Efficacy and Safety of Pyronaridine-Artesunate Versus Artemether-Lumefantrine in the Treatment of Acute Uncomplicated Malaria in Children in South-West Nigeria: An open- labelled randomized controlled trial

Efficacy and Safety of Pyronaridine-Artesunate Versus Artemether-Lumefantrine in the Treatment of Acute Uncomplicated Malaria in Children in South-West Nigeria: An open- labelled randomized controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and Safety of Pyronaridine-Artesunate Versus Artemether-Lumefantrine in the Treatment of Acute Uncomplicated Malaria in Children in South-West Nigeria: An open- labelled randomized controlled trial Catherine Olufunke Falade, Adebola Emanuel Orimadegun, Fiyinfoluwa Ibukun Olusola, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1664143/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 May, 2023 Read the published version in Malaria Journal → Version 1 posted 7 You are reading this latest preprint version Abstract Background: Declining responsiveness to artemether-lumefantrine (AL), the ACT of choice since 2005, has been reported in Nigeria. Pyronaridine-artesunate (PA) is a newer fixed-dose ACT recently included in the WHO list of prequalified medicines for the treatment of uncomplicated falciparum malaria. However, data from the Nigerian paediatric population is scarce. Therefore, we compared the efficacy and safety of pyronaridine-artesunate with artemether-lumefantrine using the WHO 28-day antimalarial efficacy protocol in Ibadan, southwest Nigeria. Method: In an open-labelled randomized controlled clinical trial children aged 3 to 144 months with a history of fever and microscopically confirmed Plasmodium falciparum malaria were enrolled. Enrolees were randomly assigned to receive pyronaridine–artesunate or artemether–lumefantrine at standard dosages according to bodyweight, for 3 days. Venous blood was obtained for haematology, blood chemistry and liver function tests on days 0, 3, 7, and 28 as part of safety evaluation. Results: One hundred and sixty-five (95.9%; 165/172) enrolees completed the study. About half [52.3%; 90/172] of enrolees were male. Eighty-seven (50.6%) received artemether-lumefantrine while 85 (49.4%) received pyronaridine-artesunate. Day 28 adequate clinical and parasitological response for pyronaridine-artesunate was 92.7% [(76/82) 95% CI: 83.1, 95.9] and 71.1% [(59/83) 95% CI: 60.4, 79.9] for artemether-lumefantrine (ρ<0.001). PCR-corrected cure rates were similar for PA and AL as all parasite recurrences [PA = 6 (7.3%); AL = 24 (28.9%)] were re-infections. Haematological recovery at day-28 was significantly better among pyronaridine-artesunate treated patients (34.9% ± 2.8) compared to those treated with artemether-lumefantrine (33.1% ±3.0) [ρ = 0.002]. Adverse events in both treatment arms were fever, chills and rigors, anorexia, cough and headache, similar to symptoms observed during malaria infection. Blood chemistry and liver function tests were mostly within normal limits, with an occasional marginal rise. There was no serious adverse event in both arms of the study. Conclusion: The two ACTs were well-tolerated. Pyronaridine-artesunate has a higher ACPR than artemether-lumefantrine in the per-protocol-population and a non-inferiority response after PCR correction in the treatment of uncomplicated malaria in Nigerian children. The results of this study support the inclusion of pyronaridine-artesunate in the antimalaria treatment guidelines in Nigeria. Retrospective Trial Registration in Clinicaltrials.gov: NCT05192265 Randomized clinical trial Pyronaridine-artesunate Artemether-lumefantrine Efficacy and safety Uncomplicated malaria Nigeria Figures Figure 1 Figure 2 Figure 3 Background Despite efforts to control and eliminate malaria, it remains a major public health concern in sub-Saharan Africa. As documented in successive editions of the World Malaria Report, malaria continues to cause unacceptably high levels of disease and death in sub-Saharan Africa. According to the 2021 WHO malaria report, there were an estimated 241 million malaria cases and 627,000 malaria deaths in 2020, representing about 14 million more cases in 2020 compared to 2019, and 69,000 more deaths [ 1 ]. Artemisinin-based combination therapy (ACT), the current WHO global standard for the treatment of acute uncomplicated malaria [ 1 ], has contributed to a significant reduction in malaria prevalence in recent years [ 2 ]. This progress is endangered, however, by the emergence of P. falciparum strains with reduced in-vivo susceptibility to artemisinin, which was first reported in Western Cambodia [ 3 , 4 ], as well as reduced political commitment and funding for malaria control [ 2 ]. Since the first report of reduced in-vivo susceptibility in the late 2000s, the prevalence of drug-resistant infections has increased and spread to other parts of Southeast Asia and the rest of the world [ 2 , 3 , 5 ]. Artemisinin resistance, which is strongly linked to a mutation in the propeller region of the P. falciparum Kelch protein gene on chromosome 13 (Kelch13), was first discovered in western Cambodia and has since spread to the majority of malaria-endemic regions around the world, including Africa and India [ 6 – 9 ]. Previous research found a lack of selection for Kelch13 in southwest Nigeria [ 10 ]. Another study also recorded low polymorphism in samples from Kano, Nigeria, indicating a lack of selection for the Kelch 13 gene [ 10 , 11 ]. Artemether-lumefantrine (AL), the most commonly used treatment for uncomplicated malaria in several African countries including Nigeria, has an impressive safety and efficacy record [ 12 , 13 ]. However, it must be taken twice daily, must be consumed with a fatty meal for optimal absorption, and the relatively short half-life puts patients at risk of reinfection [ 14 ]. There is the need to expand options for antimalarial treatment, first to delay resistance, contribute to resistance management where this is already a problem and reduce drug pressure on AL. Pyronaridine-artesunate does not have the limitations of AL and could reduce the pressure on AL thus making it a viable option to evaluate. Pyronaridine-artesunate (PA) [Pyramax™; Shin-Poong Pharma Ltd. South Korea] first received a positive scientific opinion from the European Medicines Agency under Article 58 for the tablet formulation in 2012. Pyramax™ granules (special paediatric formulation] was subsequently granted a positive scientific opinion through its Article 58 in 2015 [ 15 , 16 ]. This regulatory authority approval confirms that Pyramax™ can be used in malaria patients, particularly African children. The safety and efficacy of pyronaridine-artesunate in adults and children in Africa and Asia have been demonstrated in many randomised controlled clinical trials [ 17 – 22 ]. Consequently, PA was recommended by the WHO in 2019 as a "safe and efficacious artemisinin-based combination therapy for the treatment of uncomplicated malaria in adults and children weighing 5 kilograms or more in malaria-endemic areas" [ 23 ]. As a result, PA was included in Nigeria’s national treatment guidelines [ 13 ]. However, more research is needed to provide Nigeria with in-country data on the safety and efficacy of PA, based on the good safety and efficacy observed in the Phase III program and the CANTAM Study 2021 [ 24 ]. Furthermore, Sowunmi et al. [ 25 ] recently reported a decline in the responsiveness of childhood Plasmodium falciparum infections to ACTs (artemether-lumefantrine and artesunate-amodiaquine) in Nigeria. This underscores the importance of evaluating another effective and user-friendly antimalarial with good efficacy and tolerability in the country. This clinical trial resulted from efforts to improve efficacy, tolerability, cost, and treatment regimens. As the country is endemic for malaria, it is also critical to continue assessing the efficacy of AL, the current first-line ACT of choice in Nigeria, in order to detect early loss of efficacy. There is currently no data on the safety and efficacy of pyronaridine-artesunate in the Nigerian population. The goal of this study is to compare the safety and efficacy of pyronaridine-artesunate and artemether-lumefantrine in children aged 3 months to 12 years (144 months) with symptomatic acute uncomplicated malaria in south-west Nigeria. Methods Study design and setting This comparative, randomized, open-label, parallel-group clinical trial followed WHO guidelines [ 12 ]. Study drugs were pyronaridine-artesunate (PA) granules or tablets (Pyramax™; 60mg pyronaridine/20mg artesunate per sachet of granules, 180/60 respectively per tablet) supplied in aluminium sachets (Shin Poong Pharmaceutical Company, Ltd., Ansan, Korea), and artemether-lumefantrine (AL) tablets (Coartem™; Novartis SA, Basel, Switzerland). supplied in blister packs. Each tablet of dispersible Coartem contains 20 artemether and 120 mg lumefantrine. Patients were enrolled from the Kola Daisi Primary Healthcare Centre (PHC), University College Hospital, Ibadan and Ikereku PHC in Akinyele Local Government Area, southwest Nigeria. Study participants Children aged 3 to 144 months with clinical features consistent with acute uncomplicated malaria and microscopically confirmed Plasmodium falciparum malaria were enrolled if they had a minimum asexual parasite density of 1000/µL, an axillary temperature of ≥ 37.5°C or a history of fever within 24 hours of presentation, lived within fifteen kilometres of the study centre, and were capable of taking drugs orally. Additional inclusion criteria included the absence of artemisinin-based combination therapy (ACT) intake in the two weeks preceding enrolment and signed informed consent from prospective enrolees’ parents or guardians to participate in the study. Children with a history of allergy to any of the study drugs, including artemisinin, lumefantrine, or pyronaridine, were excluded from the study. Children with concurrent illnesses that could impair response evaluation, such as bacterial or viral infections, were also excluded. Additionally, children with clinical evidence of severe malaria were excluded from the study [ 26 ]. Children with severe malnutrition or known chronic diseases such as chronic liver disease, heart failure, or sickle cell anaemia were also excluded from the study. Children of parents/guardians who, in the investigator's opinion, will not adhere to the study protocol were not permitted to participate in the study. Randomization and blinding Patients were allocated to either PA or AL group following a pre-generated randomization table in ascending order. Different clinical personnel performed clinical assessments and drug administration. Treatments The study drugs were administered orally for three days (days 0, 1, and 2). Pyronaridine-artesunate (Pyramax™ - Shin Poong Pharmaceutical Company, Ltd., Ansan, Korea) was given once daily in the clinic by the research nurse supervised for three days. Pyramax™ contains 60mg pyronaridine/20mg artesunate per sachet of granules, 180/60 respectively per tablet supplied in aluminium sachets. Dosing was based on body weight: 5 – <8kg: one sachet; 8 – <15kg: two sachets; 15 – <20kg; three sachets; 20 – <24kg: one tablet and 24 – <45kg: two tablets. All PA doses were administered with a milk drink under the supervision of a research nurse. AL was administered as dispersible tablets (Coartem™, Novartis Pharma Basil Switzerland). Each dispersible tablet contains 20mg of artemether/120mg of lumefantrine. Study participants were dosed as follows: 5 – <15Kg; one tablet, 15 – <25Kg two tablets, 25 –<35Kg three tablets, and 35Kg and above; four tablets. AL was administered at 0, 8, 24, 36, 48, and 60 hours respectively. The first, third, and fifth doses of AL were administered supervised in the clinic with milk drinks while the second, fourth, and sixth doses of AL were administered with milk drinks at home by the parent or guardian. Mothers of children who received AL were encouraged to breastfeed very young babies who were still on the breast soon after the drug was administered. At the end of Days 0, 1, and 2 visits, parents and guardians were given a sachet of full cream powdered milk each daily for the 2nd, 4th, and 6th doses of AL and were also reminded by phone 30 minutes before the next drug dosing. Although a fatty meal was not required for optimal absorption of PA unlike for AL, all enrolees received study drugs with milk drinks because the children who were randomised to receive PA felt disadvantaged because they did not receive milk drinks, and this could lead to poor compliance with follow up visits. Each enrolee irrespective of drug group was observed in the clinic for 1 hour after drug administration for vomiting. If vomiting occurred within 30 minutes of drug administration, the full treatment drug dose (PA or AL) was re-administered. If vomiting occurred between 30–60 minutes of drug administration, half the treatment dose was re-administered. Any enrolee who vomits the repeat dose was withdrawn from the study and treated with artesunate-amodiaquine as rescue medication as per the Nigeria national malaria treatment guidelines [ 13 ]. Data collection procedures Enrolees who met the inclusion criteria were given a detailed explanation of the study and were only enrolled after the accompanying parent or guardian signed an informed consent form. The information gathered from each participant was entered into case record forms (CRF) created specifically for the study. In the individual CRF, socio-demographic information, contact information for each enrolee, past medical history, as well as clinical and laboratory details for all enrolees in the study, were recorded. Each enrolee's parent or guardian provided a detailed medical history, which included a history of the presenting symptoms as well as a list of current medications. In 2019, an electronic thermometer was used to measure axillary temperature, while an infrared thermometer (beamed at the forehead) was used in 2020 because of the SARS-CoV-2 pandemic. A few drops of capillary blood were obtained via finger prick for thick and thin blood smears and some into a capillary tube for haematocrit determination, and blood spots on filter paper for parasite genotyping at enrolment. For malaria parasite detection, thick and thin blood films were prepared from finger prick blood samples of each enrolee on Day 0, whereas only thick blood films were prepared at all other contact times and stained with fresh 10% Giemsa stain at pH 7.2. Dry stained blood films were viewed at a magnification of x1000 using a light microscope in accordance with the WHO guideline [ 27 ]. At enrolment and on all contact days, gametocyte carriage was specifically observed and counted in the thick films. At enrolment and at each follow-up visit, blood spots on filter paper were obtained for DNA analysis using the polymerase chain reaction (PCR) to differentiate re-infection from recrudescence [ 28 ]. At each point of contact, blood was drawn into capillary tubes for haematocrit determination. A five-millilitre venous blood sample was also obtained via venepuncture for the evaluation of haematological and biochemical parameters (urea and creatinine, as well as a liver function test) on days 0, 3, 7, and 28. Blood samples were collected from study participants and analysed at the chemical pathology and haematology laboratories of the University College Hospital Ibadan, Nigeria. All enrolees were followed up on out-patient basis daily from days 0 to 3 and then on days 7, 14, 21 and 28. Enrolees were also seen whenever a participant fell ill or a parent or guardian was concerned about their children's health. The day before follow-up visits, parents and guardians of enrolees were reminded by phone. Enrolees were provided transportation refunds to encourage compliance with follow-up. Evaluation at each visit included a brief clinical history and a physical examination to assess new complaints and medication side effects. A finger prick blood sample was taken on days 1, 2, 3, 7, 14, 21, 28, and any other (unscheduled) visit day for the preparation of thick blood films for the identification and quantification of asexual stages of the malaria parasite while we collected filter paper blood samples on days 0, 3, 7, 14, 21, and 28 for parasite genotyping from the same capillary blood samples. DNA Isolation and Amplification of Plasmodium falciparum Paired samples of blood spots on filter paper collected from patients with parasite recurrence on or before D28 (D0 and Day of parasite recurrence) were analysed using PCR techniques for parasite DNA. Genomic DNA extraction was performed with QIAamp DNA Mini kit blood and tissue (QIAGEN Hilden Germany) kit, according to manufacturer’s instructions. Eluted genomic DNA was stored at -20 o C until further PCR analysis. The small sub-unit ribosomal RNA (ssrRNA) gene of P. falciparum was amplified in a nested PCR using a primary genus-specific primer and a secondary P. falciparum species-specific primer following the previously described standard protocol [ 29 , 30 ]. Paired samples with confirmed parasitaemia were further genotyped to distinguish recrudescence from new infection using merozoite surface protein-1 ( msp-1 ), merozoite surface protein-2 ( msp-2 ) and glutamate-rich protein ( glurp ) genes respectively. In a 20µL reaction volume, PCR mixture containing 5X PCR Master Mix (Solis Biodyne, Estonia), 0.5mM each of forward and reverse primers, nuclease-free PCR grade water, and 5 µL of extracted genomic DNA as template was prepared for the primary reaction. In the Nested reaction, 2µL of the primary PCR product was used as a template in 18µL PCR mixture, containing the same reagents as the primary reaction except with a species-specific forward and reverse primers. The PCR thermal cycling conditions were previously described [ 29 ]. All amplification of DNA was performed in an Eppendorf AG 22331 thermal cycler (Hamburg, Germany). Genotyping of msp-1, msp-2 & Glurp antigenic loci PCR amplification targeting the polymorphic regions of msp-1 (block 2), msp-2 (block 3) and glurp (R2) regions were genotyped with allelic specific primers as previously described [ 30 , 31 ]. The antigenic allelic families of msp-1 (K1, RO33 and MAD20), msp-2 (FC27 & 3D7) were amplified in a final reaction volume of 20µL (25µL for glurp), containing 5X PCR Master mix (Solis Biodyne, Estonia), primers (forward and reverse) 0.5mM (0.75mM for glurp) each and 5 µL of extracted genomic DNA as template in the primary reaction. 