TY - JOUR
T1 - Triple therapy with artemether–lumefantrine plus amodiaquine versus artemether–lumefantrine alone for artemisinin-resistant, uncomplicated falciparum malaria
T2 - an open-label, randomised, multicentre trial
AU - Peto, Thomas J.
AU - Tripura, Rupam
AU - Callery, James J.
AU - Lek, Dysoley
AU - Nghia, Ho Dang Trung
AU - Nguon, Chea
AU - Thuong, Nguyen Thi Huyen
AU - van der Pluijm, Rob W.
AU - Dung, Nguyen Thi Phuong
AU - Sokha, Meas
AU - van Luong, Vo
AU - Long, Le Thanh
AU - Sovann, Yok
AU - Duanguppama, Jureeporn
AU - Waithira, Naomi
AU - Hoglund, Richard M.
AU - Chotsiri, Palang
AU - Chau, Nguyen Hoang
AU - Ruecker, Andrea
AU - Amaratunga, Chanaki
AU - Dhorda, Mehul
AU - Miotto, Olivo
AU - Maude, Richard J.
AU - Rekol, Huy
AU - Chotivanich, Kesinee
AU - Tarning, Joel
AU - von Seidlein, Lorenz
AU - Imwong, Mallika
AU - Mukaka, Mavuto
AU - Day, Nicholas P. J.
AU - Hien, Tran Tinh
AU - White, Nicholas J.
AU - Dondorp, Arjen M.
N1 - Funding Information: This trial was funded by the Bill & Melinda Gates Foundation (OPP1132628). AMD, TJP, RT, JJC, NJW, RH, PC, AR, CA, MD, OM, RM, JT, LvS, MM, NPJD, and NJW are supported by the Wellcome Trust (London, UK; Grant ID 220211). Parasite genotyping was supported by the Thailand Science Research and Innovation, RTA6280006, Thailand. The study sponsor was the University of Oxford (Oxford, UK). This research was funded in whole, or in part, by the Wellcome Trust grant 220211. The chief acknowledgment is to the study participants, and to the staff who conducted the trial at Binh Phuoc Medical Centre, Khanh Hoa Hospital for Tropical Diseases, Siem Pang Health Centre, Kravanh District Hospital, and Pailin Referral Hospital (Pailin, Thailand). We thank Ranitha Vongpromek, Cholrawee Promnarate, Jaruwan Tubprasert, Chhin Chhivrorth, Sin Sokhalin, Hem Lida, Patpannee Khanthagan, Tianrat Piteekan, Paphapisa Chotthanawathit, Chonticha Menggred, Marja Dondorp, Patrick Hannay, Salwaluk Panapipat, Nakarin Aud-Ai, Pongphaya Pongsuwan, and Tanya Cope. We also thank the members of the data safety monitoring board, Karen Barnes, Timothy Peto (no relation), and Julie Simpson. Funding Information: This trial was funded by the Bill & Melinda Gates Foundation (OPP1132628). AMD, TJP, RT, JJC, NJW, RH, PC, AR, CA, MD, OM, RM, JT, LvS, MM, NPJD, and NJW are supported by the Wellcome Trust (London, UK; Grant ID 220211). Parasite genotyping was supported by the Thailand Science Research and Innovation, RTA6280006, Thailand. The study sponsor was the University of Oxford (Oxford, UK). This research was funded in whole, or in part, by the Wellcome Trust grant 220211. The chief acknowledgment is to the study participants, and to the staff who conducted the trial at Binh Phuoc Medical Centre, Khanh Hoa Hospital for Tropical Diseases, Siem Pang Health Centre, Kravanh District Hospital, and Pailin Referral Hospital (Pailin, Thailand). We thank Ranitha Vongpromek, Cholrawee Promnarate, Jaruwan Tubprasert, Chhin Chhivrorth, Sin Sokhalin, Hem Lida, Patpannee Khanthagan, Tianrat Piteekan, Paphapisa Chotthanawathit, Chonticha Menggred, Marja Dondorp, Patrick Hannay, Salwaluk Panapipat, Nakarin Aud-Ai, Pongphaya Pongsuwan, and Tanya Cope. We also thank the members of the data safety monitoring board, Karen Barnes, Timothy Peto (no relation), and Julie Simpson. Editorial note: the Lancet Group takes a neutral position with respect to territorial claims in published maps and institutional affiliations. Publisher Copyright: © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2022/6
