TY - JOUR
T1 - Arterolane–piperaquine–mefloquine versus arterolane–piperaquine and artemether–lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children
T2 - a single-centre, open-label, randomised, non-inferiority trial
AU - Hamaluba, Mainga
AU - van der Pluijm, Rob W.
AU - Weya, Joseph
AU - Njuguna, Patricia
AU - Ngama, Mwanajuma
AU - Kalume, Peter
AU - Mwambingu, Gabriel
AU - Ngetsa, Caroline
AU - Wambua, Juliana
AU - Boga, Mwanamvua
AU - Mturi, Neema
AU - Lal, Altaf A.
AU - Khuroo, Arshad
AU - Taylor, Walter R. J.
AU - Gonçalves, S. nia
AU - Miotto, Olivo
AU - Dhorda, Mehul
AU - Mutinda, Brian
AU - Mukaka, Mavuto
AU - Waithira, Naomi
AU - Hoglund, Richard M.
AU - Imwong, Mallika
AU - Tarning, Joel
AU - Day, Nicholas P. J.
AU - White, Nicholas J.
AU - Bejon, Philip
AU - Dondorp, Arjen M.
N1 - Funding Information: This study was supported by the UK Department for International Development (201900). The Mahidol Oxford Tropical Medicine Research Programme and the Kenya Medical Research Institute Wellcome Trust Research Programme are funded by the Wellcome Trust of the UK. The pharmacokinetic drug measurements were funded and done by Sun Pharmaceutical Industries, Gurugram, India. The pharmacokinetic data analysis was funded by the Bill & Melinda Gates Foundation. We thank all patients who took part in our study. We also thank Brian Angus, Ric Price, and Christian Holm Hansen for their important guidance in their roles on the data and safety monitoring board. We thank Prayoon Yuentrakul for site monitoring and protocol training; Clinton Mwatata and Stephen Mwangala for data entry; Cholrawee Promnarate, Thanaporn Champathai, Ranitha Vongpromek, and Thanawat Assawariyathipat for laboratory support provided by the WorldWide Antimalarial Resistance Network; and Patrick Hannay for financial administrative support. We thank the staff of the Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, for their contribution to the PCR correction of recurrent infections. This publication uses data from the MalariaGEN SPOTMalaria Project; the project is coordinated by the MalariaGEN Resource Centre, with funding from the Wellcome Trust (206194, 090770). We thank the staff in the sample management, genotyping, sequencing, and informatics teams of the Wellcome Sanger Institute for their contribution. Funding Information: This study was supported by the UK Department for International Development (201900). The Mahidol Oxford Tropical Medicine Research Programme and the Kenya Medical Research Institute Wellcome Trust Research Programme are funded by the Wellcome Trust of the UK. The pharmacokinetic drug measurements were funded and done by Sun Pharmaceutical Industries, Gurugram, India. The pharmacokinetic data analysis was funded by the Bill & Melinda Gates Foundation. We thank all patients who took part in our study. We also thank Brian Angus, Ric Price, and Christian Holm Hansen for their important guidance in their roles on the data and safety monitoring board. We thank Prayoon Yuentrakul for site monitoring and protocol training; Clinton Mwatata and Stephen Mwangala for data entry; Cholrawee Promnarate, Thanaporn Champathai, Ranitha Vongpromek, and Thanawat Assawariyathipat for laboratory support provided by the WorldWide Antimalarial Resistance Network; and Patrick Hannay for financial administrative support. We thank the staff of the Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, for their contribution to the PCR correction of recurrent infections. This publication uses data from the MalariaGEN SPOTMalaria Project ; the project is coordinated by the MalariaGEN Resource Centre, with funding from the Wellcome Trust (206194, 090770). We thank the staff in the sample management, genotyping, sequencing, and informatics teams of the Wellcome Sanger Institute for their contribution. Publisher Copyright: © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2021/10/1
Y1 - 2021/10/1
