused the 
original illness. This is believed to result from incomplete clearance of asexual 
parasitemia because of inadequate or ineffective treatment. 
• Parasite clearance time: time from first dose of ACT until first total and continued 
disappearance of asexual parasite forms. 
• Fever clearance time: time from first dose until the first time the body temperature 
(for those with a raised temperature at enrolment) decrease to below 37.5oC and remain 
so for at least 24 hours. 
• Gametocyte carriage: proportions of patients with gametocyte at a given point in time 
using the Area Under the Curve Graph for PA will be compared with that of AL. 
 
3.7.3 Safety parameters will be evaluated as follows: 
 
• Safety will be analyzed in terms of adverse events and severe adverse events using 
clinical signs, symptoms and laboratory parameters. 
• Liver enzymes (ALT/AST) >3 times upper limit of normal (ULN) plus peak total 
bilirubin >2 times ULN in the absence of a significant alkaline phosphatase increase 
(= Hy's law) will be deemed as serious adverse effects (SAE). 
• ALT and AST >5 times ULN will be deemed an AESI. (see below) 
 
Serious Adverse Events 
An adverse event will be considered serious is it fulfils one of the following criteria: 
• causes death or 
• is life-threatening or necessitates hospitalization or prolongs hospitalization or 
results in persistent or significant disability/incapacity or is a medically important event 
constitutes a possible Hy’s Law 
An example of an important medical event is one that while not-immediately life- 
threatening might become so if there had been no intervention 
In case of SAEs, independent of causality, the healthcare personnel must immediately 
contact the PI / Investigator for validation of the seriousness and determination of the 
causality. 

13 
 
 
Subsequently, the procedure described below must be followed: 
• 
SEND (within 24 hours and pdf scanned documents) the signed and dated copy of 
the “Adverse Event form” and the form “SAE complementary information” to Shin 
Poong Pharmacovigilance (PV) (Tel/Fax +44 203 291 3032 or email: 
safety@artemidapharma.com) 
• 
Contact immediately (the same day) the medical monitor/Pyramax QPPV responsible 
for safety in case of death or life-threatening events. 
• 
The follow-up of each fatal or life-threatening AE must be provided to the medical 
monitor and Shin Poong PV within the same timeline as the initial report (within 24 
hours and preferably by email). 
• 
ATTACH to the Case Record Form (CRF) the photocopy of all available results and 
examinations which were undertaken (and their date). Analysis results must be 
accompanied by the laboratory normal ranges. Special consideration shall be taken to 
ensure patient anonymity, and to the correct completion of the patient’s study specific 
identifier in the copies of the source documents provided to the sponsor. 
 
Causality 
 
All adverse events must have causality assigned by the investigator. As a guide causality 
can be assigned as follows: 
• Not related 
o The Investigator has determined that the adverse event is not related to the 
study medication 
o The current state of knowledge indicates that a relationship to the use of 
study medication is unlikely 
• Related 
o The Investigator has determined that the event has a reasonable relationship 
to the use of the study medication 
o The Investigator has determined that the complication is more than likely 
related to the study medication 
 
3.7.4 Adverse event of special interest 
An adverse event of special interest (AESI) is an adverse event for which on-going 
monitoring is appropriate within the context of the study. These events necessitate 
complementary examinations in order to characterize and understand them. 
AESIs in this study can be related to: 
 
Hepatotoxicity 
Presenting with fatigue, nausea, abdominal pain itching or signs of jaundice such as dark 
urine, putty or mastic colored stools, jaundice 
And/or 
ALT or AST >5 x Upper Limit of Normal (ULN) (Patients with normal baseline LFTS) 
Or ALT or AST >3 x ULN and total bilirubin >2 x ULN (Potential Hy’s Law) 

14 
 
 
Or ALT or AST >2 x the baseline value if >2 x ULN at baseline 
If these occur then a hepatitis panel should be performed 
 
• 
Hypersensitivity 
o Flushing, appearance of wheals/urticaria, breathlessness, Faintness and/or fall 
in blood pressure occurring soon after Pyramax administration 
 
The study team, as well as the relevant referral facilities, should be trained to take particular 
notice of symptoms/signs suggestive of the AESIs in this study. 
In case of an AESI confirmed by the study physician, Shin Poong PV shall be informed within 
24 hours by fax or email using the contact details above, even if the event does not satisfy any 
condition of seriousness. Notification will occur through the use of an AESI form. 
Note that AESIs should only be reported as a serious adverse event if they fulfill the criteria 
for seriousness. 
3.7.5 Follow-up of Adverse Events 
 
The healthcare personnel must take all appropriate measures to protect the safety of the 
patients. Personnel must ensure to document follow-up of the evolution of each adverse event 
(clinical, biological or other) until resolution or until the stabilization of the patient’s status. 
 