2µL of the primary PCR product was used as template in the nested reaction. The PCR cycling conditions for both primary and nested reactions were as previously described [ 30 , 31 ]. Ten (10µL) of the nested PCR products (amplicon) were electrophoresed on 1.5% agarose gel pre-stained with EZ-vision blue light DNA dye (EZ-Vision® Blue light DNA Dye, VWR Chemicals USA) and was allowed to migrate at 100volt for 40–60 minutes for fragment size differentiation. The gel was visualized and photographed under a UV trans-illuminator documentation system (UVP ® DigiDoc-It™, USA). Amplified fragments were paired for base-pair sizing and comparison. Fragments with the same base pair sizes (paired samples) in the amplified loci were considered recrudescence while un-identical base pair sizes were considered new infections. Rrecrudescence was defined as when a subsequent sample from follow up contained identical alleles or a subset of the alleles present in the day 0 sample. Reinfection was defined as when a follow up sample contained only new alleles that are un-identical with day 0 sample. Study endpoints The WHO 2009 treatment outcome criteria were used to assess efficacy [ 27 ]. Early treatment failure (ETF) was defined as danger signs or severe malaria on day 1, 2 or 3 in the presence of parasitaemia; parasitaemia on day 2 higher than on day 0, irrespective of axillary temperature; parasitaemia on day 3 with an axillary temperature ≥ 37.5 ºC or parasitaemia on day 3 ≥ 25% of count on day 0. Late clinical failure (LCF) was defined as danger signs or severe malaria in the presence of parasitaemia on any day between day 4 and day 28 (day 42) in patients who had not previously met any of the criteria for early treatment failure; or the presence of parasitaemia on any day between day 4 and day 28 (day 42) with an axillary temperature of ≥ 37.5 ºC (or history of fever) in patients who had not previously met any of the criteria for early treatment failure. Late parasitological failure (LPF) is defined as the presence of parasitaemia on any day between days 7 and 28 (day 42) and an axillary temperature of < 37.5ºC in patients who did not previously meet any of the criteria for early treatment failure or late clinical failure. The main end point for the study was adequate clinical and parasitological response (ACPR), defined as the absence of parasitaemia on day 28, irrespective of axillary temperature, in patients who had not previously met any of the criteria of early treatment failure, late clinical failure, or late parasitological failure. Recrudescence was defined as the recurrence of asexual parasitaemia within 28 days of receiving antimalarial treatment that contained the same genotypes that caused the initial illness. At the time of enrolment, PCT was defined as the time from the first dose of ACT until the first total and continued disappearance of asexual parasite forms for at least 24 hours, whereas fever clearance time (FCT) was defined as the time from the first dose of ACT until the first time the body temperature (for those with a raised temperature at enrolment) drops to below 37.5 ºC and stays below 37.5 ºC for at least 24 hours. In this study, safety was evaluated in terms of adverse events and severe adverse events by examining symptoms, clinical signs, and laboratory parameters. All study participants who took at least one dose of either of the study drugs were evaluated for safety. The evaluation of liver enzymes was a special category that was evaluated due to previous reports of transaminitis [ 22 ]. Alanine transaminase (ALT)/ aspartate transaminase (AST) greater than three times the upper limit of normal (ULN) plus peak total bilirubin greater than two times the ULN in the absence of a significant alkaline phosphatase increase were considered serious adverse events (SAE). An ALT and AST level greater than 5 times the ULN were considered an adverse event of special interest (AESI). Ethics statement The University of Ibadan/University College Hospital Ethics Committee (EC approval No - UI/EC/19/0114) and the Oyo State Ministry of Health Ethics Committee (EC approval No - AD 13/479/206) both approved the study protocol. Individual written informed consent was obtained from eligible participants' parents or guardians. Our study was conducted in accordance with Good Clinical Practice and the Declaration of Helsinki [ 32 ], as well as applicable regulations. Sample size calculation We calculated the required minimum number of enrolees using the sample size formula for test of non-inferiority as written by Chow and colleagues [ 33 ], by assuming a difference of 2.5% in cure rate between PA and AL (98.9% vs 96.4%), 140 patients are required to attain a power of 90% at 95% level of confidence to demonstrate non-inferiority of PA versus AL with a non-inferiority limit of 5%. However, allowing for 20% loss to follow up, the total number of patients required would be 168 to give 84 patients per arm. Data analysis All study participants who received any amount of the study drugs were included in the intent-to-treat population. The per-protocol-population included children who received the entire course of study medication, had a known day-28 efficacy end point, and had no major protocol deviations. The data was analysed for efficacy in both the intention-to-treat and per-protocol populations. The efficacy endpoints were summarized by age. Safety outcomes were adverse events and abnormalities of laboratory results including liver function test and haematological indices. SPSS IBM Statistic Software version 20 was used to analyse the data at ρ = <0.05. Results Enrolees’ baseline characteristics and symptoms at presentation The study was conducted between May and December 2019 and between July and December 2020. A total of 1,204 febrile children were screened for malaria parasitaemia during the study period; 550 (45.7%) had patent parasitaemia, with 172 eligible patients randomly assigned to PA (n = 85) and to AL (n = 87). Figure 1 shows the details of the reasons for the exclusion of ineligible patients. Baseline demographic and clinical characteristics were similar between the two treatment groups (Table I). Table 1 Baseline Characteristics of children suffering from acute uncomplicated malaria treated with artemether-lumefantrine or pyronaridine-artesunate in Ibadan SW Nigeria Characteristics Drug Group Total ρ-value AL PA Sex • Male • Female 45 (50.0%) 42 (51.2%) 45 (50.0) 40 (48.8%) 90 (100) 82 (100) 0.880 Age (months) • Mean ± sd • Range 79.93 ± 37.16 8–144 82.39 ± 38.63 4–143 81.15 ± 39.80 4–144 0.671 • 3–11 months 3 (3.5) 5 (5.9) 8 (4.7) 0.703 • 12–59 months 20 (23.0) 21 (24.7) 41 (23.8) • 60 and above 64 (73.6) 59 (69.4) 123 (71.5) Weight (kg) • Mean ± sd • Range 18.59 ± 6.49 7.0–36.0 18.67 ± 6.74 5.5–40.0 18.63 ± 6.59 5.5–40. 0.938 Temperature ( o C) • Mean ± sd • Range 37.7 ± 1.06 35.1–40.2 37.4 ± 1.07 35.9–39.9 37.6 ± 1.08 35.1–40.2 0.074 Parasite density (/µl) • Geomean • Range 32,755 1035–758,958 28,211 1600–1,652,505 30,424 1035–1,652,505 0.815 Haematocrit (%) • Mean ± sd • Range 32.14 ± 5.06 18–41 32.14 ± 5.48 18–48 32.14 ± 5.26 18–48 0.997 Anaemic at DO (PCV < 30%) 19 (21.8) 21 (24.7) 40 (23.3) 0.396 Height (cm) • Mean ± sd • Range 110.65 ± 21.31 18–143 110.65 ± 28.90 18–186 110.38 ± 25.36 18–186 0.892 The four most common symptoms at presentation were fever (100%), headache (69.8%), chills and rigors (62.6%), and loss of appetite (57.2%) (Table 2 ). Table 2 also shows that there were statistically significant differences in the frequencies of only chills and rigors and loss of appetite which were higher in the AL group than in the PA group (ρ = 0.033 and 0.014, respectively). Five patients (5.9%) in the PA compared with 3 (3.4%) in the AL group (ρ = 0.347), vomited the first dose of the study drug and had to be re-dosed. After redosing, one of the children that received AL vomited and was withdrawn from the study. Table 2 Distribution of children with acute uncomplicated malaria according to symptoms other than fever at presentation by treatment groups Presenting complaint Total population N = 172 (100) Artemether-lumefantrine N = 87 (100%) Pyronaridine-artesunate N = 85 (100%) ρ-value Headaches 120 (69.8) 61 (70.1) 59 (69.4) 1.000 Chills & rigors 117 (68.0) 66 (75.9) 51 (60) 0.033 Loss of appetite 101 (58.7) 59 (67.8) 42 (49.4) 0.014 Vomiting 82 (47.7) 44 (50.6) 38 (44.7) 0.450 Abdominal Pain 68 (39.5) 33 (37.9) 35 (41.7) 0.642 Nausea 54 (31.4) 30 (34.5) 24 (28.6) 0.417 Cough 45 (26.2) 21 (24.1) 24 (28.6) 0.603 Diarrhoea 32 (18.6) 18 (20.7) 14 (16.5) 0.558 Irritability 33 (19.2) 13 (14.9) 20 (23.5) 0.178 Insomnia 17 (9.9) 10 (11.5) 7 (8.3) 0.611 Palpitations 10 (5.8) 5 (6.0) 5 (5.7) 1.000 Results of Efficacy Evaluation Intention-to-treat population analysis Of the 172 randomized to the study groups, 165 (95.9%) completed the study, and the primary efficacy endpoint of the study was attained. The distribution of the participants in the two study groups by treatment outcomes based on intention-to-treat and per-protocol analyses is shown in Table 3 . There were no significant differences in the number of patients who completed the study (ρ = 0.682), those who were lost to follow-up (p = 1.000) and those who withdrew (p = 1.000) between the two study groups. Table 3 Treatment outcome among patients with uncomplicated malaria treated with Artemether-lumefantrine or Pyronaridine-artesunate in Ibadan, southwest Nigeria Treatment Outcome Artemether-lumefantrine N (%) Pyronaridine-artesunate N (%) Total N (%) ρ-value TOTAL Enrolled 87 (100) 85 (100) 172 (100) • Completed study. • LTFU • Withdrawn • Withdrawal of consent 83 (95.4) 3 (3.4) 1 (1.2) 0 (0.0) 82 (96.5) 2 (2.4) 0 (0.0) 1 (1.2) 165 (95.9) 5 (2.9) 1 (0.6) 1 (0.6) .535 ITT- Uncorrected N = 87 (100) N = 85 (100) N = 172 (100) • ACPR – D28 • LPF • LCF 59 (67.8) 21 (24.1) 7 (8.1) 76 (89.4) 8 (9.4) 1 (1.2) 135 (78.5) 29 (16.9) 8 (4.7) .002 ITT – PCR Corrected N = 87 N = 85 N = 172 • Cured • Failed 83 (95.4) 4 (4.6) 82 (96.5) 3 (3.5) 165/172 (95.9) 7/172 (4.1) 1.000 PP – Uncorrected N = 83 N = 82 N = 165 • ACPR – D21 73/83 (88.0) 82/83 (98.8) 135/166 (93.4) .016 • ACPR – D28 • LPF – D28 • LCF – D28 59/83 (71.1) 17 (20.5) 7 (8.4) 76/82 (92.7) 5 (6.1) 1 (1.2) 135 (81.8) 22 (13.3) 8 (4.8) .001 PPP- PCR Corrected N = 83 N = 82 N = 165 • Cured - D28 83 (100) 82 (100) 165 (100) NA Day of Failure 24 (100) 6 (100) 30 (100) • Day 14 • Day 21 • Day 28 2 (8.3) 9 (37.5) 13 (54.2) 0 (0.0) 1 (16.7) 5 (88.3) 2 (6.7) 10 (33.3) 18 (60.0) .405 • % Failed before D28 • % Failed on D28 11 (45.8) 13 (54.2) 1 (16.7) 5 (83.3) 12 (40.0) 18 (60.0) .358 Parasite clearance time (days) • Mean ± sd • Range 2.15 ± 0.68 1–4 2.08 ± 0.64 1–3 2.12 ± 0.66 1–4 .430 Fever clearance time (days) • Mean ± sd • Range 1.11 ± 0.32 1–2 1.13 ± 0.44 1–3 1.13 ± 0.38 1–3 0.664 Haematocrit at D28 (in %) • Mean ± sd • Range 33.3 ± 2.95 23–40 34.9 ± 2.79 28–42 34.13 ± 2.95 25–42 .002 • Haematocrit < 30% D28 1 (1.4) 1 (1.4) 2 (1.4) 1.000 Among the intention-to-treat population, the percentage of patients with adequate clinical and parasitological responses (ACPR) on day-28 was significantly higher among patients in the PA group than the AL group (ρ = <0.002), but the difference was no longer significant after PCR-correction (ρ = 1.000) as shown in Table 3 . The total number of patients who experienced treatment failure in the AL group (28/87 (32.2%) was significantly higher than those who had treatment failure in the PA group [9/85 (10.6%)]. The risk of failure was also higher in the AL group than in the PA group (RR = 1.80; 95% CI: 1.39, 2.33), ρ = <0.001. Similarly, patients randomised to the AL group had an increased risk of experiencing treatment failure before day-21 compared with those in the PA group (RR = 1.87; 95% CI: 1.44, 2.43). Although haematological recovery was excellent for both study drugs, the mean haematocrit on day 28 was significantly higher in the patients randomised to the PA group (34.9 ± 2.8%) than in those in the AL group (33.3 ± 3.0%); ρ < 0.002. Conversely, there were no significant differences in the mean parasite and fever clearance times as well as the number of anaemic patients between the PA group and the AL group (Table 3 ). The graphs (Figs. 2 and 3 ) from the Kaplan-Meier survival analysis also corroborate the lack of differences in the fever and parasite clearance times between patients randomised to the PA group and those in the AL group. Per-protocol population analysis There was no early treatment failure during the study. Response to treatment was prompt in all study participants except in an enrolee among AL treated children who had recurrent vomiting and had to be withdrawn on day 0. By day 1, 11.6% (10/86) and 12.9% (n = 11/85) of patients treated with AL and PA respectively were free of patent parasitaemia while corresponding values for day 2 were 70.9% (n = 61/86) and 72.9% (n = 62/85) for AL and PA, respectively. Two (2.3%) of the study participants who received AL had patent parasitaemia at day 3, but they both recorded adequate clinical and parasitological responses at day 28. All participants were free of patent parasitaemia by day 7. However, two children among those who received AL failed treatment at day 14; one each recorded LCF and LPF. In contrast to those treated with AL, treatment failure was first seen among children who received PA on day 21. The ACPR in the per-protocol population at day 21 was significantly higher for PA than for AL treated children (98.8% versus 88.0%, respectively, ρ = 0.009). The chances of ACPR were significantly lower in the AL than PA (RR = 0.52; 95% CI: 0.40, 0.67). Similarly, ACPR (unadjusted cure rate) at day 28 was 92.7% for PA and 71.1% for AL, with PA having significantly higher chances of attaining ACPR than AL (RR = 2.81; 95% CI: 1.36, 5.85), ρ = 0.001. The efficacy outcomes observed by age in the per-protocol population are as shown in Table 4 . The ACPR was significantly higher in the PA group than in the AL group (ρ = 0.008) among children under five-year-old (< 60 months) and over 5-year-old (≥ 60 month) old children (RR = 1.64; 95% CI: 1.19, 2.26), ρ = 0.016, similar to what was recorded in the entire study population. All the 30 children with parasite recurrence among PP population - [6/82 (7.3%) for PA versus 24/83 (28.9%) for AL; ρ < 0.001] were treated with artesunate-amodiaquine (ASAQ). Response to ASAQ was prompt, leading to rapid parasite clearance and resolution of symptoms where there were symptoms. Table 4 Treatment outcome among children (PP) from southwest Nigeria with acute uncomplicated malaria treated with artemether-lumefantrine or pyronaridine-artesunate in different age groups. Treatment Outcome Drug group Total ρ-value AL PA Age < 12 months [N = 8] 3 5 8 • ACPR 2 (66.7) 5 (100) 7 (87.5) 0.375 • LCF 1 (33.3) 0 (0) 1 (12.5) • PCR Corrected ACPR 3/3 (100) 5/5 (100) 8/8 (100 Nil Age < 60 months [N = 47] N = 22 N = 25 N = 47 • ACPR 14 (63.6) 24 (96.0) 38 (80.9) 0.008 • LPF 4 (18.2) 1 (4.0) 5 (10.68) • LCF 4 (18.2) 0 (0) 4 (8.5) Age ≥ 60 months [N = 118] N = 61 N = 57 N = 118 • Cured (ACPR) • Failed (LCF + LPF) 45 (73.8) 16 (26.2) 52 (91.2) 5 (6.1) 97 (82.2) 21 (17.8) 0.016 • ACPR 45 (73.8) 52 (91.2) 97 (82.2) 0.046 • LPF 13 (21.3) 4 (7.0) 17 (14.4) • LCF 3 (4.9) 1 (1.8) 4 (3.4) Total PPP [N = 165] 83 82 165 • ACPR • LPF • LCF 59/83 (71.1) 17/83 (20.5) 7/83 (8.4) 76/82 (92.7) 5/82 (6.1) 1/82 (1.2) 135/165 (81.8) 22 (13.3) 8 (4.8) 0.001 • Cured (ACPR) • Failed (LCF + LPF) 59/83 (71.1) 24/83 (28.9) 78/82 (92.7) 6/82 (7.3) 135/165 (81.8) 30/165 (18.2) < 0.0001 • PCR Corrected cure rate • PCR corrected treatment failure rate 83/83 (100) 0/83 (0.0) 82/82 (100) 0/82 (0.0) 163/165 (98.8) 0/165 (0.0) NA Molecular analysis Molecular biology analysis of paired samples for enrolees with parasite recurrence was carried out with msp-1, msp- 2 and glurp . This showed that all six cases of parasite recurrence among children treated with PA were re-infections. In a similar manner, all the 24 cases among AL treated children were also re-infection giving PCR corrected cure rates of 100% for PA and AL for the PP sampled populations. Safety of pyronaridine-artesunate compared with artemether-lumefantrine Complaints and physical examination . The ITT population was considered as the safety population. Recorded adverse events were similar to the symptoms and signs seen during malaria infection. There was no incidence of serious adverse event throughout the study. The type and prevalence of the various adverse events were similar for the two study drugs. The five most often recorded adverse events were fever, chills and rigors, anorexia, cough, and headache. These are clinical symptoms that occur during malaria infection. Further details are provided in Table 5 . There was no clinical evidence of jaundice, intravascular haemolysis, hepatic dysfunction, or renal impairment. No death was recorded during the study. Table 5 Summary of Adverse Events among children (PP) from southwest Nigeria with acute uncomplicated malaria treated with artemether-lumefantrine or pyronaridine-artesunate Event All