Y1 - 2022/6
N2 - Background: Late treatment failures after artemisinin-based combination therapies (ACTs) for falciparum malaria have increased in the Greater Mekong subregion in southeast Asia. Addition of amodiaquine to artemether–lumefantrine could provide an efficacious treatment for multidrug-resistant infections. Methods: We conducted an open-label, randomised trial at five hospitals or health centres in three locations (western Cambodia, eastern Cambodia, and Vietnam). Eligible participants were male and female patients aged 2–65 years with uncomplicated Plasmodium falciparum malaria. Patients were randomly allocated (1:1 in blocks of eight to 12) to either artemether–lumefantrine alone (dosed according to WHO guidelines) or artemether–lumefantrine plus amodiaquine (10 mg base per kg/day), both given orally as six doses over 3 days. All received a single dose of primaquine (0·25 mg/kg) 24 h after the start of study treatment to limit transmission of the parasite. Parasites were genotyped, identifying artemisinin resistance. The primary outcome was Kaplan-Meier 42-day PCR-corrected efficacy against recrudescence of the original parasite, assessed by intent-to-treat. Safety was a secondary outcome. This completed trial is registered at ClinicalTrials.gov (NCT03355664). Findings: Between March 18, 2018, and Jan 30, 2020, 310 patients received randomly allocated treatment; 154 received artemether–lumefantrine alone and 156 received artemether–lumefantrine plus amodiaquine. Parasites from 305 of these patients were genotyped. 42-day PCR-corrected treatment efficacy was noted in 151 (97%, 95% CI 92–99) of 156 patients with artemether–lumefantrine plus amodiaquine versus 146 (95%, 89–97) of 154 patients with artemether–lumefantrine alone; hazard ratio (HR) for recrudescence 0·6 (95% CI 0·2–1·9, p=0·38). Of the 13 recrudescences, 12 were in 174 (57%) of 305 infections with pfkelch13 mutations indicating artemisinin resistance, for which 42-day efficacy was noted in 89 (96%) of 93 infections with artemether–lumefantrine plus amodiaquine versus 73 (90%) of 81 infections with artemether–lumefantrine alone; HR for recrudescence 0·44 (95% CI 0·14–1·40, p=0·17). Artemether–lumefantrine plus amodiaquine was generally well tolerated, but the number of mild (grade 1–2) adverse events, mainly gastrointestinal, was greater in this group compared with artemether–lumefantrine alone (vomiting, 12 [8%] with artemether–lumefantrine plus amodiaquine vs three [2%] with artemether–lumefantrine alone, p=0·03; and nausea, 11 [7%] with artemether–lumefantrine plus amodiaquine vs three [2%] with artemether–lumefantrine alone, p=0·05). Early vomiting within 1 h of treatment, requiring retreatment, occurred in no patients of 154 with artemether–lumefantrine alone versus five (3%) of 156 with artemether–lumefantrine plus amodiaquine, p=0·06. Bradycardia (≤54 beats/min) of any grade was noted in 59 (38%) of 154 patients with artemether–lumefantrine alone and 95 (61%) of 156 with artemether–lumefantrine plus amodiaquine, p=0·0001. Interpretation: Artemether–lumefantrine plus amodiaquine provides an alternative to artemether–lumefantrine alone as first-line treatment for multidrug-resistant P falciparum malaria in the Greater Mekong subregion, and could prolong the therapeutic lifetime of artemether–lumefantrine in malaria-endemic populations. Funding: Bill & Melinda Gates Foundation, Wellcome Trust.