All new relevant information concerning the initial SAE shall be recorded on a form “SAE 
follow-up information form” by the nursing staff of the health centre, and shall be validated by 
the PI/co-PI who shall transfer the form to the local person/physician responsible for the 
pharmacovigilance of the project and Shin Poong PV. 
In case of a serious adverse event the patient must be followed until complete resolution and 
normalization of all analysis results, or until chronicity of the patient’s status. This can imply 
that the follow-up of the patient must continue beyond the period of follow-up per protocol, 
and that additional investigations could be requested. 
 
 
 
DATA ANALYSIS. 
 
Data will be entered into the computer using the Epi-data software. This subsequently would 
be cleaned and transferred to SPSS Statistic Software version 20 for analysis. The outcome of 
interest (dependent variable) presented as a categorical variable with, presence of malarial 
parasitemia, and the level of efficacy reported. The independent or explanatory variable of 
interest in this study would be use of chemotherapy. All independent variable would be 
reported as categorical. Proportions of treatment outcome will be compared by using chi 
square. Normally distributed continuous data will be compared using unpaired student t-test. 
Mean values will be given as mean ± SD and values of P <0.05 will be considered statistically 
significant. 

15 
 
 
 

16 
 
 
ETHICAL CONSIDERATIONS 
 
 
This study, will be a prospective randomized open label clinical trial comparing the safety and 
efficacy of Pyronaridine-artesunate and Artemether-lumefantrine in the treatment of 
symptomatic acute uncomplicated malaria in Nigerian children aged 3 to 144 months who 
seek treatment in the study hospital. The studies will be conducted according to  Good 
Clinical Practice and the Declaration of Helsinki. 
 
Confidentiality of data: Personal details of enrollees in the study will be treated with utmost 
confidentiality, as it is against the principles of good clinical practice to make such information 
public. Also, codes will be assigned to all participants. 
 
Translation of the informed consent to the local language: The informed consent has been 
translated to Yoruba (the local language) and is attached. Translation will has been verified for 
consistency and accuracy by an independent translator. The consent form will include the 
purpose of the study, risks and benefits to participants, confidentiality and voluntariness. 
Beneficence to Enrollees: Enrollees in this study will have the advantage of been treated for 
malaria and any related febrile illnesses with no cost. Also, findings in the study will be useful 
in monitoring artemisinin resistance in Nigeria. 
 
Non-maleficence to Enrollees: There is little or no risk involved in this study. Blood samples 
that will be collected from the prospective arm of the study will be via venipuncture technique 
which will be done by a qualified medical officer. The participant will only feel a mild pain 
and there may be a bruise which will go away in a few days. 
 
Voluntariness: Enrollees in the study are absolutely free to decline or withdraw from the study 
without jeopardy and without loss of benefits to which they are entitled. 

17 
 
 
 
Summary of Activities 
 
ACTIVITY 
Day 0 
Day 1 
Day 2 
Day 3 
Day 7 
Day 14 
Day 21 Day 28 
Extra 
Visit 
Extra 
Visit 
Demographic data and 
clinical assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood smear – (Thick & 
Thin) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood spot on filter paper 
(for PCR) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haematocrit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full blood count 
X 
 X 
 X 
X 
X 
X 
Blood Chemistry – 
Creatinine & Random 
Blood glucose 
X 
X 
X 
X 
Liver Function test- AST, 
ALT, Bilirubin & Alkaline 
Phosphate 
X 
X 
X 
X 
Adverse events recording 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant treatments 
recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study medications (AL or 
PA) 
X 
X 
X 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER- 
LUMEFANTRINE STUDY 
Study ID- PAAL: …………. 
24 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMED CONSENT FORM 
 
IRB Research approval number ------------------------------ 
 
This approval will lapse on ------------------------------ 
 
Title: COMPARATIVE SAFETY AND EFFICACY OF PYRONARIDINE-ARTESUNATE 
VERSUS 
ARTEMETHER-LUMEFANTRINE 
FOR 
THE 
TREATMENT 
OF 
UNCOMPLICATED MALARIA IN SOUTH-WEST NIGERIA. 
 
NAME AND AFFILIATION OF RESEARCHER: 
 
This study is being conducted by Professor Catherine Falade of the Institute for Advanced Medical 
Research & Training, College of Medicine, University of Ibadan. 
 