patients N = 172 Artemether-lumefantrine N = 87 Pyronaridine-artesunate N = 85 p Adverse event from any cause, 53 (30.8) 27 (31.0) 26 (30.6) 0.949 Fever 58 (34.1) 24 (27.9) 34 (40.5) 0.106 Chills and rigors 33 (19.6) 16 (18.6) 17 (20.5) 0.847 Anorexia 29 (17.1) 16 (18.6) 13 (15.5) 0.685 Cough 28 (16.6) 14 (16.3) 14 (16.9) 1.000 Headache 27 (16.0) 12 (14.1) 15 (17.9) 0.536 Fatigue 22 (12.9) 11 (12.6) 11 (13.1) 1.000 Pallor 17 (10.1) 9 (10.6) 8 (9.6) 1.000 Abdominal pains 12 (7.1) 5 (5.8) 7 (8.3) 0.563 Vomiting 11 (6.4) 6 (7.0) 5 (5.9) 1.000 Diarrhea 11 (6.4) 4 (4.6) 5 (6.0) 0.744 Palpitations 6 (3.5) 3(3.4) 3 (3.6) 1.000 Nausea 6 (3.5) 3 (3.5) 3 (3.6) 1.000 Rashes 1 (0.6) 0 (0.00) 1 (1.2) 1.000 Laboratory results were mostly within normal ranges, with occasional marginal increases as (shown in Supplementary file 1 – Tables 6a – 6h, Tables 7a to 7h and Figs. 4–11). There were no records of blood urea, creatinine, random blood glucose, or total bilirubin levels that were more than twice the upper limit of normal after receiving either study drugs. Both PA and AL had no deleterious effect on the transaminases. On day-0 (before antimalarial administration), two study participants who received AL had alanine transaminase (ALT) levels that were twice the upper limit of normal. By day 3, the elevated ALT levels had returned to normal. On day 0, one of the two children who received AL and had ALT more than twice the upper limit of normal also had aspartate aminotransferase (AST) more than twice the upper limit of normal, which returned to normal by day 3. On day-3, one participant in the PA group had AST level that was twice the upper limit of normal. By day 7, the elevated AST level had returned to normal. There was no instance of any adverse event of interest. Changes in blood levels of various enzymes and other parameters measured among participants in the two drug groups were statistically significant on Days 7 and 28 with ALT and Day 28 with AST and alkaline phosphatase (ALP). The observed increases in liver enzymes, bilirubin, urea, creatinine, and random blood sugar levels were not clinically significant (Supplementary file 1). Gametocyte carriage The number of participants who received PA with gametocyte carriage was consistently higher than that of those who received AL, except on day 28, when only one of the PA-treated children and two of the AL-treated children had gametocytes. However, the differences were only statistically significant on day 7. Supplementary file 2 - Table 8a contains further information on gametocyte carriage. The number of participants with gametocytes was not only higher in children treated with PA, but the gametocytes densities were also consistently higher (supplementary file 2 - Table 8b). One participant in particular stood out because he had gametocytes from day 0 to day 28. The gametocyte counts were also high, ranging from 728/µL to 3,088/µL. Two other participants did not clear their gametocytes until day 21, and another participant had gametocytaemia until day 14. All four participants who had delayed gametocyte clearance had received PA. Discussion During this study, we evaluated the comparative efficacy and safety of pyronaridine-artesunate [Pyramax™; Shin Poong Pharm Co., Ltd, Seoul, South Korea] and artemether-lumefantrine [Coartem™; Novartis Pharma; Switzerland] in the treatment of acute uncomplicated falciparum malaria among Nigerian children. The two ACTs were found to be efficacious and well tolerated by the study participants. There was no record of early treatment failure in any arm of the study, and only one participant who received AL was withdrawn as a result of recurrent vomiting. The day-28 PCR-corrected cure rate in children with uncomplicated falciparum malaria treated with PA granules or tablets was 100.0% in the per-protocol population and 96.5% in the intention-to-treat population. The primary efficacy outcome for pyronaridine–artesunate was greater than 95% in all age groups, be it among children under one year (< 12 months) of age, under-five years old (< 60 months) or 60 to 144 months old. The efficacy of pyronaridine–artesunate against falciparum malaria was generally consistent with previous studies on the use of pyronaridine–artesunate [ 17 – 24 , 34 , 35 ]. A highly significant efficacy finding in this study is that pyronaridine–artesunate had a significantly higher ACPR than artemether–lumefantrine in both the intent-to-treat (89.4% versus 67.8%) and per-protocol populations (92.7% versus 71.1%). However, because recurrent parasites were re-infections, there was no significant difference in the PCR-corrected cure rates of pyronaridine–artesunate and artemether–lumefantrine at day 28. This finding raises concern about the post treatment prophylaxis of AL compared with PA. Our findings are in keeping with reports of pyronaridine–artesunate and artemether–lumefantrine efficacy in the treatment of acute uncomplicated malaria among Gabonese children [ 35 ], Kenyan children [ 34 ], and children from Burkina Faso, Guinea, and Mali [ 21 ]. Although there are no reports on the efficacy and safety of PA in Nigeria, numerous studies have reported on the efficacy of AL, the comparator drug in our study in the management of acute uncomplicated malaria in Africa in general and Nigeria in particular [ 36 – 39 ]. It is particularly noteworthy that PA demonstrated a statistically significant higher efficacy among under 5-year-olds during this study [96.0% vs 63.6% for PA and AL, respectively, as shown in Table 4 (ρ = .008). PA also recorded a better and statistically significantly higher efficacy among children ≥ 60 months than AL [91.2%vs 73.8% for PA vs AL; ρ = 0.016]. Details are shown in Table 4 . It can be assumed that PA’s significant superiority among children ≤ 59 months of age reflects its true efficacy since this group of children are generally believed to be relatively immuno-naïve and the chemotherapeutic effect of AL was not augmented by immunity. There was no difference in parasite clearance time between pyronaridine–artesunate and artemether–lumefantrine treated groups, and our findings are consistent with Roth and colleagues' findings in Kenyan children [ 34 ]. In contrast, three previous studies demonstrated that pyronaridine–artesunate group cleared P. falciparum more rapidly than artemether–lumefantrine [ 17 , 40 ]. On day 3, all enrolees were fever-free, and no difference in fever clearance time was observed, which is consistent with a previous study [ 20 ], though another study found that pyronaridine–artesunate caused faster fever clearance [ 17 ]. The occurrence of one LCF and one LPF on D14 among participants who received AL is worrisome. This suggests declining efficacy of AL in the treatment of malaria in the study area. Sowunmi et al. [ 25 ] previously reported a decline in the responsiveness of uncomplicated malaria to Nigeria's preferred antimalarial drugs – artemether-lumefantrine and artesunate-amodiaquine. This was stated in a report detailing a post-hoc analysis of clinical trials in south-west of Nigeria among 360 children under 16 years at 5-year intervals in 2009–2010, and 2014–2015, and 1341 children under 5 years in studies from six-geopolitical zones from the Nigerian national antimalaria efficacy studies conducted at 2-year intervals in 2009–2010 and 2012–2015, respectively, after deployment in 2005. In our study, both artemether-lumefantrine and pyronaridine-artesunate had good safety profiles. The commonly observed adverse events were fever, chills and rigors, anorexia, and headache. These symptoms are similar to those seen in malaria patients and resolve as the infection is cleared. These observations are similar to reports by previous workers [ 22 , 24 , 35 , 37 , 40 ]. There was no record of clinical hepatic impairment for PA or AL. Laboratory evaluation of liver transaminases, alkaline phosphatase, and bilirubin only revealed marginal increases with very few records of twice the upper limit of normal in both treatment arms (Supplementary file 1 – Tables 6a – 6h, Tables 7a − 7h and Figs. 4–11). The alterations in transaminases were similar in both treatment arms and were not clinically significant. This contrasts with the findings of Sagara et al . [ 41 ], who found that 13 out of 996 (1.3%) patients had transaminases increase after the first cure, including one possible Hy's law case, and two out of 311 (0.32%) after a retreatment of a second bout of malaria with PA. The lack of any cases of significant transaminase increases could be attributed to the relatively small number of participants (85) in our study compared to 996 in the study reported by Sagara et al. [ 41 ]. Our observation is, however, supported by the report of Lutete et al. [ 24 ] in their cohort event monitoring study in five African countries involving over 7,000 malaria patients in a protocol resembling real-world clinical practice. Another notable finding from the present study is that from days 0 to 21, gametocyte carriage was consistently higher in PA-treated children compared to AL-treated children, but the observed differences were not statistically significant -(Supplementary file 2 - Tables 8a and 8b). The significance of this relatively higher gametocyte carriage is unclear, as the presence of gametocytes does not always indicate infectivity [ 41 – 44 ]. Gametocytes are the stage in the plasmodial life cycle that is infectious to mosquitoes; the insect in which sexual multiplication of malaria parasites occurs, leading to the development of sporozoites, which in turn infect humans. However, only mature gametocytes are infectious to mosquitos after ingestion. Furthermore, microscopy cannot distinguish between viable living gametocytes and dead or drug-affected gametocytes. Nonetheless, the high gametocyte carriage suggests that pyronaridine does not have particularly effective gametocidal properties. The pyronaridine nucleus is derived from mepacrine (a 9-aminoacridine) and contains an amodiaquine-like side chain. The WWARN study group reported clear differences in gametocyte clearance between various ACTs in a systematic review [ 45 ]. The WWARN study group reported that ACTs with 4-aminoquinoline partner drugs, such as dihydroartemisinin-piperaquine and artesunate amodiaquine, clear gametocytes at a much slower rate than those with aryl-amino alcohol and related structures (artesunate-mefloquine and artemether lumefantrine). This study's findings should be viewed with a few caveats in mind. The current study included only eight children under the age of 12 months, of which only five were randomly assigned to the pyronaridine-artesunate group. Despite the fact that the ACPR for pyronaridine-artesunate group was 100 percent on day 28, the number of enrolees is insufficient to draw any conclusions about efficacy and safety in that age group. As a result, more information on this patient population is needed for pyronaridine-artesunate. Conclusion The efficacy and safety of PA among Nigerian children is both impressive and important as Nigeria is one of the highest burden countries for malaria in sub-Saharan Africa especially as this is being recorded at a time that AL has started to show declining efficacy. This study provides empirical evidence for the inclusion of PA in the National Treatment Guidelines and it is hoped that findings from routine TES will provide relevant updates on the efficacy of ACTs in the country for their sustained recommendation. Declarations Conflicts of interests The authors declare that they have no conflict of interest Authors’ contribution COF, OEA and OAM designed the study. COF, FIO, OSM, ADA, AEO and BEO conducted the studies, RIF ran the molecular analysis, COF and AEO analysed the data and drafted the manuscript. All authors read and approved the manuscript, Funding The study was funded by Shin Poong Pharm Co., Ltd, Seoul, South Korea Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Acknowledgements We thank the children and their families for participating in this study. We also thank all health care workers of our study sites - nurses and staff of the malaria clinic, health care workers of Ikereku PHC in Akinyele Local Govt Area for their assistance and cooperation. 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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. 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. Falade CO, Ogunkunle OO, Dada-Adegbola HO, Falade AG, de Palacios PI, Hunt P, Virtanen M, Oduola AM, Salako LA: Evaluation of the efficacy and safety of artemether-lumefantrine in the treatment of acute uncomplicated Plasmodium falciparum malaria in Nigerian infants and children. Malar J 2008, 7: 246. 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. Oguche S, Okafor HU, Watila I, Meremikwu M, Agomo P, Ogala W, Agomo C, Ntadom G, Banjo O, Okuboyejo T, et al : Efficacy of artemisinin-based combination treatments of uncomplicated falciparum malaria in under-five-year-old Nigerian children. Am J Trop Med Hyg 2014, 91: 925-935. 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. Sagara I, Beavogui AH, Zongo I, Soulama I, Borghini-Fuhrer I, Fofana B, Camara D, Somé 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. Kone A, van de Vegte-Bolmer M, Siebelink-Stoter R, van Gemert G-J, Dara A, Niangaly H, Luty A, Doumbo OK, Sauerwein R, Djimde AA: Sulfadoxine-pyrimethamine impairs Plasmodium falciparum gametocyte infectivity and Anopheles mosquito survival. International journal for parasitology 2010, 40: 1221-1228. Beavogui AH, Djimde AA, Gregson A, Toure AM, Dao A, Coulibaly B, Ouologuem D, Fofana B, Sacko A, Tekete M, et al : Low infectivity of Plasmodium falciparum gametocytes to Anopheles gambiae following treatment with sulfadoxine-pyrimethamine in Mali. International journal for parasitology 2010, 40: 1213-1220. Karunajeewa HA, Mueller I: How important is gametocyte clearance after malaria therapy? BMC Medicine 2016, 14: 93. WWARN Gametocyte Study Group (2016). Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: a systematic review and meta-analysis of individual patient data . BMC Med. 2016 May 24;14:79. doi: 10.1186/s12916-016-0621-7. Additional Declarations No competing interests reported. Supplementary Files MalariaJournalsubmitPAvsALNigeraSupplementaryFile1.docx Supplementary file 1 Tables of results showing liver enzymes, serm bilirubin, urea, creatinine, g;ucose and glucose of children enrolled in the study. MalariaJournalsubmitPAvsALSupplementaryfile2.docx Supplementary file 2 Tables 8a and 8b showing gametocyte carriage among children treated with artemether-lumefantrine and pyronaridine-artesunate during the study. Cite Share Download PDF Status: Published Journal Publication published 13 May, 2023 Read the published version in Malaria Journal → Version 1 posted Editorial decision: Major revision 19 Jun, 2022 Reviews received at journal 01 Jun, 2022 Reviewers agreed at journal 22 May, 2022 Reviewers invited by journal 22 May, 2022 Submission checks completed at journal 18 May, 2022 Editor assigned by journal 18 May, 2022 First submitted to journal 17 May, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1664143","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":106851486,"identity":"d10f3a23-0e5c-4d9f-8721-caa2ebc7db81","order_by":0,"name":"Catherine Olufunke Falade","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBElEQVRIie2PoU5DMRSGT2lyMR2zXRC8wsiSGm7uHgRzmpt0CgwGMdGZzfAAEMjeAIvuTZNhll27ZKbXIyaHWdZOkBnK5BL6qZ4//9fTAiQSJ8gFpSMDOQAHagw++hMQn0TIKNEGVFAy6dxcBUXHFfhRWO+6Gdt9GlfOibYM7X1nogXHrC7eJ9ZfMsxvYw8LysMlM4ojW5Ufc+mVmbrTMaW1sXLKccaRr0phvOLDuOK3yOlVM+bYXZSibo5UXjmlXURTiOURW6o3HMiXJ0UcmhLF0m/ByF/abVu5L7yRz5/1uvreFn1RDxq3Hua/KoEzdjDIfRMj9QDZHAz9P8qJRCLxD9kBpnxo4ICX04UAAAAASUVORK5CYII=","orcid":"","institution":"University of Ibadan","correspondingAuthor":true,"prefix":"","firstName":"Catherine","middleName":"Olufunke","lastName":"Falade","suffix":""},{"id":106851489,"identity":"e0d6fad2-5016-4eba-9d56-324e0cba6283","order_by":1,"name":"Adebola Emanuel Orimadegun","email":"","orcid":"","institution":"University of Ibadan","correspondingAuthor":false,"prefix":"","firstName":"Adebola","middleName":"Emanuel","lastName":"Orimadegun","suffix":""},{"id":106851494,"identity":"2831c7e7-ad22-4d4e-bf21-46af81fc56e8","order_by":2,"name":"Fiyinfoluwa Ibukun Olusola","email":"","orcid":"","institution":"University of Ibadan","correspondingAuthor":false,"prefix":"","firstName":"Fiyinfoluwa","middleName":"Ibukun","lastName":"Olusola","suffix":""},{"id":106851497,"identity":"5e60f619-823b-478e-af32-865e4398b976","order_by":3,"name":"Obaro S. Michael","email":"","orcid":"","institution":"University of Ibadan","correspondingAuthor":false,"prefix":"","firstName":"Obaro","middleName":"S.","lastName":"Michael","suffix":""},{"id":106851502,"identity":"07a028de-1506-4c2f-ae14-9a3126b9318c","order_by":4,"name":"Oluwafunmibi Enitan Anjorin","email":"","orcid":"","institution":"Obafemi Awolowo University Teaching Hospital","correspondingAuthor":false,"prefix":"","firstName":"Oluwafunmibi","middleName":"Enitan","lastName":"Anjorin","suffix":""},{"id":106851503,"identity":"d1904e78-abf8-40f1-9e54-f6ccf10edba3","order_by":5,"name":"Roland Ibenipere Funwei","email":"","orcid":"","institution":"Babcock University","correspondingAuthor":false,"prefix":"","firstName":"Roland","middleName":"Ibenipere","lastName":"Funwei","suffix":""},{"id":106851506,"identity":"4da31b4c-506d-4b01-9078-51c2fb68af60","order_by":6,"name":"Aduragbenro Deborah Adedapo","email":"","orcid":"","institution":"University of Ibadan","correspondingAuthor":false,"prefix":"","firstName":"Aduragbenro","middleName":"Deborah","lastName":"Adedapo","suffix":""},{"id":106851508,"identity":"86bcbacc-aca1-446f-9e83-88cfc4acb0a8","order_by":7,"name":"Abiola Lukman Olusanya","email":"","orcid":"","institution":"University