N2 - Background: Triple antimalarial combination therapies combine potent and rapidly cleared artemisinins or related synthetic ozonides, such as arterolane, with two, more slowly eliminated partner drugs to reduce the risk of resistance. We aimed to assess the safety, tolerability, and efficacy of arterolane–piperaquine–mefloquine versus arterolane–piperaquine and artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in Kenyan children. Methods: In this single-centre, open-label, randomised, non-inferiority trial done in Kilifi County Hospital, Kilifi, coastal Kenya, children with uncomplicated Plasmodium falciparum malaria were recruited. Eligible patients were aged 2–12 years and had an asexual parasitaemia of 5000–250 000 parasites per μL. The exclusion criteria included the presence of an acute illness other than malaria, the inability to tolerate oral medications, treatment with an artemisinin derivative in the previous 7 days, a known hypersensitivity or contraindication to any of the study drugs, and a QT interval corrected for heart rate (QTc interval) longer than 450 ms. Patients were randomly assigned (1:1:1), by use of blocks of six, nine, and 12, and opaque, sealed, and sequentially numbered envelopes, to receive either arterolane–piperaquine, arterolane–piperaquine–mefloquine, or artemether–lumefantrine. Laboratory staff, but not the patients, the patients' parents or caregivers, clinical or medical officers, nurses, or trial statistician, were masked to the intervention groups. For 3 days, oral artemether–lumefantrine was administered twice daily (target dose 5–24 mg/kg of bodyweight of artemether and 29–144 mg/kg of bodyweight of lumefantrine), and oral arterolane–piperaquine (arterolane dose 4 mg/kg of bodyweight; piperaquine dose 20 mg/kg of bodyweight) and oral arterolane–piperaquine–mefloquine (mefloquine dose 8 mg/kg of bodyweight) were administered once daily. All patients received 0·25 mg/kg of bodyweight of oral primaquine at hour 24. All patients were admitted to Kilifi County Hospital for at least 3 consecutive days and followed up at day 7 and, thereafter, weekly for up to 42 days. The primary endpoint was 42-day PCR-corrected efficacy, defined as the absence of treatment failure in the first 42 days post-treatment, of arterolane–piperaquine–mefloquine versus artemether–lumefantrine, and, along with safety, was analysed in the intention-to-treat population, which comprised all patients who received at least one dose of a study drug. The 42-day PCR-corrected efficacy of arterolane–piperaquine–mefloquine versus arterolane–piperaquine was an important secondary endpoint and was also analysed in the intention-to-treat population. The non-inferiority margin for the risk difference between treatments was −7%. The study is registered in ClinicalTrials.gov, NCT03452475, and is completed. Findings: Between March 7, 2018, and May 2, 2019, 533 children with P falciparum were screened, of whom 217 were randomly assigned to receive either arterolane–piperaquine (n=73), arterolane–piperaquine–mefloquine (n=72), or artemether–lumefantrine (n=72) and comprised the intention-to-treat population. The 42-day PCR-corrected efficacy after treatment with arterolane–piperaquine–mefloquine (100%, 95% CI 95–100; 72/72) was non-inferior to that after treatment with artemether–lumefantrine (96%, 95% CI 88–99; 69/72; risk difference 4%, 95% CI 0–9; p=0·25). The 42-day PCR-corrected efficacy of arterolane–piperaquine–mefloquine was non-inferior to that of arterolane–piperaquine (100%, 95% CI 95–100; 73/73; risk difference 0%). Vomiting rates in the first hour post-drug administration were significantly higher in patients treated with arterolane–piperaquine (5%, 95% CI 2–9; ten of 203 drug administrations; p=0·0013) or arterolane–piperaquine–mefloquine (5%, 3–9; 11 of 209 drug administrations; p=0·0006) than in patients treated with artemether–lumefantrine (1%, 0–2; three of 415 drug administrations). Upper respiratory tract complaints (n=26 for artemether–lumefantrine; n=19 for arterolane–piperaquine–mefloquine; n=23 for arterolane–piperaquine), headache (n=13; n=4; n=5), and abdominal pain (n=7; n=5; n=5) were the most frequently reported adverse events. There were no deaths. Interpretation: This study shows that arterolane–piperaquine–mefloquine is an efficacious and safe treatment for uncomplicated falciparum malaria in children and could potentially be used to prevent or delay the emergence of antimalarial resistance. Funding: UK Department for International Development, The Wellcome Trust, The Bill & Melinda Gates Foundation, Sun Pharmaceutical Industries