PURPOSE OF RESEARCH: The purpose of the research is to determine the safety and how well 
two important drugs named Pyronaridine-artesunate (PA) and artemether-lumefantrine (AL) work 
when they are given to children suffering from simple malaria. 
 
PROCEDURE OF THE RESEARCH: Malaria is a parasitic infection and an important cause of 
ill health in the world especially in tropical regions such as Nigeria. Children are particularly 
affected by malaria which can very easily become serious sometimes leading to hospitalization and 
even death. Illness and death from malaria has reduced in the last ten years because of the use of 
very effective antimalarial drugs called artemisinin-based combination therapy (ACT) and the use 
of protective measures such as insecticide treated nets (ITN). 
 
AL is the first ACT approved by the World Health Organization and also the drug recommended 
in the Nigerian National Malaria Treatment Guidelines while PA is a newer ACT recently approved 
for the treatment of malaria by the WHO. During this study we will treat children aged between 3 
and 144 months who have confirmed malaria with AL or PA. This is to allow us to determine the 
safety and efficacy of PA compared with AL. The results will also provide an evidence for use of 
another ACT for treatment of malaria among Nigerian children. 
I am asking for your permission to allow your child to take part in this study because your child has 
malaria. Your child will be examined thoroughly by a doctor. A few drops of blood will be obtained 
by finger prick. This will be used to prepare blood smear on glass slides for malaria parasite, blood 
spots on filter paper for advanced biology studies and into a thin glass tubes to measure how much 
blood the child has. About a teaspoon of blood will be taken from an arm vein to assess the state of 
the liver and kidneys on the day of enrolment, on Days 3, 7 and 28 days after starting treatment to 
be sure the drug has no effects on the kidneys and liver of your child. 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER- 
LUMEFANTRINE STUDY 
Study ID- PAAL: …………. 
25 
 
 
Your children will be treated with PA or AL given at the clinic daily for 3 days. The treatment of 
choice will be administered supervised. He/she will be will be expected to come to the clinic for 
follow up visit daily on days 7,14, 21 and 28. At every visit, you will be asked to tell us about the 
progress of your child’s health and any unusual symptoms you have noticed. Your child will also 
be examined properly and a finger prick for blood tests as previously done. This is to find out how 
rapidly the parasites are clearing from the blood and also to check other parameters about your 
child. 
EXPECTED DURATION OF RESEARCH: The study will run for 28 days for each child and you 
are expected to bring your child all through this period. It is important that they are brought to the 
clinic on these scheduled days and if you are not able to return on these days please let us know. 
The regular follow up visit will allow us to monitor the progress of your child and also to treat them 
if they are unwell at any time during the study. Do not hesitate to bring your child back to the clinic 
at any time if you have concerns. 
RISK: This study to the best of our knowledge will not expose your child unnecessarily to any 
danger. However, the child may experience slight pain and bruises from the needle prick and 
venepuncture. This pain will go away in a few days. There is also a possibility for the enzymes from 
the liver to rise temporarily. Usually this will correct in a few days. 
COST TO PARTICIPANTS: All tests as well as treatment will not cost you any money. The cost 
of transportation to and from the hospital will also be refunded at each follow up visit. 
BENEFIT: Your child will be evaluated, investigated and treated very closely. The data will be 
used in scientific publications and also for improving the healthcare of the children with malaria. 
CONFIDENTIALITY: Data collected from this study will be treated with strict confidentiality. 
Your name will not be made public by the investigators and only authorized research staff will have 
access to your child’s details. 
VOLUNTARINESS: Taking part in this study is voluntary. You are free not to participate in this 
study. 
ALTERNATIVES TO PARTICIPATION: If you choose not to allow your child participate in this 
study, the child will receive care from health care workers in the study center. 
CONSEQUENCES OF WITHDRAWAL AND TERMINATION OF PARTICIPATION: You 
have the right to withdraw from the study at any time if you so wish without any repercussion. 
However, it may not be possible to remove all information and test results obtained before 
withdrawal. After withdrawal from the study, your child will continue to receive care from the study 
hospital (Oni memorial children’s hospital). 
If your child comes with or develop other serious illnesses or fails to respond to treatment given 
during this study, your child will be given an alternative drug. If your child develops a side effect 
or another illness, he/she will be given immediate medical care and referred to the appropriate 
specialist at Oni memorial hospital or UCH, Ibadan for further care. 
IN CASE OF INJURY OR ADVERSE EFFECTS: All procedures in this study are not harmful 
and we will not involve your child in any harmful practices. In case of adverse events from the 
medications, your child will be treated at UCH at no cost to you. 
AFTER THE RESEARCH, WHAT HAPPENS? After the study you may have access to 
information about your child's health status. 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER- 
LUMEFANTRINE STUDY 
Study ID- PAAL: …………. 
26 
 
 
STATEMENT OF PERSON TAKING INFORMED CONSENT: 
Do you have any questions? 
 