of Ibadan","correspondingAuthor":false,"prefix":"","firstName":"Abiola","middleName":"Lukman","lastName":"Olusanya","suffix":""},{"id":106851509,"identity":"fe44a187-de3b-46bf-9b43-a2697043f67f","order_by":8,"name":"Bose E. Orimadegun","email":"","orcid":"","institution":"University of Ibadan","correspondingAuthor":false,"prefix":"","firstName":"Bose","middleName":"E.","lastName":"Orimadegun","suffix":""},{"id":106851510,"identity":"ff50138e-2c07-4c84-a87d-3d582cba244e","order_by":9,"name":"Olugbenga Ayodeji Moluolu","email":"","orcid":"","institution":"University of Ilorin Teaching Hospital","correspondingAuthor":false,"prefix":"","firstName":"Olugbenga","middleName":"Ayodeji","lastName":"Moluolu","suffix":""}],"badges":[],"createdAt":"2022-05-17 06:59:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1664143/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1664143/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12936-023-04574-7","type":"published","date":"2023-05-13T20:46:47+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":21714297,"identity":"062c75c4-7ccf-4ecc-b0d2-d3da7b6b3d0d","added_by":"auto","created_at":"2022-05-20 15:26:28","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":32552,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy design and patient flow among children from southwest Nigeria with acute uncomplicated malaria treated with artemether-lumefantrine or pyronaridine-artesunate\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-1664143/v1/ddef25bd525bf265eb87a8e6.png"},{"id":21715320,"identity":"14f6010f-4bf5-408d-b126-3a4d5d4549b4","added_by":"auto","created_at":"2022-05-20 15:36:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":25895,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier analysis (intent-to-treat population) comparing fever clearance time between Pyronaridine-Artesunate and Artemether-Lumefantrine\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-1664143/v1/e0bfb811f24a4a1558758662.png"},{"id":21715004,"identity":"cb36a687-af6d-4529-830f-3823f53090f6","added_by":"auto","created_at":"2022-05-20 15:31:28","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":25807,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier analysis (intent-to-treat population) comparing parasite clearance time between pyronaridine-artesunate and artemether-lumefantrine\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-1664143/v1/77711250f25e4c5b84ec44e1.png"},{"id":44730633,"identity":"ae69e392-27f6-4847-9c6e-1b2163442947","added_by":"auto","created_at":"2023-10-16 21:32:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1943150,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1664143/v1/922eb84e-9c87-42dc-9862-256eec7a99ad.pdf"},{"id":21714298,"identity":"566b295d-68a6-48fb-8937-fdd0605d5b91","added_by":"auto","created_at":"2022-05-20 15:26:28","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":309641,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSupplementary file 1\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eTables of results showing liver enzymes, serm bilirubin, urea, creatinine, g;ucose and glucose of children enrolled in the study.\u003c/p\u003e","description":"","filename":"MalariaJournalsubmitPAvsALNigeraSupplementaryFile1.docx","url":"https://assets-eu.researchsquare.com/files/rs-1664143/v1/7eba042e5a83c00e9e3bae9f.docx"},{"id":21714301,"identity":"9e38b22b-63d9-4ba5-b22b-1c063da2fb3a","added_by":"auto","created_at":"2022-05-20 15:26:28","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":36199,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSupplementary file 2\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eTables 8a and 8b showing gametocyte carriage among children treated with artemether-lumefantrine and pyronaridine-artesunate during the study.\u003c/p\u003e","description":"","filename":"MalariaJournalsubmitPAvsALSupplementaryfile2.docx","url":"https://assets-eu.researchsquare.com/files/rs-1664143/v1/f363e2c7a400237c12e576c0.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and Safety of Pyronaridine-Artesunate Versus Artemether-Lumefantrine in the Treatment of Acute Uncomplicated Malaria in Children in South-West Nigeria: An open- labelled randomized controlled trial","fulltext":[{"header":"Background","content":"\u003cp\u003eDespite efforts to control and eliminate malaria, it remains a major public health concern in sub-Saharan Africa. As documented in successive editions of the World Malaria Report, malaria continues to cause unacceptably high levels of disease and death in sub-Saharan Africa. According to the 2021 WHO malaria report, there were an estimated 241\u0026nbsp;million malaria cases and 627,000 malaria deaths in 2020, representing about 14\u0026nbsp;million more cases in 2020 compared to 2019, and 69,000 more deaths [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Artemisinin-based combination therapy (ACT), the current WHO global standard for the treatment of acute uncomplicated malaria [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], has contributed to a significant reduction in malaria prevalence in recent years [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This progress is endangered, however, by the emergence of \u003cem\u003eP. falciparum\u003c/em\u003e strains with reduced \u003cem\u003ein-vivo\u003c/em\u003e susceptibility to artemisinin, which was first reported in Western Cambodia [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], as well as reduced political commitment and funding for malaria control [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSince the first report of reduced \u003cem\u003ein-vivo\u003c/em\u003e susceptibility in the late 2000s, the prevalence of drug-resistant infections has increased and spread to other parts of Southeast Asia and the rest of the world [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Artemisinin resistance, which is strongly linked to a mutation in the propeller region of the \u003cem\u003eP. falciparum\u003c/em\u003e Kelch protein gene on chromosome 13 (Kelch13), was first discovered in western Cambodia and has since spread to the majority of malaria-endemic regions around the world, including Africa and India [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Previous research found a lack of selection for Kelch13 in southwest Nigeria [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Another study also recorded low polymorphism in samples from Kano, Nigeria, indicating a lack of selection for the Kelch 13 gene [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eArtemether-lumefantrine (AL), the most commonly used treatment for uncomplicated malaria in several African countries including Nigeria, has an impressive safety and efficacy record [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, it must be taken twice daily, must be consumed with a fatty meal for optimal absorption, and the relatively short half-life puts patients at risk of reinfection [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. There is the need to expand options for antimalarial treatment, first to delay resistance, contribute to resistance management where this is already a problem and reduce drug pressure on AL. Pyronaridine-artesunate does not have the limitations of AL and could reduce the pressure on AL thus making it a viable option to evaluate.\u003c/p\u003e \u003cp\u003ePyronaridine-artesunate (PA) [Pyramax\u0026trade;; Shin-Poong Pharma Ltd. South Korea] first received a positive scientific opinion from the European Medicines Agency under Article 58 for the tablet formulation in 2012. Pyramax\u0026trade; granules (special paediatric formulation] was subsequently granted a positive scientific opinion through its Article 58 in 2015 [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This regulatory authority approval confirms that Pyramax\u0026trade; can be used in malaria patients, particularly African children. The safety and efficacy of pyronaridine-artesunate in adults and children in Africa and Asia have been demonstrated in many randomised controlled clinical trials [\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Consequently, PA was recommended by the WHO in 2019 as a \"safe and efficacious artemisinin-based combination therapy for the treatment of uncomplicated malaria in adults and children weighing 5 kilograms or more in malaria-endemic areas\" [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. As a result, PA was included in Nigeria\u0026rsquo;s national treatment guidelines [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, more research is needed to provide Nigeria with in-country data on the safety and efficacy of PA, based on the good safety and efficacy observed in the Phase III program and the CANTAM Study 2021 [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, Sowunmi et al. [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] recently reported a decline in the responsiveness of childhood \u003cem\u003ePlasmodium falciparum\u003c/em\u003e infections to ACTs (artemether-lumefantrine and artesunate-amodiaquine) in Nigeria. This underscores the importance of evaluating another effective and user-friendly antimalarial with good efficacy and tolerability in the country. This clinical trial resulted from efforts to improve efficacy, tolerability, cost, and treatment regimens. As the country is endemic for malaria, it is also critical to continue assessing the efficacy of AL, the current first-line ACT of choice in Nigeria, in order to detect early loss of efficacy. There is currently no data on the safety and efficacy of pyronaridine-artesunate in the Nigerian population. The goal of this study is to compare the safety and efficacy of pyronaridine-artesunate and artemether-lumefantrine in children aged 3 months to 12 years (144 months) with symptomatic acute uncomplicated malaria in south-west Nigeria.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and setting\u003c/h2\u003e \u003cp\u003eThis comparative, randomized, open-label, parallel-group clinical trial followed WHO guidelines [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Study drugs were pyronaridine-artesunate (PA) granules or tablets (Pyramax\u0026trade;; 60mg pyronaridine/20mg artesunate per sachet of granules, 180/60 respectively per tablet) supplied in aluminium sachets (Shin Poong Pharmaceutical Company, Ltd., Ansan, Korea), and artemether-lumefantrine (AL) tablets (Coartem\u0026trade;; Novartis SA, Basel, Switzerland). supplied in blister packs. Each tablet of dispersible Coartem contains 20 artemether and 120 mg lumefantrine. Patients were enrolled from the Kola Daisi Primary Healthcare Centre (PHC), University College Hospital, Ibadan and Ikereku PHC in Akinyele Local Government Area, southwest Nigeria.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy participants\u003c/h2\u003e \u003cp\u003eChildren aged 3 to 144 months with clinical features consistent with acute uncomplicated malaria and microscopically confirmed \u003cem\u003ePlasmodium falciparum\u003c/em\u003e malaria were enrolled if they had a minimum asexual parasite density of 1000/\u0026micro;L, an axillary temperature of \u0026ge;\u0026thinsp;37.5\u0026deg;C or a history of fever within 24 hours of presentation, lived within fifteen kilometres of the study centre, and were capable of taking drugs orally. Additional inclusion criteria included the absence of artemisinin-based combination therapy (ACT) intake in the two weeks preceding enrolment and signed informed consent from prospective enrolees\u0026rsquo; parents or guardians to participate in the study. Children with a history of allergy to any of the study drugs, including artemisinin, lumefantrine, or pyronaridine, were excluded from the study. Children with concurrent illnesses that could impair response evaluation, such as bacterial or viral infections, were also excluded. Additionally, children with clinical evidence of severe malaria were excluded from the study [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Children with severe malnutrition or known chronic diseases such as chronic liver disease, heart failure, or sickle cell anaemia were also excluded from the study. Children of parents/guardians who, in the investigator's opinion, will not adhere to the study protocol were not permitted to participate in the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eRandomization and blinding\u003c/h2\u003e \u003cp\u003ePatients were allocated to either PA or AL group following a pre-generated randomization table in ascending order. Different clinical personnel performed clinical assessments and drug administration.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eTreatments\u003c/h2\u003e \u003cp\u003eThe study drugs were administered orally for three days (days 0, 1, and 2). Pyronaridine-artesunate (Pyramax\u0026trade; - Shin Poong Pharmaceutical Company, Ltd., Ansan, Korea) was given once daily in the clinic by the research nurse supervised for three days. Pyramax\u0026trade; contains 60mg pyronaridine/20mg artesunate per sachet of granules, 180/60 respectively per tablet supplied in aluminium sachets. Dosing was based on body weight: 5 \u0026ndash; \u0026lt;8kg: one sachet; 8 \u0026ndash; \u0026lt;15kg: two sachets; 15 \u0026ndash; \u0026lt;20kg; three sachets; 20 \u0026ndash; \u0026lt;24kg: one tablet and 24 \u0026ndash; \u0026lt;45kg: two tablets. All PA doses were administered with a milk drink under the supervision of a research nurse. AL was administered as dispersible tablets (Coartem\u0026trade;, Novartis Pharma Basil Switzerland). Each dispersible tablet contains 20mg of artemether/120mg of lumefantrine. Study participants were dosed as follows: 5 \u0026ndash; \u0026lt;15Kg; one tablet, 15 \u0026ndash; \u0026lt;25Kg two tablets, 25 \u0026ndash;\u0026lt;35Kg three tablets, and 35Kg and above; four tablets. AL was administered at 0, 8, 24, 36, 48, and 60 hours respectively. The first, third, and fifth doses of AL were administered supervised in the clinic with milk drinks while the second, fourth, and sixth doses of AL were administered with milk drinks at home by the parent or guardian. Mothers of children who received AL were encouraged to breastfeed very young babies who were still on the breast soon after the drug was administered. At the end of Days 0, 1, and 2 visits, parents and guardians were given a sachet of full cream powdered milk each daily for the 2nd, 4th, and 6th doses of AL and were also reminded by phone 30 minutes before the next drug dosing. Although a fatty meal was not required for optimal absorption of PA unlike for AL, all enrolees received study drugs with milk drinks because the children who were randomised to receive PA felt disadvantaged because they did not receive milk drinks, and this could lead to poor compliance with follow up visits.\u003c/p\u003e \u003cp\u003eEach enrolee irrespective of drug group was observed in the clinic for 1 hour after drug administration for vomiting. If vomiting occurred within 30 minutes of drug administration, the full treatment drug dose (PA or AL) was re-administered. If vomiting occurred between 30\u0026ndash;60 minutes of drug administration, half the treatment dose was re-administered. Any enrolee who vomits the repeat dose was withdrawn from the study and treated with artesunate-amodiaquine as rescue medication as per the Nigeria national malaria treatment guidelines [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eData collection procedures\u003c/h2\u003e \u003cp\u003e Enrolees who met the inclusion criteria were given a detailed explanation of the study and were only enrolled after the accompanying parent or guardian signed an informed consent form. The information gathered from each participant was entered into case record forms (CRF) created specifically for the study. In the individual CRF, socio-demographic information, contact information for each enrolee, past medical history, as well as clinical and laboratory details for all enrolees in the study, were recorded. Each enrolee's parent or guardian provided a detailed medical history, which included a history of the presenting symptoms as well as a list of current medications. In 2019, an electronic thermometer was used to measure axillary temperature, while an infrared thermometer (beamed at the forehead) was used in 2020 because of the SARS-CoV-2 pandemic.\u003c/p\u003e \u003cp\u003eA few drops of capillary blood were obtained via finger prick for thick and thin blood smears and some into a capillary tube for haematocrit determination, and blood spots on filter paper for parasite genotyping at enrolment. For malaria parasite detection, thick and thin blood films were prepared from finger prick blood samples of each enrolee on Day 0, whereas only thick blood films were prepared at all other contact times and stained with fresh 10% Giemsa stain at pH 7.2. Dry stained blood films were viewed at a magnification of x1000 using a light microscope in accordance with the WHO guideline [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. At enrolment and on all contact days, gametocyte carriage was specifically observed and counted in the thick films. At enrolment and at each follow-up visit, blood spots on filter paper were obtained for DNA analysis using the polymerase chain reaction (PCR) to differentiate re-infection from recrudescence [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. At each point of contact, blood was drawn into capillary tubes for haematocrit determination. A five-millilitre venous blood sample was also obtained via venepuncture for the evaluation of haematological and biochemical parameters (urea and creatinine, as well as a liver function test) on days 0, 3, 7, and 28. Blood samples were collected from study participants and analysed at the chemical pathology and haematology laboratories of the University College Hospital Ibadan, Nigeria.