AB - Background: Triple antimalarial combination therapies combine potent and rapidly cleared artemisinins or related synthetic ozonides, such as arterolane, with two, more slowly eliminated partner drugs to reduce the risk of resistance. We aimed to assess the safety, tolerability, and efficacy of arterolane–piperaquine–mefloquine versus arterolane–piperaquine and artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in Kenyan children. Methods: In this single-centre, open-label, randomised, non-inferiority trial done in Kilifi County Hospital, Kilifi, coastal Kenya, children with uncomplicated Plasmodium falciparum malaria were recruited. Eligible patients were aged 2–12 years and had an asexual parasitaemia of 5000–250 000 parasites per μL. The exclusion criteria included the presence of an acute illness other than malaria, the inability to tolerate oral medications, treatment with an artemisinin derivative in the previous 7 days, a known hypersensitivity or contraindication to any of the study drugs, and a QT interval corrected for heart rate (QTc interval) longer than 450 ms. Patients were randomly assigned (1:1:1), by use of blocks of six, nine, and 12, and opaque, sealed, and sequentially numbered envelopes, to receive either arterolane–piperaquine, arterolane–piperaquine–mefloquine, or artemether–lumefantrine. Laboratory staff, but not the patients, the patients' parents or caregivers, clinical or medical officers, nurses, or trial statistician, were masked to the intervention groups. For 3 days, oral artemether–lumefantrine was administered twice daily (target dose 5–24 mg/kg of bodyweight of artemether and 29–144 mg/kg of bodyweight of lumefantrine), and oral arterolane–piperaquine (arterolane dose 4 mg/kg of bodyweight; piperaquine dose 20 mg/kg of bodyweight) and oral arterolane–piperaquine–mefloquine (mefloquine dose 8 mg/kg of bodyweight) were administered once daily. All patients received 0·25 mg/kg of bodyweight of oral primaquine at hour 24. All patients were admitted to Kilifi County Hospital for at least 3 consecutive days and followed up at day 7 and, thereafter, weekly for up to 42 days. The primary endpoint was 42-day PCR-corrected efficacy, defined as the absence of treatment failure in the first 42 days post-treatment, of arterolane–piperaquine–mefloquine versus artemether–lumefantrine, and, along with safety, was analysed in the intention-to-treat population, which comprised all patients who received at least one dose of a study drug. The 42-day PCR-corrected efficacy of arterolane–piperaquine–mefloquine versus arterolane–piperaquine was an important secondary endpoint and was also analysed in the intention-to-treat population. The non-inferiority margin for the risk difference between treatments was −7%. The study is registered in ClinicalTrials.gov, NCT03452475, and is completed. Findings: Between March 7, 2018, and May 2, 2019, 533 children with P falciparum were screened, of whom 217 were randomly assigned to receive either arterolane–piperaquine (n=73), arterolane–piperaquine–mefloquine (n=72), or artemether–lumefantrine (n=72) and comprised the intention-to-treat population. The 42-day PCR-corrected efficacy after treatment with arterolane–piperaquine–mefloquine (100%, 95% CI 95–100; 72/72) was non-inferior to that after treatment with artemether–lumefantrine (96%, 95% CI 88–99; 69/72; risk difference 4%, 95% CI 0–9; p=0·25). The 42-day PCR-corrected efficacy of arterolane–piperaquine–mefloquine was non-inferior to that of arterolane–piperaquine (100%, 95% CI 95–100; 73/73; risk difference 0%). Vomiting rates in the first hour post-drug administration were significantly higher in patients treated with arterolane–piperaquine (5%, 95% CI 2–9; ten of 203 drug administrations; p=0·0013) or arterolane–piperaquine–mefloquine (5%, 3–9; 11 of 209 drug administrations; p=0·0006) than in patients treated with artemether–lumefantrine (1%, 0–2; three of 415 drug administrations). Upper respiratory tract complaints (n=26 for artemether–lumefantrine; n=19 for arterolane–piperaquine–mefloquine; n=23 for arterolane–piperaquine), headache (n=13; n=4; n=5), and abdominal pain (n=7; n=5; n=5) were the most frequently reported adverse events. There were no deaths. Interpretation: This study shows that arterolane–piperaquine–mefloquine is an efficacious and safe treatment for uncomplicated falciparum malaria in children and could potentially be used to prevent or delay the emergence of antimalarial resistance. Funding: UK Department for International Development, The Wellcome Trust, The Bill & Melinda Gates Foundation, Sun Pharmaceutical Industries
UR - http://www.scopus.com/inward/record.url?scp=85109372761&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/S1473-3099(20)30929-4
DO - https://doi.org/10.1016/S1473-3099(20)30929-4
M3 - Article
C2 - 34111412
SN - 1473-3099
VL - 21
SP - 1395
EP - 1406
JO - The Lancet Infectious Diseases
JF - The Lancet Infectious Diseases
IS - 10
ER -