 
 
I have fully explained this research to -------------------------------------------------------- and have 
given sufficient information including the risks and benefits to make an informed consent. 
STATEMENT OF PERSON GIVING INFORMED CONSENT: 
I have read the above information or it has been read to me and I understand the contents. I have 
also asked questions about the study and my questions have been answered to my satisfaction. 
I  
of  -----------------------  
hereby consent 
that my child/ward -------------------------------study ID ----------- participate in this study. 
I understand that I have the right to withdraw my child/ward from the study at any time without it 
affecting his/her medical care in any way. 
 
 
 
 
Parents Name/signature, date 
Investigators Name/signature, date 
 
 
 
 
Witness Name and signature & date 
 
 
In case of emergency, please contact Professor Catherine O. Falade Institute for Advance 
Medical Research and Training, College of Medicine, Ibadan. Telephone 08033264593, E-mail 
– lillyfunke@yahoo.com 
OR 
Dr. Fiyinfoluwa Olusola, Institute for Advance Medical Research and Training, College of 
Medicine, UCH Ibadan. Telephone - 08099471018. Email – fiyinesan@gmail,com. 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER- 
LUMEFANTRINE STUDY 
Study ID- PAAL: …………. 
27 
 
 
 
 
 
 
 
CASE RECORD FORM 
 
 
 
 
 
 
COMPARATIVE EFFICACY AND SAFETY OF PYRONARIDINE- 
ARTESUNATE VERSUS ARTEMETHER-LUMEFANTRINE IN THE 
TREATMENT OF MALRIA AMONG CHILDREN IN SOUTH-WEST 
NIGERIA 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER- 
LUMEFANTRINE STUDY 
Study ID- PAAL: …………. 
28 
 
 
 
 
Study ID: ……………. 
Hosp.No: ……………… 
Date of enrollment: …………………… 
 
Sex: ………………………………………………............ 
Age (months): …………. 
 
Date of birth ……./…………/………./ 
Weight (kg): ……… Height (CM): ………… 
 
Temp (oC): …………….. 
Phone no: ………………….................... 
 
Address (+ brief description): 
………….…………………………………………………………………………………………………… 
………......…………………………………………………………………………………………………… 
……………………… 
Symptoms History 
 
Record duration of symptoms in days (Today = 1) Fever: ( ) Vomiting: ( ) Chills & rigors ( ) 
Diarrhoea: ( ) Headache: ( ) Abdominal pains: ( ) Irritability: ( ) Loss of appetite ( ) 
Other complaint 1: ………………………………. Other complaint 2: …………………………… 
 
Past medical history: 
 
History of drug allergy: (Yes/No) If yes, name of drug: …………………………. 
 
Any other relevant history 1: ………………………………………………… 
 
Any other relevant history 2: ………………………………………………….. 
 
Treatment history: Has the child received any of the following drugs in the last 2 weeks (Yes/No) 
CQ (  ) 
SP (  ) 
PCM (  ) 
ACT ( ) Specify.......................................................... 
Antibiotic (  ) Specify...................................................... Other: ……………………….. 
 
Clinical examination: 
 
General: Palor (Yes/No)  Icterus (Yes/No) 
Fever (Yes/No) Dehydration ( Yes/No) 
 
CVS: Pulse/min………..……. Apex Beat………..………….........Heart sounds…………………............ 
 
Respiratory system: Resp. rate…………………Breath sound…………………………….......................... 
 
Abdomen: Liver size (Below costal margin)………… Spleen size……………….. Kidneys…………….. 
 
Muscle tone: (1) Normal 
(2) Hypotonia 
(3) hypertonia 
Eyes: conjuctivitis/Discharge (Yes/No) 
Ears: Discharge (Yes/No) 
MP result: ……………………….. PCV......................................................................................... 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER- 
LUMEFANTRINE STUDY 
Study ID- PAAL: …………. 
29 
 
 
 
Study ID -------------------------------------------- 
 
Study Drug Schedule 
 
Study 
Day 
Date 
Drug [PA or AL] 
Name of Drug 
………………………. 
Dose 
Time Drug 
Given 
Day 0 
1st 
2nd 
Day 1 
1st 
2nd 
Day 2 
1st 
2nd 
 
 
 