\u003c/p\u003e \u003cp\u003eAll enrolees were followed up on out-patient basis daily from days 0 to 3 and then on days 7, 14, 21 and 28. Enrolees were also seen whenever a participant fell ill or a parent or guardian was concerned about their children's health. The day before follow-up visits, parents and guardians of enrolees were reminded by phone. Enrolees were provided transportation refunds to encourage compliance with follow-up. Evaluation at each visit included a brief clinical history and a physical examination to assess new complaints and medication side effects. A finger prick blood sample was taken on days 1, 2, 3, 7, 14, 21, 28, and any other (unscheduled) visit day for the preparation of thick blood films for the identification and quantification of asexual stages of the malaria parasite while we collected filter paper blood samples on days 0, 3, 7, 14, 21, and 28 for parasite genotyping from the same capillary blood samples.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eDNA Isolation and Amplification of Plasmodium falciparum\u003c/h2\u003e \u003cp\u003ePaired samples of blood spots on filter paper collected from patients with parasite recurrence on or before D28 (D0 and Day of parasite recurrence) were analysed using PCR techniques for parasite DNA. Genomic DNA extraction was performed with QIAamp DNA Mini kit blood and tissue (QIAGEN Hilden Germany) kit, according to manufacturer\u0026rsquo;s instructions. Eluted genomic DNA was stored at -20\u003csup\u003eo\u003c/sup\u003eC until further PCR analysis. The small sub-unit ribosomal RNA (ssrRNA) gene of \u003cem\u003eP. falciparum\u003c/em\u003e was amplified in a nested PCR using a primary genus-specific primer and a secondary \u003cem\u003eP. falciparum\u003c/em\u003e species-specific primer following the previously described standard protocol [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Paired samples with confirmed parasitaemia were further genotyped to distinguish recrudescence from new infection using merozoite surface protein-1 (\u003cem\u003emsp-1\u003c/em\u003e), merozoite surface protein-2 (\u003cem\u003emsp-2\u003c/em\u003e) and glutamate-rich protein (\u003cem\u003eglurp\u003c/em\u003e) genes respectively.\u003c/p\u003e \u003cp\u003eIn a 20\u0026micro;L reaction volume, PCR mixture containing 5X PCR Master Mix (Solis Biodyne, Estonia), 0.5mM each of forward and reverse primers, nuclease-free PCR grade water, and 5 \u0026micro;L of extracted genomic DNA as template was prepared for the primary reaction. In the Nested reaction, 2\u0026micro;L of the primary PCR product was used as a template in 18\u0026micro;L PCR mixture, containing the same reagents as the primary reaction except with a species-specific forward and reverse primers. The PCR thermal cycling conditions were previously described [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. All amplification of DNA was performed in an Eppendorf AG 22331 thermal cycler (Hamburg, Germany).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eGenotyping of msp-1, msp-2 \u0026amp; Glurp antigenic loci\u003c/h2\u003e \u003cp\u003ePCR amplification targeting the polymorphic regions of \u003cem\u003emsp-1\u003c/em\u003e (block 2), \u003cem\u003emsp-2\u003c/em\u003e (block 3) and glurp (R2) regions were genotyped with allelic specific primers as previously described [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The antigenic allelic families of \u003cem\u003emsp-1\u003c/em\u003e (K1, RO33 and MAD20), \u003cem\u003emsp-2\u003c/em\u003e (FC27 \u0026amp; 3D7) were amplified in a final reaction volume of 20\u0026micro;L (25\u0026micro;L for glurp), containing 5X PCR Master mix (Solis Biodyne, Estonia), primers (forward and reverse) 0.5mM (0.75mM for glurp) each and 5 \u0026micro;L of extracted genomic DNA as template in the primary reaction. 2\u0026micro;L of the primary PCR product was used as template in the nested reaction. The PCR cycling conditions for both primary and nested reactions were as previously described [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Ten (10\u0026micro;L) of the nested PCR products (amplicon) were electrophoresed on 1.5% agarose gel pre-stained with EZ-vision blue light DNA dye (EZ-Vision\u0026reg; Blue light DNA Dye, VWR Chemicals USA) and was allowed to migrate at 100volt for 40\u0026ndash;60 minutes for fragment size differentiation. The gel was visualized and photographed under a UV trans-illuminator documentation system (UVP\u003csup\u003e\u0026reg;\u003c/sup\u003e DigiDoc-It\u0026trade;, USA). Amplified fragments were paired for base-pair sizing and comparison. Fragments with the same base pair sizes (paired samples) in the amplified loci were considered recrudescence while un-identical base pair sizes were considered new infections. Rrecrudescence was defined as when a subsequent sample from follow up contained identical alleles or a subset of the alleles present in the day 0 sample. Reinfection was defined as when a follow up sample contained only new alleles that are un-identical with day 0 sample.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStudy endpoints\u003c/h2\u003e \u003cp\u003eThe WHO 2009 treatment outcome criteria were used to assess efficacy [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Early treatment failure (ETF) was defined as danger signs or severe malaria on day 1, 2 or 3 in the presence of parasitaemia; parasitaemia on day 2 higher than on day 0, irrespective of axillary temperature; parasitaemia on day 3 with an axillary temperature\u0026thinsp;\u0026ge;\u0026thinsp;37.5 \u0026ordm;C or parasitaemia on day 3\u0026thinsp;\u0026ge;\u0026thinsp;25% of count on day 0. Late clinical failure (LCF) was defined as danger signs or severe malaria in the presence of parasitaemia on any day between day 4 and day 28 (day 42) in patients who had not previously met any of the criteria for early treatment failure; or the presence of parasitaemia on any day between day 4 and day 28 (day 42) with an axillary temperature of \u0026ge;\u0026thinsp;37.5 \u0026ordm;C (or history of fever) in patients who had not previously met any of the criteria for early treatment failure. Late parasitological failure (LPF) is defined as the presence of parasitaemia on any day between days 7 and 28 (day 42) and an axillary temperature of \u0026lt;\u0026thinsp;37.5\u0026ordm;C in patients who did not previously meet any of the criteria for early treatment failure or late clinical failure. The main end point for the study was adequate clinical and parasitological response (ACPR), defined as the absence of parasitaemia on day 28, irrespective of axillary temperature, in patients who had not previously met any of the criteria of early treatment failure, late clinical failure, or late parasitological failure.\u003c/p\u003e \u003cp\u003eRecrudescence was defined as the recurrence of asexual parasitaemia within 28 days of receiving antimalarial treatment that contained the same genotypes that caused the initial illness. At the time of enrolment, PCT was defined as the time from the first dose of ACT until the first total and continued disappearance of asexual parasite forms for at least 24 hours, whereas fever clearance time (FCT) was defined as the time from the first dose of ACT until the first time the body temperature (for those with a raised temperature at enrolment) drops to below 37.5 \u0026ordm;C and stays below 37.5 \u0026ordm;C for at least 24 hours.\u003c/p\u003e \u003cp\u003eIn this study, safety was evaluated in terms of adverse events and severe adverse events by examining symptoms, clinical signs, and laboratory parameters. All study participants who took at least one dose of either of the study drugs were evaluated for safety. The evaluation of liver enzymes was a special category that was evaluated due to previous reports of transaminitis [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Alanine transaminase (ALT)/ aspartate transaminase (AST) greater than three times the upper limit of normal (ULN) plus peak total bilirubin greater than two times the ULN in the absence of a significant alkaline phosphatase increase were considered serious adverse events (SAE). An ALT and AST level greater than 5 times the ULN were considered an adverse event of special interest (AESI).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003eEthics statement\u003c/h2\u003e \u003cp\u003e The University of Ibadan/University College Hospital Ethics Committee (EC approval No - UI/EC/19/0114) and the Oyo State Ministry of Health Ethics Committee (EC approval No - AD 13/479/206) both approved the study protocol. Individual written informed consent was obtained from eligible participants' parents or guardians. Our study was conducted in accordance with Good Clinical Practice and the Declaration of Helsinki [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], as well as applicable regulations.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSample size calculation\u003c/h2\u003e \u003cp\u003eWe calculated the required minimum number of enrolees using the sample size formula for test of non-inferiority as written by Chow and colleagues [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], by assuming a difference of 2.5% in cure rate between PA and AL (98.9% vs 96.4%), 140 patients are required to attain a power of 90% at 95% level of confidence to demonstrate non-inferiority of PA versus AL with a non-inferiority limit of 5%. However, allowing for 20% loss to follow up, the total number of patients required would be 168 to give 84 patients per arm.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eAll study participants who received any amount of the study drugs were included in the intent-to-treat population. The per-protocol-population included children who received the entire course of study medication, had a known day-28 efficacy end point, and had no major protocol deviations. The data was analysed for efficacy in both the intention-to-treat and per-protocol populations. The efficacy endpoints were summarized by age. Safety outcomes were adverse events and abnormalities of laboratory results including liver function test and haematological indices. SPSS IBM Statistic Software version 20 was used to analyse the data at ρ = \u0026lt;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv class=\"Section2\" id=\"Sec15\"\u003e\n \u003ch2\u003eEnrolees\u0026rsquo; baseline characteristics and symptoms at presentation\u003c/h2\u003e\n \u003cp\u003eThe study was conducted between May and December 2019 and between July and December 2020. A total of 1,204 febrile children were screened for malaria parasitaemia during the study period; 550 (45.7%) had patent parasitaemia, with 172 eligible patients randomly assigned to PA (n\u0026thinsp;=\u0026thinsp;85) and to AL (n\u0026thinsp;=\u0026thinsp;87). Figure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e shows the details of the reasons for the exclusion of ineligible patients.\u003c/p\u003e\n \u003cp\u003eBaseline demographic and clinical characteristics were similar between the two treatment groups (Table I).\u0026nbsp;\u003c/p\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline Characteristics of children suffering from acute uncomplicated malaria treated with artemether-lumefantrine or pyronaridine-artesunate in Ibadan SW Nigeria\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDrug Group\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u0026rho;-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAL\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePA\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003cp\u003e\u0026bull; Male\u003c/p\u003e\n \u003cp\u003e\u0026bull; Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45 (50.0%)\u003c/p\u003e\n \u003cp\u003e42 (51.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45 (50.0)\u003c/p\u003e\n \u003cp\u003e40 (48.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90 (100)\u003c/p\u003e\n \u003cp\u003e82 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.880\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (months)\u003c/p\u003e\n \u003cp\u003e\u0026bull; Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;sd\u003c/p\u003e\n \u003cp\u003e\u0026bull; Range\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e79.93\u0026thinsp;\u0026plusmn;\u0026thinsp;37.16\u003c/p\u003e\n \u003cp\u003e8\u0026ndash;144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82.39\u0026thinsp;\u0026plusmn;\u0026thinsp;38.63\u003c/p\u003e\n \u003cp\u003e4\u0026ndash;143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e81.15\u0026thinsp;\u003cspan class=\"Underline\" name=\"Emphasis\" type=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;39.80\u003c/p\u003e\n \u003cp\u003e4\u0026ndash;144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.671\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; 3\u0026ndash;11 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e0.703\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; 12\u0026ndash;59 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20 (23.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e21 (24.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e41 (23.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; 60 and above\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e64 (73.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e59 (69.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e123 (71.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeight (kg)\u003c/p\u003e\n \u003cp\u003e\u0026bull; Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;sd\u003c/p\u003e\n \u003cp\u003e\u0026bull; Range\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.59\u0026thinsp;\u003cspan class=\"Underline\" name=\"Emphasis\" type=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;6.49\u003c/p\u003e\n \u003cp\u003e7.0\u0026ndash;36.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.67\u0026thinsp;\u003cspan class=\"Underline\" name=\"Emphasis\" type=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;6.74\u003c/p\u003e\n \u003cp\u003e5.5\u0026ndash;40.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.63\u0026thinsp;\u003cspan class=\"Underline\" name=\"Emphasis\" type=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;6.59\u003c/p\u003e\n \u003cp\u003e5.5\u0026ndash;40.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.938\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTemperature (\u003csup\u003eo\u003c/sup\u003eC)\u003c/p\u003e\n \u003cp\u003e\u0026bull; Mean\u0026thinsp;\u003cspan class=\"Underline\" name=\"Emphasis\" type=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;sd\u003c/p\u003e\n \u003cp\u003e\u0026bull; Range\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37.7\u0026thinsp;\u003cspan class=\"Underline\" name=\"Emphasis\" type=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.06\u003c/p\u003e\n \u003cp\u003e35.1\u0026ndash;40.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37.4\u0026thinsp;\u003cspan class=\"Underline\" name=\"Emphasis\" type=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.07\u003c/p\u003e\n \u003cp\u003e35.9\u0026ndash;39.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37.6\u0026thinsp;\u003cspan class=\"Underline\" name=\"Emphasis\" type=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.08\u003c/p\u003e\n \u003cp\u003e35.1\u0026ndash;40.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.074\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eParasite density (/\u0026micro;l)\u003c/p\u003e\n \u003cp\u003e\u0026bull; Geomean\u003c/p\u003e\n \u003cp\u003e\u0026bull; Range\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32,755\u003c/p\u003e\n \u003cp\u003e1035\u0026ndash;758,958\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28,211\u003c/p\u003e\n \u003cp\u003e1600\u0026ndash;1,652,505\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30,424\u003c/p\u003e\n \u003cp\u003e1035\u0026ndash;1,652,505\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.815\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHaematocrit (%)\u003c/p\u003e\n \u003cp\u003e\u0026bull; Mean\u0026thinsp;\u003cspan class=\"Underline\" name=\"Emphasis\" type=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;sd\u003c/p\u003e\n \u003cp\u003e\u0026bull; Range\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.14\u0026thinsp;\u003cspan class=\"Underline\" name=\"Emphasis\" type=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;5.06\u003c/p\u003e\n \u003cp\u003e18\u0026ndash;41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.14\u0026thinsp;\u003cspan class=\"Underline\" name=\"Emphasis\" type=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;5.48\u003c/p\u003e\n \u003cp\u003e18\u0026ndash;48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.14\u0026thinsp;\u003cspan class=\"Underline\" name=\"Emphasis\" type=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;5.26\u003c/p\u003e\n \u003cp\u003e18\u0026ndash;48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.997\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnaemic at DO\u003c/p\u003e\n \u003cp\u003e(PCV\u0026thinsp;\u0026lt;\u0026thinsp;30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (21.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (24.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40 (23.