Evaluation of the effectiveness of artemether-lumefantrine and artesunate-pyronaridine each combined with single low-dose primaquine in adults with Plasmodium falciparum infection in Ethiopia: a phase 2/3, observer-masked, randomised, parallel-group trial.

BACKGROUND

Plasmodium falciparum parasites carrying the pfkelch13 R622I variant, associated with artemisinin resistance, are prevalent in the Horn of Africa. These parasites can also harbour histidine rich protein 2/3 (pfhrp2/3) gene deletions that are associated with false-negative rapid diagnostic tests. This study assessed the efficacy of artemisinin-based combination therapies artemether-lumefantrine plus primaquine or pyronaridine-artesunate plus primaquine in an area with high levels of pfkelch13 mutations and pfhrp2/3 gene deletions.

METHODS

We conducted a phase 2/3, observer-masked, randomised, parallel-group trial at the Maksegnit and Enfranz health centres (primary health-care units) in Ethiopia. Individuals with fever (measured or history of fever in the past 24 h) with uncomplicated P falciparum-caused malaria were randomly assigned (1:1 per health centre) to receive artemether-lumefantrine plus primaquine or pyronaridine-artesunate plus primaquine. Patients with severe anaemia, chronic diseases, or who were pregnant or breastfeeding were excluded from enrolment. Outcome assessors, but not participants or clinicians, were masked to treatment allocation. Primary outcomes were PCR-corrected adequate clinical and parasitological response (ACPR) on day 28 for artemether-lumefantrine plus primaquine and on days 28 and 42 for pyronaridine-artesunate plus primaquine, analysed per protocol, and safety profile and tolerability monitored at each visit (on days 0-3 and weekly from days 7-42) through clinical assessments and self-reports. The study was powered to assess ACPR per group and not for a comparison between the groups. The study was registered with the Pan African Clinical Trials Registry (PACTR202110520435408) and is now completed.

FINDINGS: Between Dec 17, 2021, and May 20, 2022, 199 individuals (136 [68%] male and 63 [32%] female; median age 25 years [IQR 19-36]) with microscopy-confirmed P falciparum were enrolled into the artemether-lumefantrine plus primaquine (n=101) and pyronaridine-artesunate plus primaquine (n=98) groups. Day 28 PCR-corrected ACPR was 96·8% (95% CI 90·9-99·3) for the artemether-lumefantrine plus primaquine group and 98·9% (93·9-99·9) for the pyronaridine-artesunate plus primaquine group; day 42 ACPR in the pyronaridine-artesunate plus primaquine group was 96·5% (90·0-99·3). No early treatment failures were observed. The most commonly detected mild adverse events were headache, weakness, and body ache. Headaches were recorded in 46 (45%) of 101 participants in the artemether-lumefantrine plus primaquine group vs 43 (44%) of 98 participants in the pyronaridine-artesunate plus primaquine group on day 1, declining to eight (8%) of 96 vs 18 (19%) of 95 on day 7. Weakness was reported in 27 (27%) of 101 participants in the artemether-lumefantrine plus primaquine group vs 24 (24%) of 98 in the pyronaridine-artesunate plus primaquine group on day 1, declining to five (5%) of 96 vs six (6%) of 95 on day 7. Body ache was reported in 24 (24%) of 101 participants in the artemether-lumefantrine plus primaquine group vs 24 (24%) of 98 participants in the pyronaridine-artesunate plus primaquine group on day 1, declining to three (3%) of 96 vs seven (7%) of 95 on day 7. No serious adverse events were reported.

INTERPRETATION: Our findings reinforce the continued use of artemether-lumefantrine plus primaquine for treating uncomplicated P falciparum malaria. Pyronaridine-artesunate plus primaquine also shows promise as an alternative regimen. Continued surveillance remains essential to safeguarding both therapeutic effectiveness and diagnostic accuracy.

FUNDING: FGT was supported by grants from the US President's Malaria Initiative, Gates Foundation, and the Wellcome Trust.