 
Comments: 
Any vomiting? Yes/No 
Time …………… 
 
Any Redosing? 
Time …………….. 
Any vomiting? Yes/No 
 
Any other comments 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER-LUMEFANTRINE STUDY 
…………. 
Study ID- PAAL: 
30 
 
 
CLINICAL FOLLOW UP RECORD 
 
D0 
D1 
D2 
D3 
D7 
D14 
D21 
D28 
Day 35 
Day 42 
Other 
visit 
Date 
Temp (oC) 
Pallor 
Jaundice 
HR/Pulse Rate 
Resp Rate 
Lung Fields 
Liver (cm) 
Spleen (cm) 
Weight (kg) 
PCV (%) 
Parasite 
Density/μL 
Gametocyte 
Count/ μL 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER-LUMEFANTRINE STUDY 
…………. 
Study ID- PAAL: 
31 
 
 
TREATMENT EMERGENT SIGNS AND SYMPTOMS (TESS) 
 
 
Features 
Day 0 
P 
S 
Day 1 
P 
S 
Day 2 
P 
S 
Day 3 
P 
S 
Day 7 
P 
S 
Day 14 
P 
S 
Day 21 
P 
S 
Day 28 
P 
S 
Day 35 
P 
S 
Day 42 
P 
S 
Extra Visit 
P 
S 
Extra Visit 
P 
S 
Date 
Chills/Rigors 
Fever 
Anorexia 
Nausea 
Vomiting 
Diarrhoea 
Abd. Pains 
Cough 
Palpitation 
Insomnia 
 
Present (P): 0 = Not present, 1= Present, 2 = Not evaluable 
Severity (S):  1 = Mild 2 = Moderate 3 = Severe 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER-LUMEFANTRINE STUDY 
…………. 
Study ID- PAAL: 
32 
 
 
 
 
 
 
TREATMENT EMERGENT SIGNS AND SYMPTOMS (TESS) 
 
Features 
Day 0 
P 
S 
Day 1 
P 
S 
Day 2 
P 
S 
Day 3 
P 
S 
Day 7 
P 
S 
Day 14 
P 
S 
Day 21 
P 
S 
Day 28 
P 
S 
EXTRA 
VISIT 
Date 
Pallor 
Yellow eyes 
Headaches 
Rash 
Reflex 
Diplopia 
Fatigue 
Other 
Other 
 
Present (P): 0 = Not present, 1= Present, 2 = Not evaluable 
Severity (S):  1 = Mild 2 = Moderate 3 = Severe 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER-LUMEFANTRINE STUDY 
…………. 
Study ID- PAAL: 
33 
 
 
LABORATORY RESULTS: LFT & BLOOD CHEMISTRY 
 
 
 
 
PARAMETER 
DAY 0 
DAY 3 
DAY 7 
DAY 27 
DAY 35 
DAY 42 
Date 
Urea 
Creatinine 
Random Blood sugar 
Total bilirubin 
Conjugated bilirubin 
ALT 
AST 
ALP 
GGT 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER-LUMEFANTRINE STUDY 
…………. 
Study ID- PAAL: 
34 
 
 
 
 
 
 
 
LABORATORY RESULTS: HAEMATOLOGY 
 
 
PARAMETERS 
D0 
DAY 3 
DAY7 
D28 
EXTRA 
VISIT 
EXTRA 
VISIT 
White blood cell count 
Eosinophils 
Platelet count 
Neutrophils 
Basophils 
Lymphocytes 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER-LUMEFANTRINE STUDY 
…………. 
Study ID- PAAL: 
35 
 
 
 
 
ADVERSE EVENTS RECORD 
 
 
 
 
ADVERSE EVENT 
DAY 0 
DAY 3 
DAY 7 
DAY 28 
EXTRA 
VISIT 
EXTRA 
VISIT 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER-LUMEFANTRINE STUDY 
…………. 
Study ID- PAAL: 
36 
 
 
 
 
SUMMARY: EFFICACY 
 
: D14 [ ], D21 [ ], D28 [ ]. {ETF = 1, LPF = 2, LCF = 3, ACPR = 4, Withdrawn = 5, Lost to follow up = 6} 
 
Treatment outcome 
ETF 
LPF 
LCF 
ACPR 
WITHDRAWN 
LOST TO 
FOLLOW UP 
Day 7 
Day 14 
Day 21 
Day 28 
Day 35 
Day 42 
Extra visit (Date------------------ ) 
Extra visit (Date------------------ ) 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER- 
LUMEFANTRINE STUDY 
Study ID- PAAL: …………. 
37 
 
 
 
 
 Enrollee’s Initials …………………….. 
 