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.396\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHeight (cm)\u003c/p\u003e\n \u003cp\u003e\u0026bull; Mean\u0026thinsp;\u003cspan class=\"Underline\" name=\"Emphasis\" type=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;sd\u003c/p\u003e\n \u003cp\u003e\u0026bull; Range\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e110.65\u0026thinsp;\u003cspan class=\"Underline\" name=\"Emphasis\" type=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;21.31\u003c/p\u003e\n \u003cp\u003e18\u0026ndash;143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e110.65\u0026thinsp;\u003cspan class=\"Underline\" name=\"Emphasis\" type=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;28.90\u003c/p\u003e\n \u003cp\u003e18\u0026ndash;186\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e110.38\u0026thinsp;\u003cspan class=\"Underline\" name=\"Emphasis\" type=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;25.36\u003c/p\u003e\n \u003cp\u003e18\u0026ndash;186\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.892\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003eThe four most common symptoms at presentation were fever (100%), headache (69.8%), chills and rigors (62.6%), and loss of appetite (57.2%) (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ealso shows that there were statistically significant differences in the frequencies of only chills and rigors and loss of appetite which were higher in the AL group than in the PA group (\u0026rho;\u0026thinsp;=\u0026thinsp;0.033 and 0.014, respectively). Five patients (5.9%) in the PA compared with 3 (3.4%) in the AL group (\u0026rho;\u0026thinsp;=\u0026thinsp;0.347), vomited the first dose of the study drug and had to be re-dosed. After redosing, one of the children that received AL vomited and was withdrawn from the study. \u0026nbsp;\u003c/p\u003e\n \u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDistribution of children with acute uncomplicated malaria according to symptoms other than fever at presentation by treatment groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePresenting complaint\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal population\u003c/p\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;172 (100)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eArtemether-lumefantrine\u003c/p\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;87 (100%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePyronaridine-artesunate\u003c/p\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;85 (100%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026rho;-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHeadaches\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e120 (69.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e61 (70.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59 (69.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChills \u0026amp; rigors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e117 (68.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e66 (75.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51 (60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLoss of appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e101 (58.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e59 (67.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42 (49.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e82 (47.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e44 (50.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38 (44.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.450\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbdominal Pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e68 (39.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33 (37.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35 (41.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.642\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e54 (31.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30 (34.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.417\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCough\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e45 (26.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e21 (24.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.603\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiarrhoea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32 (18.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18 (20.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (16.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.558\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIrritability\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33 (19.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13 (14.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.178\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInsomnia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17 (9.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.611\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePalpitations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10 (5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cdiv class=\"Section3\" id=\"Sec16\"\u003e\n \u003ch2\u003eResults of Efficacy Evaluation\u003c/h2\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec17\"\u003e\n \u003ch2\u003eIntention-to-treat population analysis\u003c/h2\u003e\n \u003cp\u003eOf the 172 randomized to the study groups, 165 (95.9%) completed the study, and the primary efficacy endpoint of the study was attained. The distribution of the participants in the two study groups by treatment outcomes based on intention-to-treat and per-protocol analyses is shown in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. There were no significant differences in the number of patients who completed the study (\u0026rho;\u0026thinsp;=\u0026thinsp;0.682), those who were lost to follow-up (p\u0026thinsp;=\u0026thinsp;1.000) and those who withdrew (p\u0026thinsp;=\u0026thinsp;1.000) between the two study groups. \u0026nbsp;\u003c/p\u003e\n \u003ctable border=\"1\" id=\"Tab3\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTreatment outcome among patients with uncomplicated malaria treated with Artemether-lumefantrine or Pyronaridine-artesunate in Ibadan, southwest Nigeria\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTreatment Outcome\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eArtemether-lumefantrine\u003c/p\u003e\n \u003cp\u003eN (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePyronaridine-artesunate\u003c/p\u003e\n \u003cp\u003eN (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003cp\u003eN (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026rho;-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTOTAL Enrolled\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e87 (100)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e85 (100)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e172 (100)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; Completed study.\u003c/p\u003e\n \u003cp\u003e\u0026bull; LTFU\u003c/p\u003e\n \u003cp\u003e\u0026bull; Withdrawn\u003c/p\u003e\n \u003cp\u003e\u0026bull; Withdrawal of consent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83 (95.4)\u003c/p\u003e\n \u003cp\u003e3 (3.4)\u003c/p\u003e\n \u003cp\u003e1 (1.2)\u003c/p\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82 (96.5)\u003c/p\u003e\n \u003cp\u003e2 (2.4)\u003c/p\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003cp\u003e1 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e165 (95.9)\u003c/p\u003e\n \u003cp\u003e5 (2.9)\u003c/p\u003e\n \u003cp\u003e1 (0.6)\u003c/p\u003e\n \u003cp\u003e1 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.535\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eITT- Uncorrected\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;87 (100)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;85 (100)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;172 (100)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; ACPR \u0026ndash; D28\u003c/p\u003e\n \u003cp\u003e\u0026bull; LPF\u003c/p\u003e\n \u003cp\u003e\u0026bull; LCF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59 (67.8)\u003c/p\u003e\n \u003cp\u003e21 (24.1)\u003c/p\u003e\n \u003cp\u003e7 (8.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76 (89.4)\u003c/p\u003e\n \u003cp\u003e8 (9.4)\u003c/p\u003e\n \u003cp\u003e1 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e135 (78.5)\u003c/p\u003e\n \u003cp\u003e29 (16.9)\u003c/p\u003e\n \u003cp\u003e8 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eITT \u0026ndash; PCR Corrected\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;87\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;85\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;172\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; \u003cstrong\u003eCured\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026bull; \u003cstrong\u003eFailed\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83 (95.4)\u003c/p\u003e\n \u003cp\u003e4 (4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82 (96.5)\u003c/p\u003e\n \u003cp\u003e3 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e165/172 (95.9)\u003c/p\u003e\n \u003cp\u003e7/172 (4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePP \u0026ndash; Uncorrected\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;83\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;82\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;165\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; ACPR \u0026ndash; D21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73/83 (88.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82/83 (98.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e135/166 (93.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.016\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; ACPR \u0026ndash; D28\u003c/p\u003e\n \u003cp\u003e\u0026bull; LPF \u0026ndash; D28\u003c/p\u003e\n \u003cp\u003e\u0026bull; LCF \u0026ndash; D28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59/83 (71.1)\u003c/p\u003e\n \u003cp\u003e17 (20.5)\u003c/p\u003e\n \u003cp\u003e7 (8.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76/82 (92.7)\u003c/p\u003e\n \u003cp\u003e5 (6.1)\u003c/p\u003e\n \u003cp\u003e1 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e135 (81.8)\u003c/p\u003e\n \u003cp\u003e22 (13.3)\u003c/p\u003e\n \u003cp\u003e8 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePPP- PCR Corrected\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;83\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;82\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;165\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; Cured - D28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e165 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay of Failure\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e24 (100)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e6 (100)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e30 (100)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; Day 14\u003c/p\u003e\n \u003cp\u003e\u0026bull; Day 21\u003c/p\u003e\n \u003cp\u003e\u0026bull; Day 28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (8.3)\u003c/p\u003e\n \u003cp\u003e9 (37.5)\u003c/p\u003e\n \u003cp\u003e13 (54.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003cp\u003e5 (88.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (6.7)\u003c/p\u003e\n \u003cp\u003e10 (33.3)\u003c/p\u003e\n \u003cp\u003e18 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.405\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; % Failed before D28\u003c/p\u003e\n \u003cp\u003e\u0026bull; % Failed on D28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (45.8)\u003c/p\u003e\n \u003cp\u003e13 (54.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003cp\u003e5 (83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (40.0)\u003c/p\u003e\n \u003cp\u003e18 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.358\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eParasite clearance time (days)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;sd\u003c/p\u003e\n \u003cp\u003e\u0026bull; Range\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.68\u003c/p\u003e\n \u003cp\u003e1\u0026ndash;4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.64\u003c/p\u003e\n \u003cp\u003e1\u0026ndash;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.66\u003c/p\u003e\n \u003cp\u003e1\u0026ndash;4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.430\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFever clearance time (days)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;sd\u003c/p\u003e\n \u003cp\u003e\u0026bull; Range\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.32\u003c/p\u003e\n \u003cp\u003e1\u0026ndash;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.44\u003c/p\u003e\n \u003cp\u003e1\u0026ndash;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.38\u003c/p\u003e\n \u003cp\u003e1\u0026ndash;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.664\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHaematocrit at D28 (in %)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;sd\u003c/p\u003e\n \u003cp\u003e\u0026bull; Range\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.95\u003c/p\u003e\n \u003cp\u003e23\u0026ndash;40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.79\u003c/p\u003e\n \u003cp\u003e28\u0026ndash;42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34.13\u0026thinsp;\u0026plusmn;\u0026thinsp;2.95\u003c/p\u003e\n \u003cp\u003e25\u0026ndash;42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; Haematocrit\u0026thinsp;\u0026lt;\u0026thinsp;30% D28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003eAmong the intention-to-treat population, the percentage of patients with adequate clinical and parasitological responses (ACPR) on day-28 was significantly higher among patients in the PA group than the AL group (\u0026rho; = \u0026lt;0.002), but the difference was no longer significant after PCR-correction (\u0026rho;\u0026thinsp;=\u0026thinsp;1.000) as shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. The total number of patients who experienced treatment failure in the AL group (28/87 (32.2%) was significantly higher than those who had treatment failure in the PA group [9/85 (10.6%)]. The risk of failure was also higher in the AL group than in the PA group (RR\u0026thinsp;=\u0026thinsp;1.80; 95% CI: 1.39, 2.33), \u0026rho; = \u0026lt;0.001. Similarly, patients randomised to the AL group had an increased risk of experiencing treatment failure before day-21 compared with those in the PA group (RR\u0026thinsp;=\u0026thinsp;1.87; 95% CI: 1.44, 2.43).\u003c/p\u003e\n \u003cp\u003eAlthough haematological recovery was excellent for both study drugs, the mean haematocrit on day 28 was significantly higher in the patients randomised to the PA group (34.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8%) than in those in the AL group (33.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0%); \u0026rho;\u0026thinsp;\u0026lt;\u0026thinsp;0.002. Conversely, there were no significant differences in the mean parasite and fever clearance times as well as the number of anaemic patients between the PA group and the AL group (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). The graphs (Figs. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e) from the Kaplan-Meier survival analysis also corroborate the lack of differences in the fever and parasite clearance times between patients randomised to the PA group and those in the AL group.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec18\"\u003e\n \u003ch2\u003ePer-protocol population analysis\u003c/h2\u003e\n \u003cp\u003eThere was no early treatment failure during the study. Response to treatment was prompt in all study participants except in an enrolee among AL treated children who had recurrent vomiting and had to be withdrawn on day 0. By day 1, 11.6% (10/86) and 12.9% (n\u0026thinsp;=\u0026thinsp;11/85) of patients treated with AL and PA respectively were free of patent parasitaemia while corresponding values for day 2 were 70.9% (n\u0026thinsp;=\u0026thinsp;61/86) and 72.9% (n\u0026thinsp;=\u0026thinsp;62/85) for AL and PA, respectively. Two (2.3%) of the study participants who received AL had patent parasitaemia at day 3, but they both recorded adequate clinical and parasitological responses at day 28. All participants were free of patent parasitaemia by day 7. However, two children among those who received AL failed treatment at day 14; one each recorded LCF and LPF.\u003c/p\u003e\n \u003cp\u003eIn contrast to those treated with AL, treatment failure was first seen among children who received PA on day 21. The ACPR in the per-protocol population at day 21 was significantly higher for PA than for AL treated children (98.8% versus 88.0%, respectively, \u0026rho;\u0026thinsp;=\u0026thinsp;0.009). The chances of ACPR were significantly lower in the AL than PA (RR\u0026thinsp;=\u0026thinsp;0.52; 95% CI: 0.40, 0.67). Similarly, ACPR (unadjusted cure rate) at day 28 was 92.7% for PA and 71.1% for AL, with PA having significantly higher chances of attaining ACPR than AL (RR\u0026thinsp;=\u0026thinsp;2.81; 95% CI: 1.36, 5.85), \u0026rho;\u0026thinsp;=\u0026thinsp;0.001.\u003c/p\u003e\n \u003cp\u003eThe efficacy outcomes observed by age in the per-protocol population are as shown in Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e. The ACPR was significantly higher in the PA group than in the AL group (\u0026rho;\u0026thinsp;=\u0026thinsp;0.008) among children under five-year-old (\u0026lt;\u0026thinsp;60 months) and over 5-year-old (\u0026ge;\u0026thinsp;60 month) old children (RR\u0026thinsp;=\u0026thinsp;1.64; 95% CI: 1.19, 2.26), \u0026rho;\u0026thinsp;=\u0026thinsp;0.016, similar to what was recorded in the entire study population.