AB - Background: Late treatment failures after artemisinin-based combination therapies (ACTs) for falciparum malaria have increased in the Greater Mekong subregion in southeast Asia. Addition of amodiaquine to artemether–lumefantrine could provide an efficacious treatment for multidrug-resistant infections. Methods: We conducted an open-label, randomised trial at five hospitals or health centres in three locations (western Cambodia, eastern Cambodia, and Vietnam). Eligible participants were male and female patients aged 2–65 years with uncomplicated Plasmodium falciparum malaria. Patients were randomly allocated (1:1 in blocks of eight to 12) to either artemether–lumefantrine alone (dosed according to WHO guidelines) or artemether–lumefantrine plus amodiaquine (10 mg base per kg/day), both given orally as six doses over 3 days. All received a single dose of primaquine (0·25 mg/kg) 24 h after the start of study treatment to limit transmission of the parasite. Parasites were genotyped, identifying artemisinin resistance. The primary outcome was Kaplan-Meier 42-day PCR-corrected efficacy against recrudescence of the original parasite, assessed by intent-to-treat. Safety was a secondary outcome. This completed trial is registered at ClinicalTrials.gov (NCT03355664). Findings: Between March 18, 2018, and Jan 30, 2020, 310 patients received randomly allocated treatment; 154 received artemether–lumefantrine alone and 156 received artemether–lumefantrine plus amodiaquine. Parasites from 305 of these patients were genotyped. 42-day PCR-corrected treatment efficacy was noted in 151 (97%, 95% CI 92–99) of 156 patients with artemether–lumefantrine plus amodiaquine versus 146 (95%, 89–97) of 154 patients with artemether–lumefantrine alone; hazard ratio (HR) for recrudescence 0·6 (95% CI 0·2–1·9, p=0·38). Of the 13 recrudescences, 12 were in 174 (57%) of 305 infections with pfkelch13 mutations indicating artemisinin resistance, for which 42-day efficacy was noted in 89 (96%) of 93 infections with artemether–lumefantrine plus amodiaquine versus 73 (90%) of 81 infections with artemether–lumefantrine alone; HR for recrudescence 0·44 (95% CI 0·14–1·40, p=0·17). Artemether–lumefantrine plus amodiaquine was generally well tolerated, but the number of mild (grade 1–2) adverse events, mainly gastrointestinal, was greater in this group compared with artemether–lumefantrine alone (vomiting, 12 [8%] with artemether–lumefantrine plus amodiaquine vs three [2%] with artemether–lumefantrine alone, p=0·03; and nausea, 11 [7%] with artemether–lumefantrine plus amodiaquine vs three [2%] with artemether–lumefantrine alone, p=0·05). Early vomiting within 1 h of treatment, requiring retreatment, occurred in no patients of 154 with artemether–lumefantrine alone versus five (3%) of 156 with artemether–lumefantrine plus amodiaquine, p=0·06. Bradycardia (≤54 beats/min) of any grade was noted in 59 (38%) of 154 patients with artemether–lumefantrine alone and 95 (61%) of 156 with artemether–lumefantrine plus amodiaquine, p=0·0001. Interpretation: Artemether–lumefantrine plus amodiaquine provides an alternative to artemether–lumefantrine alone as first-line treatment for multidrug-resistant P falciparum malaria in the Greater Mekong subregion, and could prolong the therapeutic lifetime of artemether–lumefantrine in malaria-endemic populations. Funding: Bill & Melinda Gates Foundation, Wellcome Trust.
UR - http://www.scopus.com/inward/record.url?scp=85127316290&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/S1473-3099(21)00692-7
DO - https://doi.org/10.1016/S1473-3099(21)00692-7
M3 - Article
C2 - 35276064
SN - 1473-3099
VL - 22
SP - 867
EP - 878
JO - The Lancet Infectious Diseases
JF - The Lancet Infectious Diseases
IS - 6
ER -