STUDY OUTCOME 
 
 
 
1. COMPLETED 
 
2. LOST TO FOLLOW UP 
 
3. WITHDRAL OF INFORMED CONSENT 
 
4. PROTOCOL VIOLATION 
 
 
 
 
STUDY CONCLUSION 
 
 
 
1. ACPR 
 
2. LPT 
 
3. LCF 
 
4. ETF 
 
 
 
Investigator - Name ……………………………………… 
 
Signature & Date ………………………………………… 
 
 
 
Principal investigator - Name ………………………… 
 
Signature & Date …………………………………… 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER- 
LUMEFANTRINE STUDY 
Study ID- PAAL: …………. 
38 
 
 
 
 
 
REFERENCES 
1. 
World Health Organisation: In Guidelines for the Treatment of Malaria (3d Edition), 
3rd edition. Geneva2015. 
2. 
World Health Organisation: World Malaria Report 2016. Geneva: Licence: CC BY- 
NC-SA 3.0 IGO; 2016. 
3. 
FMOH: National Malaria Strategic Plan 2014-2020. Abuja, Nigeria: Federal Ministry 
of Health, Nigeria; 2014. 
4. 
Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, Ezzati M, Shibuya 
K, Salomon JA, Abdalla S, et al: Disability-adjusted life years (DALYs) for 291 
diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global 
Burden of Disease Study 2010. Lancet 2012, 380:2197-2223. 
5. 
World Health Organisation: World Malaria Report 2017. Geneva: License: CC BY- 
NC-SA 3.0 IGO; 2017. 
6. 
World Health Organisation: WHO guidelines for the treatment of malaria.: 
WHO/HTM/MAL/2006.1108; 2006. 
7. 
Andagalu B, Mativo J, Kamau E, Ogutu B: Longitudinal study on Plasmodium 
falciparum 
gametocyte 
carriage 
following 
artemether-lumefantrine 
administration in a cohort of children aged 12-47 months living in Western Kenya, 
a high transmission area. Malar J 2014, 13:265. 
8. 
World Health Organisation: WHO briefing on Malaria Treatment Guidelines and 
artemisinin monotherapies GenevaApril, 2006. 
9. 
Falade CO, Ogundele AO, Yusuf BO, Ademowo OG, Ladipo SM: High efficacy of 
two artemisinin-based combinations (artemether-lumefantrine and artesunate 
plus amodiaquine) for acute uncomplicated malaria in Ibadan, Nigeria. Trop Med 
Int Health 2008, 13:635-643. 
10. 
Falade CO, Dada-Adegbola HO, Ogunkunle OO, Oguike MC, Nash O, Ademowo OG: 
Evaluation of the comparative efficacy and safety of artemether-lumefantrine, 
artesunate-amodiaquine 
and 
artesunate-amodiaquine-chlorpheniramine 
(Artemoclo) for the treatment of acute uncomplicated malaria in Nigerian 
children. Med Princ Pract 2014, 23:204-211. 
11. 
Falade C, Makanga M, Premji Z, Ortmann CE, Stockmeyer M, de Palacios PI: Efficacy 
and safety of artemether-lumefantrine (Coartem) tablets (six-dose regimen) in 
African infants and children with acute, uncomplicated falciparum malaria. Trans 
R Soc Trop Med Hyg 2005, 99:459-467. 
12. 
Oduro AR, Anyorigiya T, Anto F, Amenga-Etego L, Ansah NA, Atobrah P, Ansah P, 
Koram K, Hodgson A: A randomized, comparative study of supervised and 
unsupervised artesunate-amodiaquine, for the treatment of uncomplicated 
malaria in Ghana. Ann Trop Med Parasitol 2008, 102:565-576. 
13. 
Ahorlu C: The Efficacy of Amodiaquine plus Artesunate Combination in Ghana. 
Ghana Med J 2008, 42:54. 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER- 
LUMEFANTRINE STUDY 
Study ID- PAAL: …………. 
39 
 
 
 
 
 