\u003c/p\u003e\n \u003cp\u003eAll the 30 children with parasite recurrence among PP population - [6/82 (7.3%) for PA versus 24/83 (28.9%) for AL; \u0026rho;\u0026thinsp;\u0026lt;\u0026thinsp;0.001] were treated with artesunate-amodiaquine (ASAQ). Response to ASAQ was prompt, leading to rapid parasite clearance and resolution of symptoms where there were symptoms.\u0026nbsp;\u003c/p\u003e\n \u003ctable border=\"1\" id=\"Tab4\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTreatment outcome among children (PP) from southwest Nigeria with acute uncomplicated malaria treated with artemether-lumefantrine or pyronaridine-artesunate in different age groups.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eTreatment Outcome\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDrug group\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u0026rho;-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAL\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePA\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eAge\u0026thinsp;\u0026lt;\u0026thinsp;12 months [N\u0026thinsp;=\u0026thinsp;8]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003e3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003e5\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003e8\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; ACPR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (87.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e0.375\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; LCF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; PCR Corrected ACPR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3/3 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5/5 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8/8 (100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNil\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eAge\u0026thinsp;\u0026lt;\u0026thinsp;60 months [N\u0026thinsp;=\u0026thinsp;47]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eN\u0026thinsp;=\u0026thinsp;22\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eN\u0026thinsp;=\u0026thinsp;25\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eN\u0026thinsp;=\u0026thinsp;47\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; ACPR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (63.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (96.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38 (80.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; LPF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (4.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (10.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; LCF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eAge\u0026thinsp;\u0026ge;\u0026thinsp;60 months [N\u0026thinsp;=\u0026thinsp;118]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eN\u0026thinsp;=\u0026thinsp;61\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eN\u0026thinsp;=\u0026thinsp;57\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eN\u0026thinsp;=\u0026thinsp;118\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; Cured (ACPR)\u003c/p\u003e\n \u003cp\u003e\u0026bull; Failed (LCF\u0026thinsp;+\u0026thinsp;LPF)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45 (73.8)\u003c/p\u003e\n \u003cp\u003e16 (26.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52 (91.2)\u003c/p\u003e\n \u003cp\u003e5 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97 (82.2)\u003c/p\u003e\n \u003cp\u003e21 (17.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.016\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; ACPR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45 (73.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52 (91.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97 (82.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e0.046\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; LPF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (21.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (7.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (14.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; LCF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eTotal PPP [N\u0026thinsp;=\u0026thinsp;165]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003e83\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003e82\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003e165\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; ACPR\u003c/p\u003e\n \u003cp\u003e\u0026bull; LPF\u003c/p\u003e\n \u003cp\u003e\u0026bull; LCF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59/83 (71.1)\u003c/p\u003e\n \u003cp\u003e17/83 (20.5)\u003c/p\u003e\n \u003cp\u003e7/83 (8.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76/82 (92.7)\u003c/p\u003e\n \u003cp\u003e5/82 (6.1)\u003c/p\u003e\n \u003cp\u003e1/82 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e135/165 (81.8)\u003c/p\u003e\n \u003cp\u003e22 (13.3)\u003c/p\u003e\n \u003cp\u003e8 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; Cured (ACPR)\u003c/p\u003e\n \u003cp\u003e\u0026bull; Failed (LCF\u0026thinsp;+\u0026thinsp;LPF)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59/83 (71.1)\u003c/p\u003e\n \u003cp\u003e24/83 (28.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78/82 (92.7)\u003c/p\u003e\n \u003cp\u003e6/82 (7.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e135/165 (81.8)\u003c/p\u003e\n \u003cp\u003e30/165 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; PCR Corrected cure rate\u003c/p\u003e\n \u003cp\u003e\u0026bull; PCR corrected treatment failure rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83/83 (100)\u003c/p\u003e\n \u003cp\u003e0/83 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82/82 (100)\u003c/p\u003e\n \u003cp\u003e0/82 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e163/165 (98.8)\u003c/p\u003e\n \u003cp\u003e0/165 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003ch2\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eMolecular analysis\u003c/span\u003e\u003c/h2\u003e\n \u003cp\u003eMolecular biology analysis of paired samples for enrolees with parasite recurrence was carried out with \u003cem\u003emsp-1, msp-\u003c/em\u003e2 and \u003cem\u003eglurp\u003c/em\u003e. This showed that all six cases of parasite recurrence among children treated with PA were re-infections. In a similar manner, all the 24 cases among AL treated children were also re-infection giving PCR corrected cure rates of 100% for PA and AL for the PP sampled populations.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec19\"\u003e\n \u003ch2\u003eSafety of pyronaridine-artesunate compared with artemether-lumefantrine\u003c/h2\u003e\n \u003cp\u003e\u003cem\u003eComplaints and physical examination\u003c/em\u003e.\u003c/p\u003e\n \u003cp\u003eThe ITT population was considered as the safety population. Recorded adverse events were similar to the symptoms and signs seen during malaria infection. There was no incidence of serious adverse event throughout the study. The type and prevalence of the various adverse events were similar for the two study drugs. The five most often recorded adverse events were fever, chills and rigors, anorexia, cough, and headache. These are clinical symptoms that occur during malaria infection. Further details are provided in Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e. There was no clinical evidence of jaundice, intravascular haemolysis, hepatic dysfunction, or renal impairment. No death was recorded during the study.\u0026nbsp;\u003c/p\u003e\n \u003ctable border=\"1\" id=\"Tab5\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSummary of Adverse Events among children (PP) from southwest Nigeria with acute uncomplicated malaria treated with artemether-lumefantrine or pyronaridine-artesunate\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEvent\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAll patients\u003c/p\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;172\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eArtemether-lumefantrine\u003c/p\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;87\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePyronaridine-artesunate\u003c/p\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;85\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdverse event from any cause,\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53 (30.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27 (31.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26 (30.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.949\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e58 (34.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24 (27.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e34 (40.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.106\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChills and rigors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33 (19.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16 (18.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17 (20.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.847\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnorexia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e29 (17.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16 (18.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13 (15.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.685\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCough\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e28 (16.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14 (16.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14 (16.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e27 (16.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12 (14.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15 (17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.536\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22 (12.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11 (12.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11 (13.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePallor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17 (10.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9 (10.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbdominal pains\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.563\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6 (7.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.744\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePalpitations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3(3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRashes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0 (0.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003eLaboratory results were mostly within normal ranges, with occasional marginal increases as (shown in Supplementary file 1 \u0026ndash; Tables\u0026nbsp;6a \u0026ndash; 6h, Tables\u0026nbsp;7a to 7h and Figs.\u0026nbsp;4\u0026ndash;11). There were no records of blood urea, creatinine, random blood glucose, or total bilirubin levels that were more than twice the upper limit of normal after receiving either study drugs. Both PA and AL had no deleterious effect on the transaminases. On day-0 (before antimalarial administration), two study participants who received AL had alanine transaminase (ALT) levels that were twice the upper limit of normal. By day 3, the elevated ALT levels had returned to normal. On day 0, one of the two children who received AL and had ALT more than twice the upper limit of normal also had aspartate aminotransferase (AST) more than twice the upper limit of normal, which returned to normal by day 3.\u003c/p\u003e\n \u003cp\u003eOn day-3, one participant in the PA group had AST level that was twice the upper limit of normal. By day 7, the elevated AST level had returned to normal. There was no instance of any adverse event of interest. Changes in blood levels of various enzymes and other parameters measured among participants in the two drug groups were statistically significant on Days 7 and 28 with ALT and Day 28 with AST and alkaline phosphatase (ALP). The observed increases in liver enzymes, bilirubin, urea, creatinine, and random blood sugar levels were not clinically significant (Supplementary file 1).\u003c/p\u003e\n \u003cdiv class=\"Section3\" id=\"Sec20\"\u003e\n \u003ch2\u003eGametocyte carriage\u003c/h2\u003e\n \u003cp\u003eThe number of participants who received PA with gametocyte carriage was consistently higher than that of those who received AL, except on day 28, when only one of the PA-treated children and two of the AL-treated children had gametocytes. However, the differences were only statistically significant on day 7. Supplementary file 2 - Table\u0026nbsp;8a contains further information on gametocyte carriage. The number of participants with gametocytes was not only higher in children treated with PA, but the gametocytes densities were also consistently higher (supplementary file 2 - Table\u0026nbsp;8b). One participant in particular stood out because he had gametocytes from day 0 to day 28. The gametocyte counts were also high, ranging from 728/\u0026micro;L to 3,088/\u0026micro;L. Two other participants did not clear their gametocytes until day 21, and another participant had gametocytaemia until day 14. All four participants who had delayed gametocyte clearance had received PA.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eDuring this study, we evaluated the comparative efficacy and safety of pyronaridine-artesunate [Pyramax\u0026trade;; Shin Poong Pharm Co., Ltd, Seoul, South Korea] and artemether-lumefantrine [Coartem\u0026trade;; Novartis Pharma; Switzerland] in the treatment of acute uncomplicated falciparum malaria among Nigerian children. The two ACTs were found to be efficacious and well tolerated by the study participants. There was no record of early treatment failure in any arm of the study, and only one participant who received AL was withdrawn as a result of recurrent vomiting.\u003c/p\u003e \u003cp\u003eThe day-28 PCR-corrected cure rate in children with uncomplicated falciparum malaria treated with PA granules or tablets was 100.0% in the per-protocol population and 96.5% in the intention-to-treat population. The primary efficacy outcome for pyronaridine\u0026ndash;artesunate was greater than 95% in all age groups, be it among children under one year (\u0026lt;\u0026thinsp;12 months) of age, under-five years old (\u0026lt;\u0026thinsp;60 months) or 60 to 144 months old. The efficacy of pyronaridine\u0026ndash;artesunate against falciparum malaria was generally consistent with previous studies on the use of pyronaridine\u0026ndash;artesunate [\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22 CR23\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA highly significant efficacy finding in this study is that pyronaridine\u0026ndash;artesunate had a significantly higher ACPR than artemether\u0026ndash;lumefantrine in both the intent-to-treat (89.4% versus 67.8%) and per-protocol populations (92.7% versus 71.1%). However, because recurrent parasites were re-infections, there was no significant difference in the PCR-corrected cure rates of pyronaridine\u0026ndash;artesunate and artemether\u0026ndash;lumefantrine at day 28. This finding raises concern about the post treatment prophylaxis of AL compared with PA. Our findings are in keeping with reports of pyronaridine\u0026ndash;artesunate and artemether\u0026ndash;lumefantrine efficacy in the treatment of acute uncomplicated malaria among Gabonese children [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], Kenyan children [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], and children from Burkina Faso, Guinea, and Mali [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Although there are no reports on the efficacy and safety of PA in Nigeria, numerous studies have reported on the efficacy of AL, the comparator drug in our study in the management of acute uncomplicated malaria in Africa in general and Nigeria in particular [\u003cspan additionalcitationids=\"CR37 CR38\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. It is particularly noteworthy that PA demonstrated a statistically significant higher efficacy among under 5-year-olds during this study [96.0% vs 63.6% for PA and AL, respectively, as shown in Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e (ρ\u0026thinsp;=\u0026thinsp;.008). PA also recorded a better and statistically significantly higher efficacy among children\u0026thinsp;\u0026ge;\u0026thinsp;60 months than AL [91.2%vs 73.8% for PA vs AL; ρ\u0026thinsp;=\u0026thinsp;0.016]. Details are shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. It can be assumed that PA\u0026rsquo;s significant superiority among children\u0026thinsp;\u0026le;\u0026thinsp;59 months of age reflects its true efficacy since this group of children are generally believed to be relatively immuno-na\u0026iuml;ve and the chemotherapeutic effect of AL was not augmented by immunity.\u003c/p\u003e \u003cp\u003eThere was no difference in parasite clearance time between pyronaridine\u0026ndash;artesunate and artemether\u0026ndash;lumefantrine treated groups, and our findings are consistent with Roth and colleagues' findings in Kenyan children [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. In contrast, three previous studies demonstrated that pyronaridine\u0026ndash;artesunate group cleared \u003cem\u003eP. falciparum\u003c/em\u003e more rapidly than artemether\u0026ndash;lumefantrine [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. On day 3, all enrolees were fever-free, and no difference in fever clearance time was observed, which is consistent with a previous study [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], though another study found that pyronaridine\u0026ndash;artesunate caused faster fever clearance [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The occurrence of one LCF and one LPF on D14 among participants who received AL is worrisome. This suggests declining efficacy of AL in the treatment of malaria in the study area. Sowunmi \u003cem\u003eet al.