The Lancet. Microbe · 2026
Efficacy of chloroquine plus low-dose primaquine and pyronaridine-artesunate plus low-dose primaquine against Plasmodium vivax malaria in adults and transmission to mosquitoes in Ethiopia: a phase 2/3, observer-masked, randomised, parallel-group trial.
СтатьяРандомизированное исследованиеКлиническое исследование II фазыКлиническое исследование III фазыПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Bezabih Migbaru Keffale, Sisay Solomon, Behaksera Sinknesh Wolde, Ramjith Jordache, Teka Hiwot, Girma Samuel, Shimelash Amanuel, Ejigu Legesse Alamerie, Kassa Fikregabrail Aberra, Hailegiorgis Bereket, Tadesse Mekonnen, Misganaw Tadesse, Gizat Addisu, Gashaw Abrham, Habtamu Getinet, Legesse Negash Seyoum, Hundera Natnael Lemessa, Milki Daniel Woldesenbet, Abdo Melat, Chali Wakweya, Tongren Jon Eric, Hwang Jimee, Bousema Teun, Tadesse Fitsum G
Аннотация
BACKGROUND: In areas co-endemic for Plasmodium vivax and Plasmodium falciparum, artemisinin-based combination therapy is being considered as unified treatment strategy. The clinical and transmission-reducing efficacy of antimalarials remain understudied for P vivax, particularly in Africa. In this study, we aimed to evaluate the in-vivo efficacy, safety, and tolerability of pyronaridine-artesunate and chloroquine, each combined with a 14-day low-dose primaquine regimen, to treat uncomplicated P vivax malaria in Ethiopia and to assess the gametocytocidal and transmission-blocking effects of pyronaridine-artesunate and chloroquine, with or without low-dose primaquine, through direct mosquito feeding assays.
METHODS: Two parallel-group, observer-masked, randomised, phase 2/3 trials were conducted at two health centres (primary health-care units) in Maksegnit and Enfranz, Ethiopia, to evaluate the efficacy of chloroquine and pyronaridine-artesunate, each combined with low-dose primaquine, in adult febrile participants aged 18 years or older with microscopy-confirmed asexual P vivax malaria. Participants were randomly assigned 1:1 to receive either chloroquine plus low-dose primaquine or pyronaridine-artesunate plus low-dose primaquine using simple randomisation. Microscopists assessing outcomes were masked to treatment allocation. Clinical assessments and fingerprick blood collection for microscopy and molecular analysis were conducted on days 0-3 and weekly on days 7-42. The primary outcomes were adequate clinical and parasitological response (ACPR), assessed at day 28 in both chloroquine plus low-dose primaquine and pyronaridine-artesunate plus low-dose primaquine groups and at day 42 in the pyronaridine-artesunate plus low-dose primaquine group, analysed per protocol. Safety and tolerability were monitored in the intention-to-treat population throughout the 42-day follow-up period via clinician assessments and participant self-reports. In the transmission substudy, individuals carrying gametocytes, per microscopy detection, were recruited and randomly assigned to receive chloroquine or pyronaridine-artesunate, with immediate or delayed (day 3) low-dose primaquine administration. Mosquito infectivity was assessed before and on days 1-3 after treatment. The completed trial is registered at the Pan African Clinical Trials Registry (PACTR202110520435408).
FINDINGS: Between Jan 3, and June 17, 2022, 176 participants (122 [69%] male and 54 [31%] female) were enrolled (88 per group), and 79 in the chloroquine group and 83 in the pyronaridine-artesunate group were included in primary outcome analyses. Day-28 ACPR was 98·7% (78 of 79; 95% CI 91·3-99·8) for the chloroquine plus low-dose primaquine group and 98·8% (82 of 83; 95% CI 91·7-99·8) for the pyronaridine-artesunate plus low-dose primaquine group; day-42 ACPR in the pyronaridine-artesunate plus low-dose primaquine group was 96·4% (80 of 83; 95% CI 89·2-98·8). The most common adverse events were mild and included headache (45 [51%] of 88 in the chloroquine group vs 49 [56%] in the pyronaridine-artesunate group), weakness (28 [32%] vs 25 [28%]), body pain (27 [31%] vs 25 [28%]), and chills (20 [23%] vs 23 [26%]). No serious adverse events or treatment-related deaths occurred. Both treatment regimens were well tolerated. 60 participants were enrolled in the transmission substudy during the same time period as the main treatment efficacy study; 55 (92%) participants were infectious to mosquitoes at baseline. By day 1, infectivity was completely blocked in 15 (100%) of 15 participants in the pyronaridine-artesunate plus low-dose primaquine group, but residual transmission was observed in the chloroquine (seven [47%] of 15), pyronaridine-artesunate (two [13%] of 15), and chloroquine plus low-dose primaquine groups (four [27%] of 15). No mosquito infections occurred on day 2 or day 3 in any group.