14. 
Abuaku BK, Mensah BA, Ofori MF, Myers-Hansen J, Derkyi-Kwarteng AN, Essilfie 
F, Dokurugu M, 
Amoakoh E, Koram 
KA, Ghansah 
A: 
Efficacy 
of 
Artesunate/Amodiaquine in the Treatment of Uncomplicated Malaria among 
Children in Ghana. Am J Trop Med Hyg 2017, 97:690-695. 
15. 
WorldWide Antimalarial Resistance Network ASAQSG, Adjuik MA, Allan R, Anvikar 
AR, Ashley EA, Ba MS, Barennes H, Barnes KI, Bassat Q, Baudin E, et al: The effect 
of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for 
uncomplicated malaria: a meta-analysis of individual patient data. BMC Med 2015, 
13:66. 
16. 
Beeson JG, Boeuf P, Fowkes FJ: Maximizing antimalarial efficacy and the 
importance of dosing strategies. BMC Med 2015, 13:110. 
17. 
Mori AT, Ngalesoni F, Norheim OF, Robberstad B: Cost-effectiveness of 
dihydroartemisinin-piperaquine compared with artemether-lumefantrine for 
treating uncomplicated malaria in children at a district hospital in Tanzania. 
Malar J 2014, 13:363. 
18. 
Pfeil J, Borrmann S, Tozan Y: Dihydroartemisinin-piperaquine vs. artemether- 
lumefantrine for first-line treatment of uncomplicated malaria in African 
children: a cost-effectiveness analysis. PLoS One 2014, 9:e95681. 
19. 
Kamya MR, Yeka A, Bukirwa H, Lugemwa M, Rwakimari JB, Staedke SG, Talisuna 
AO, Greenhouse B, Nosten F, Rosenthal PJ, et al: Artemether-lumefantrine versus 
dihydroartemisinin-piperaquine for treatment of malaria: a randomized trial. 
PLoS Clin Trials 2007, 2:e20. 
20. 
Ramharter M, Kurth F, Schreier AC, Nemeth J, Glasenapp I, Belard S, Schlie M, 
Kammer J, Koumba PK, Cisse B, et al: Fixed-dose pyronaridine-artesunate 
combination for treatment of uncomplicated falciparum malaria in pediatric 
patients in Gabon. J Infect Dis 2008, 198:911-919. 
21. 
Poravuth Y, Socheat D, Rueangweerayut R, Uthaisin C, Pyae Phyo A, Valecha N, Rao 
BH, Tjitra E, Purnama A, Borghini-Fuhrer I, et al: Pyronaridine-artesunate versus 
chloroquine in patients with acute Plasmodium vivax malaria: a randomized, 
double-blind, non-inferiority trial. PLoS One 2011, 6:e14501. 
22. 
Price RN, Marfurt J, Chalfein F, Kenangalem E, Piera KA, Tjitra E, Anstey NM, 
Russell B: In vitro activity of pyronaridine against multidrug-resistant 
Plasmodium falciparum and Plasmodium vivax. Antimicrob Agents Chemother 
2010, 54:5146-5150. 
23. 
Duparc S, Borghini-Fuhrer I, Craft CJ, Arbe-Barnes S, Miller RM, Shin CS, 
Fleckenstein L: Safety and efficacy of pyronaridine-artesunate in uncomplicated 
acute malaria: an integrated analysis of individual patient data from six 
randomized clinical trials. Malar J 2013, 12:70. 
24. 
Sagara I, Beavogui AH, Zongo I, Soulama I, Borghini-Fuhrer I, Fofana B, Camara D, 
Some AF, Coulibaly AS, Traore OB, et al: Safety and efficacy of re-treatments with 
pyronaridine-artesunate in African patients with malaria: a substudy of the 
WANECAM randomised trial. Lancet Infect Dis 2016, 16:189-198. 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER- 
LUMEFANTRINE STUDY 
Study ID- PAAL: …………. 
40 
 