\u003c/em\u003e [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] previously reported a decline in the responsiveness of uncomplicated malaria to Nigeria's preferred antimalarial drugs \u0026ndash; artemether-lumefantrine and artesunate-amodiaquine. This was stated in a report detailing a post-hoc analysis of clinical trials in south-west of Nigeria among 360 children under 16 years at 5-year intervals in 2009\u0026ndash;2010, and 2014\u0026ndash;2015, and 1341 children under 5 years in studies from six-geopolitical zones from the Nigerian national antimalaria efficacy studies conducted at 2-year intervals in 2009\u0026ndash;2010 and 2012\u0026ndash;2015, respectively, after deployment in 2005.\u003c/p\u003e \u003cp\u003eIn our study, both artemether-lumefantrine and pyronaridine-artesunate had good safety profiles. The commonly observed adverse events were fever, chills and rigors, anorexia, and headache. These symptoms are similar to those seen in malaria patients and resolve as the infection is cleared. These observations are similar to reports by previous workers [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. There was no record of clinical hepatic impairment for PA or AL. Laboratory evaluation of liver transaminases, alkaline phosphatase, and bilirubin only revealed marginal increases with very few records of twice the upper limit of normal in both treatment arms (Supplementary file 1 \u0026ndash; Tables\u0026nbsp;6a \u0026ndash; 6h, Tables\u0026nbsp;7a \u0026minus;\u0026thinsp;7h and Figs.\u0026nbsp;4\u0026ndash;11). The alterations in transaminases were similar in both treatment arms and were not clinically significant. This contrasts with the findings of Sagara \u003cem\u003eet al\u003c/em\u003e. [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], who found that 13 out of 996 (1.3%) patients had transaminases increase after the first cure, including one possible Hy's law case, and two out of 311 (0.32%) after a retreatment of a second bout of malaria with PA. The lack of any cases of significant transaminase increases could be attributed to the relatively small number of participants (85) in our study compared to 996 in the study reported by Sagara \u003cem\u003eet al.\u003c/em\u003e [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Our observation is, however, supported by the report of Lutete \u003cem\u003eet al.\u003c/em\u003e [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] in their cohort event monitoring study in five African countries involving over 7,000 malaria patients in a protocol resembling real-world clinical practice.\u003c/p\u003e \u003cp\u003eAnother notable finding from the present study is that from days 0 to 21, gametocyte carriage was consistently higher in PA-treated children compared to AL-treated children, but the observed differences were not statistically significant -(Supplementary file 2 - Tables\u0026nbsp;8a and 8b). The significance of this relatively higher gametocyte carriage is unclear, as the presence of gametocytes does not always indicate infectivity [\u003cspan additionalcitationids=\"CR42 CR43\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Gametocytes are the stage in the plasmodial life cycle that is infectious to mosquitoes; the insect in which sexual multiplication of malaria parasites occurs, leading to the development of sporozoites, which in turn infect humans. However, only mature gametocytes are infectious to mosquitos after ingestion. Furthermore, microscopy cannot distinguish between viable living gametocytes and dead or drug-affected gametocytes. Nonetheless, the high gametocyte carriage suggests that pyronaridine does not have particularly effective gametocidal properties. The pyronaridine nucleus is derived from mepacrine (a 9-aminoacridine) and contains an amodiaquine-like side chain. The WWARN study group reported clear differences in gametocyte clearance between various ACTs in a systematic review [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. The WWARN study group reported that ACTs with 4-aminoquinoline partner drugs, such as dihydroartemisinin-piperaquine and artesunate amodiaquine, clear gametocytes at a much slower rate than those with aryl-amino alcohol and related structures (artesunate-mefloquine and artemether lumefantrine).\u003c/p\u003e \u003cp\u003eThis study's findings should be viewed with a few caveats in mind. The current study included only eight children under the age of 12 months, of which only five were randomly assigned to the pyronaridine-artesunate group. Despite the fact that the ACPR for pyronaridine-artesunate group was 100 percent on day 28, the number of enrolees is insufficient to draw any conclusions about efficacy and safety in that age group. As a result, more information on this patient population is needed for pyronaridine-artesunate.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe efficacy and safety of PA among Nigerian children is both impressive and important as Nigeria is one of the highest burden countries for malaria in sub-Saharan Africa especially as this is being recorded at a time that AL has started to show declining efficacy. This study provides empirical evidence for the inclusion of PA in the National Treatment Guidelines and it is hoped that findings from routine TES will provide relevant updates on the efficacy of ACTs in the country for their sustained recommendation.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflicts of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCOF, OEA and OAM designed the study. COF, FIO, OSM, ADA, AEO and BEO conducted the studies, RIF ran the molecular analysis, COF and AEO analysed the data and drafted the manuscript. All authors read and approved the manuscript,\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was funded by Shin Poong Pharm Co., Ltd, Seoul, South Korea \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the children and their families for participating in this study. We also thank all health care workers of our study sites - nurses and staff of the malaria clinic, health care workers of Ikereku PHC in Akinyele Local Govt Area for their assistance and cooperation. Our appreciation goes to our microscopists and research assistants Mrs. Bola Akinyele, Mrs. Iyabo Abdusalam and Miss Grace Egunyomi.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eWHO, \u003cstrong\u003eWorld malaria report 2021. Geneva: World Health Organization; 2021\u003c/strong\u003e. 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United States of America: Taylor \u0026amp; Francis Group, LLC; 2018: 71-102\u003c/li\u003e\n \u003cli\u003eRoth JM, Sawa P, Makio N, Omweri G, Osoti V, Okach S, Choy F, Schallig HDFH, Mens P: \u003cstrong\u003ePyronaridine-artesunate and artemether-lumefantrine for the treatment of uncomplicated \u003cem\u003ePlasmodium falciparum\u003c/em\u003e malaria in Kenyan children: a randomized controlled non-inferiority trial.\u003c/strong\u003e\u003cem\u003eMalaria journal\u0026nbsp;\u003c/em\u003e2018, \u003cstrong\u003e17:\u003c/strong\u003e199-199.\u003c/li\u003e\n \u003cli\u003eRamharter M, Kurth F, Schreier AC, Nemeth J, Glasenapp I, Belard S, Schlie M, Kammer J, Koumba PK, Cisse B, \u003cem\u003eet al\u003c/em\u003e: \u003cstrong\u003eFixed-dose pyronaridine-artesunate combination for treatment of uncomplicated \u003cem\u003efalciparum\u003c/em\u003e malaria in pediatric patients in Gabon.\u003c/strong\u003e\u003cem\u003eJ Infect Dis\u0026nbsp;\u003c/em\u003e2008, \u003cstrong\u003e198:\u003c/strong\u003e911-919.\u003c/li\u003e\n \u003cli\u003eFalade C, Makanga M, Premji Z, Ortmann CE, Stockmeyer M, de Palacios PI: \u003cstrong\u003eEfficacy and safety of artemether-lumefantrine (Coartem) tablets (six-dose regimen) in African infants and children with acute, uncomplicated \u003cem\u003efalciparum\u003c/em\u003e malaria.\u003c/strong\u003e\u003cem\u003eTrans R Soc Trop Med Hyg\u0026nbsp;\u003c/em\u003e2005, \u003cstrong\u003e99:\u003c/strong\u003e459-467.\u003c/li\u003e\n \u003cli\u003eFalade CO, Ogunkunle OO, Dada-Adegbola HO, Falade AG, de Palacios PI, Hunt P, Virtanen M, Oduola AM, Salako LA: \u003cstrong\u003eEvaluation of the efficacy and safety of artemether-lumefantrine in the treatment of acute uncomplicated \u003cem\u003ePlasmodium falciparum\u003c/em\u003e malaria in Nigerian infants and children.\u003c/strong\u003e\u003cem\u003eMalar J\u0026nbsp;\u003c/em\u003e2008, \u003cstrong\u003e7:\u003c/strong\u003e246.\u003c/li\u003e\n \u003cli\u003eFalade CO, Dada-Adegbola HO, Ogunkunle OO, Oguike MC, Nash O, Ademowo OG: \u003cstrong\u003eEvaluation 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.\u003c/strong\u003e\u003cem\u003eMed Princ Pract\u0026nbsp;\u003c/em\u003e2014, \u003cstrong\u003e23:\u003c/strong\u003e204-211.\u003c/li\u003e\n \u003cli\u003eOguche S, Okafor HU, Watila I, Meremikwu M, Agomo P, Ogala W, Agomo C, Ntadom G, Banjo O, Okuboyejo T, \u003cem\u003eet al\u003c/em\u003e: \u003cstrong\u003eEfficacy of artemisinin-based combination treatments of uncomplicated \u003cem\u003efalciparum\u003c/em\u003e malaria in under-five-year-old Nigerian children.\u003c/strong\u003e\u003cem\u003eAm J Trop Med Hyg\u0026nbsp;\u003c/em\u003e2014, \u003cstrong\u003e91:\u003c/strong\u003e925-935.\u003c/li\u003e\n \u003cli\u003eTshefu AK, Gaye O, Kayentao K, Thompson R, Bhatt KM, Sesay SS, Bustos DG, Tjitra E, Bedu-Addo G, Borghini-Fuhrer I, \u003cem\u003eet al\u003c/em\u003e: \u003cstrong\u003eEfficacy and safety of a fixed-dose oral combination of pyronaridine-artesunate compared with artemether-lumefantrine in children and adults with uncomplicated \u003cem\u003ePlasmodium falciparum\u0026nbsp;\u003c/em\u003emalaria: a randomised non-inferiority trial.\u003c/strong\u003e\u003cem\u003eLancet\u0026nbsp;\u003c/em\u003e2010, \u003cstrong\u003e375:\u003c/strong\u003e1457-1467.\u003c/li\u003e\n \u003cli\u003eSagara I, Beavogui AH, Zongo I, Soulama I, Borghini-Fuhrer I, Fofana B, Camara D, Som\u0026eacute; AF, Coulibaly AS, Traore OB, \u003cem\u003eet al\u003c/em\u003e: \u003cstrong\u003eSafety and efficacy of re-treatments with pyronaridine-artesunate in African patients with malaria: a substudy of the WANECAM randomised trial.\u003c/strong\u003e\u003cem\u003eLancet Infect Dis\u0026nbsp;\u003c/em\u003e2016, \u003cstrong\u003e16:\u003c/strong\u003e189-198.\u003c/li\u003e\n \u003cli\u003eKone A, van de Vegte-Bolmer M, Siebelink-Stoter R, van Gemert G-J, Dara A, Niangaly H, Luty A, Doumbo OK, Sauerwein R, Djimde AA: \u003cstrong\u003eSulfadoxine-pyrimethamine impairs \u003cem\u003ePlasmodium falciparum\u003c/em\u003e gametocyte infectivity and Anopheles mosquito survival.\u003c/strong\u003e\u003cem\u003eInternational journal for parasitology\u0026nbsp;\u003c/em\u003e2010, \u003cstrong\u003e40:\u003c/strong\u003e1221-1228.\u003c/li\u003e\n \u003cli\u003eBeavogui AH, Djimde AA, Gregson A, Toure AM, Dao A, Coulibaly B, Ouologuem D, Fofana B, Sacko A, Tekete M, \u003cem\u003eet al\u003c/em\u003e: \u003cstrong\u003eLow infectivity of \u003cem\u003ePlasmodium falciparum\u003c/em\u003e gametocytes to Anopheles gambiae following treatment with sulfadoxine-pyrimethamine in Mali.\u003c/strong\u003e\u003cem\u003eInternational journal for parasitology\u0026nbsp;\u003c/em\u003e2010, \u003cstrong\u003e40:\u003c/strong\u003e1213-1220.\u003c/li\u003e\n \u003cli\u003eKarunajeewa HA, Mueller I: \u003cstrong\u003eHow important is gametocyte clearance after malaria therapy?\u003c/strong\u003e\u003cem\u003eBMC Medicine\u0026nbsp;\u003c/em\u003e2016, \u003cstrong\u003e14:\u003c/strong\u003e93.\u003c/li\u003e\n \u003cli\u003eWWARN Gametocyte Study Group (2016). \u003cstrong\u003eGametocyte carriage in uncomplicated Plasmodium \u003cem\u003efalciparum\u003c/em\u003e malaria following treatment with artemisinin combination therapy: a systematic review and meta-analysis of individual patient data\u003c/strong\u003e. BMC Med. 2016 May 24;14:79. doi: 10.1186/s12916-016-0621-7. \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"malaria-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"malj","sideBox":"Learn more about [Malaria Journal](http://malariajournal.biomedcentral.com/)","snPcode":"12936","submissionUrl":"https://submission.nature.com/new-submission/12936/3","title":"Malaria Journal","twitterHandle":"@malariajournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Randomized clinical trial, Pyronaridine-artesunate, Artemether-lumefantrine, Efficacy and safety, Uncomplicated malaria, Nigeria","lastPublishedDoi":"10.21203/rs.3.rs-1664143/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1664143/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Declining responsiveness to artemether-lumefantrine (AL), the ACT of choice since 2005, has been reported in Nigeria. Pyronaridine-artesunate (PA) is a newer fixed-dose ACT recently included in the WHO list of prequalified medicines for the treatment of uncomplicated falciparum malaria. However, data from the Nigerian paediatric population is scarce. Therefore, we compared the efficacy and safety of pyronaridine-artesunate with artemether-lumefantrine using the WHO 28-day antimalarial efficacy protocol in Ibadan, southwest Nigeria.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethod:\u003c/strong\u003e \u0026nbsp;In an open-labelled randomized controlled clinical trial children aged 3 to 144 months with a history of fever and microscopically confirmed \u003cem\u003ePlasmodium\u003c/em\u003e \u003cem\u003efalciparum\u003c/em\u003e malaria were enrolled. Enrolees were randomly assigned to receive pyronaridine–artesunate or artemether–lumefantrine at standard dosages according to bodyweight, for 3 days. Venous blood was obtained for haematology, blood chemistry and liver function tests on days 0, 3, 7, and 28 as part of safety evaluation.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u0026nbsp;One hundred and sixty-five (95.9%; 165/172) enrolees completed the study. About half [52.3%; 90/172] of enrolees were male. Eighty-seven (50.6%) received artemether-lumefantrine while 85 (49.4%) received pyronaridine-artesunate. Day 28 adequate clinical and parasitological response for pyronaridine-artesunate was 92.7% [(76/82) 95% CI: 83.1, 95.9] and 71.1% [(59/83) 95% CI: 60.4, 79.9] for artemether-lumefantrine (ρ\u0026lt;0.001). PCR-corrected cure rates were similar for PA and AL as all parasite recurrences [PA = 6 (7.3%); AL = 24 (28.9%)] were re-infections. Haematological recovery at day-28 was significantly better among pyronaridine-artesunate treated patients (34.9% ± 2.8) compared to those treated with artemether-lumefantrine (33.1% ±3.0) [ρ = 0.002]. Adverse events in both treatment arms were fever, chills and rigors, anorexia, cough and headache, similar to symptoms observed during malaria infection. Blood chemistry and liver function tests were mostly within normal limits, with an occasional marginal rise. There was no serious adverse event in both arms of the study. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e The two ACTs were well-tolerated. Pyronaridine-artesunate has a higher ACPR than artemether-lumefantrine in the per-protocol-population and a non-inferiority response after PCR correction in the treatment of uncomplicated malaria in Nigerian children. The results of this study support the inclusion of pyronaridine-artesunate in the antimalaria treatment guidelines in Nigeria.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eRetrospective Trial Registration in Clinicaltrials.gov: NCT05192265\u003c/strong\u003e\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of Pyronaridine-Artesunate Versus Artemether-Lumefantrine in the Treatment of Acute Uncomplicated Malaria in Children in South-West Nigeria: An open- labelled randomized controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-05-20 15:26:26","doi":"10.21203/rs.3.rs-1664143/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2022-06-19T07:53:47+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-06-01T16:19:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"ba6b9e7b-abc4-4af2-b36c-d81e181485a3","date":"2022-05-22T16:59:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-05-22T06:50:30+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2022-05-18T05:11:35+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-05-18T05:11:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"Malaria Journal","date":"2022-05-17T06:52:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"malaria-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"malj","sideBox":"Learn more about [Malaria Journal](http://malariajournal.biomedcentral.com/)","snPcode":"12936","submissionUrl":"https://submission.nature.com/new-submission/12936/3","title":"Malaria Journal","twitterHandle":"@malariajournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fdd02a84-0137-4546-ad2e-d20b1c1b3684","owner":[],"postedDate":"May 20th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T21:16:33+00:00","versionOfRecord":{"articleIdentity":"rs-1664143","link":"https://doi.org/10.1186/s12936-023-04574-7","journal":{"identity":"malaria-journal","isVorOnly":false,"title":"Malaria Journal"},"publishedOn":"2023-05-13 20:46:47","publishedOnDateReadable":"May 13th, 2023"},"versionCreatedAt":"2022-05-20 15:26:26","video":"","vorDoi":"10.1186/s12936-023-04574-7","vorDoiUrl":"https://doi.org/10.1186/s12936-023-04574-7","workflowStages":[]},"version":"v1","identity":"rs-1664143","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1664143","identity":"rs-1664143","version":["v1"]},"buildId":"J0_U0BvcaRcwD8yVFaRlm","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}