INTERPRETATION: Both regimens treated P vivax malaria with high efficacy. Pyronaridine-artesunate plus low-dose primaquine rapidly interrupted transmission. The findings support further evaluation of pyronaridine-artesunate plus low-dose primaquine as a unified treatment strategy in co-endemic settings to improve malaria control and support malaria elimination efforts.
FUNDING: US President's Malaria Initiative and Wellcome Trust.
METHODS: Two parallel-group, observer-masked, randomised, phase 2/3 trials were conducted at two health centres (primary health-care units) in Maksegnit and Enfranz, Ethiopia, to evaluate the efficacy of chloroquine and pyronaridine-artesunate, each combined with low-dose primaquine, in adult febrile participants aged 18 years or older with microscopy-confirmed asexual P vivax malaria. Participants were randomly assigned 1:1 to receive either chloroquine plus low-dose primaquine or pyronaridine-artesunate plus low-dose primaquine using simple randomisation. Microscopists assessing outcomes were masked to treatment allocation. Clinical assessments and fingerprick blood collection for microscopy and molecular analysis were conducted on days 0-3 and weekly on days 7-42. The primary outcomes were adequate clinical and parasitological response (ACPR), assessed at day 28 in both chloroquine plus low-dose primaquine and pyronaridine-artesunate plus low-dose primaquine groups and at day 42 in the pyronaridine-artesunate plus low-dose primaquine group, analysed per protocol. Safety and tolerability were monitored in the intention-to-treat population throughout the 42-day follow-up period via clinician assessments and participant self-reports. In the transmission substudy, individuals carrying gametocytes, per microscopy detection, were recruited and randomly assigned to receive chloroquine or pyronaridine-artesunate, with immediate or delayed (day 3) low-dose primaquine administration. Mosquito infectivity was assessed before and on days 1-3 after treatment. The completed trial is registered at the Pan African Clinical Trials Registry (PACTR202110520435408).
FINDINGS: Between Jan 3, and June 17, 2022, 176 participants (122 [69%] male and 54 [31%] female) were enrolled (88 per group), and 79 in the chloroquine group and 83 in the pyronaridine-artesunate group were included in primary outcome analyses. Day-28 ACPR was 98·7% (78 of 79; 95% CI 91·3-99·8) for the chloroquine plus low-dose primaquine group and 98·8% (82 of 83; 95% CI 91·7-99·8) for the pyronaridine-artesunate plus low-dose primaquine group; day-42 ACPR in the pyronaridine-artesunate plus low-dose primaquine group was 96·4% (80 of 83; 95% CI 89·2-98·8). The most common adverse events were mild and included headache (45 [51%] of 88 in the chloroquine group vs 49 [56%] in the pyronaridine-artesunate group), weakness (28 [32%] vs 25 [28%]), body pain (27 [31%] vs 25 [28%]), and chills (20 [23%] vs 23 [26%]). No serious adverse events or treatment-related deaths occurred. Both treatment regimens were well tolerated. 60 participants were enrolled in the transmission substudy during the same time period as the main treatment efficacy study; 55 (92%) participants were infectious to mosquitoes at baseline. By day 1, infectivity was completely blocked in 15 (100%) of 15 participants in the pyronaridine-artesunate plus low-dose primaquine group, but residual transmission was observed in the chloroquine (seven [47%] of 15), pyronaridine-artesunate (two [13%] of 15), and chloroquine plus low-dose primaquine groups (four [27%] of 15). No mosquito infections occurred on day 2 or day 3 in any group.
INTERPRETATION: Both regimens treated P vivax malaria with high efficacy. Pyronaridine-artesunate plus low-dose primaquine rapidly interrupted transmission. The findings support further evaluation of pyronaridine-artesunate plus low-dose primaquine as a unified treatment strategy in co-endemic settings to improve malaria control and support malaria elimination efforts.
FUNDING: US President's Malaria Initiative and Wellcome Trust.