 
25. 
Tshefu AK, Gaye O, Kayentao K, Thompson R, Bhatt KM, Sesay SS, Bustos DG, Tjitra 
E, Bedu-Addo G, Borghini-Fuhrer I, et al: Efficacy and safety of a fixed-dose oral 
combination of pyronaridine-artesunate compared with artemether-lumefantrine 
in children and adults with uncomplicated Plasmodium falciparum malaria: a 
randomised non-inferiority trial. Lancet 2010, 375:1457-1467. 
26. 
Croft SL, Duparc S, Arbe-Barnes SJ, Craft JC, Shin CS, Fleckenstein L, Borghini- 
Fuhrer I, Rim HJ: Review of pyronaridine anti-malarial properties and product 
characteristics. Malar J 2012, 11:270. 
27. 
Kayentao K, Doumbo OK, Penali LK, Offianan AT, Bhatt KM, Kimani J, Tshefu AK, 
Kokolomami JH, Ramharter M, de Salazar PM, et al: Pyronaridine-artesunate 
granules versus artemether-lumefantrine crushed tablets in children with 
Plasmodium falciparum malaria: a randomized controlled trial. Malar J 2012, 
11:364. 
28. 
West African Network for Clinical Trials of Antimalarial D: Pyronaridine-artesunate 
or dihydroartemisinin-piperaquine versus current first-line therapies for repeated 
treatment of uncomplicated malaria: a randomised, multicentre, open-label, 
longitudinal, controlled, phase 3b/4 trial. Lancet 2018, 391:1378-1390. 
29. 
Mahotorn K, Tan-Ariya P, Thita T, Ruang-Areerate T, Sittichot N, Suwandittakul N, 
Mungthin M: In Vitro Sensitivity of Pyronaridine in Thai Isolates of Plasmodium 
falciparum. Am J Trop Med Hyg 2018, 98:51-56. 
30. 
Chow S, Shao J, Wang H. 2008. Sample Size Calculations in Clinical Research. 2nd 
Ed. Chapman & Hall/CRC Biostatistics Series 
31. 
Sealed Envelope Ltd. 2012. Power calculator for binary outcome non-inferiority 
trial. [Online] Available from: https://www.sealedenvelope.com/power/binary- 
noninferior/ [Accessed Wed Mar 20 2019]. 
32. 
Roth MJ, Sawa P, Makio N, Omweri G, Osoti V, Okach S, Choy F, Schallig HDFH & 
Mens P (2018) Pyronaridine-artesunate and artemether-lumefantrine for the 
treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children: 
a randomized controlled non-inferiority trial. Malaria Journal (2018) 17:199. 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER- 
LUMEFANTRINE STUDY 
Study ID- PAAL: …………. 
41 
 
 
 
 
TABLE OF NORMAL VALUES – IBADAN, SOUTHWEST NIGERIA 
HAEMATOLOGY 
 
PARAMETR 
NORMAL VALUE 
UNIT OF 
MEASUREMENT 
Red Blood Cell Counts 
Male 
Female 
4.0 - 6.5 
3.5 - 5.5 
x 1012/l 
x 1012/l 
Hemoglobin 
Male 
Female 
130 – 180 
115 - 165 
g/l 
g/l 
Packed Cell Volume 
Male 
Female 
39 – 54 
36 - 46. 
% 
% 
Mean Cell Volume 
80 - 100 
Fl 
Mean Cell Hemoglobin (MCH) 
27 -32 
P/g 
Mean Cell Hemoglobin Concentration 
(MCHC) 
300 – 350 
g/l 
White blood cell count (WBC) 
150 - 350 
x 109/l 
Platelet count 
90 – 300 
x 109/l 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER- 
LUMEFANTRINE STUDY 
Study ID- PAAL: …………. 
42 
 
 
 
 
LIVER FUNCTION TEST 
 
 
 
PARAMETER 
NORMAL RANGE 
UNIT OF 
MEASUREMENT 
Total Bilirubin 
0.2 -1.0 
mg/dl 
Direct Bilirubin 
0 – 0.4 
mg/dl 
Alkaline phosphatase (ALP) 
35 - 105 
IU/L 
Aspartate transaminase (AST) 
0 - 37 
IU/L 
Alanine transaminase (ALT) 
0 - 40 
IU/L 
Gamma glutamate transaminase (GGT) 
7 - 50 
IU/L 
Total protein 
3.5 -8.0 
g/dl 
Albumin 
3.2 – 5.7 
g/dl 
 
 
PLASMA GLUCOSE 
 
 
 
PARAMETER 
NORMAL RANGE 
UNIT OF 
MEASUREMENT 
Fasting plasma glucose 
65 - 110 
mg/dl 
2 Hours Post prandial plasma glucose 
60 -140 
mg/dl 

PYRONARIDINE-ARTESUNATE VERSUS ARTEMETHER- 
LUMEFANTRINE STUDY 
Study ID- PAAL: …………. 
43 
 
 
 
 
FASTING LIPID PROFILE 
 
PARAMETER 
NORMAL RANGE 
UNIT OF 
MEASUREMENT 
Total cholesterol 
<200 
mg/dl 
Triglyceride 
0 - 200 
mg/dl 
HDL – Cholesterol 
35 - 86 
mg/dl 
LDL - Cholesterol 
80 - 120 
mg/dl 
 
 
 
ELECTROLYTE & UREA 
 
 
 
PARAMETER 
NORMAL RANGE 
UNIT OF 
MEASUREMENT 
Sodium 
130 -145 
mmol/L 
Potassium 
3.5 – 5.0 
mmol/L 
Chloride 
95 – 110 
mmol/L 
Bicarbonate 
20 - 30 
mmol/L 
Urea 
15 - 45 
mg/dl 
Creatinine 
0.5 – 1.5 
mg/dl