Comparison of artesunate–mefloquine and artemether–lumefantrine fixed-dose combinations for treatment of uncomplicated Plasmodium falciparum malaria in children younger than 5 years in sub-Saharan Africa: a randomised, multicentre, phase 4 trial

20 Oct 2016

Sodiomon B Sirima, Bernhards Ogutu, John P A Lusingu, Ali Mtoro, Zakayo Mrango, Alphonse Ouedraogo, Jean Baptiste Yaro,
Kevin Omondi Onyango, Samwel Gesase, Ernest Mnkande, James Samwel Ngocho, Isabelle Ackermann, François Aubin, Joelle Vanraes, Nathalie Strub, Gwenaelle Carn

The Lancet Infectious Diseases

DOI: 10.1016/S1473-3099(16)30020-2

Summary

Background
WHO recommends combinations of an artemisinin derivative plus an antimalarial drug of longer half-life as treatment options for uncomplicated Plasmodium falciparum infection. In Africa, artemether–lumefantrine is the most widely used artemisinin-based combination therapy, whereas artesunate–mefloquine is used infrequently because of a perceived poor tolerance to mefloquine. WHO recommends reconsideration of the use of artesunate–mefloquine in Africa. We compared the efficacy and safety of fixed-dose artesunate–mefloquine with that of artemether–lumefantrine for treatment of children younger than 5 years with uncomplicated P falciparum malaria.
 
Methods
We did this multicentre, phase 4, open-label, non-inferiority trial in Burkina Faso, Kenya, and Tanzania. Children aged 6–59 months with uncomplicated malaria were randomly assigned (1:1), via a computer-generated randomisation list, to receive 3 days’ treatment with either one or two artesunate–mefl oquine tablets (25 mg artesunate and 55 mg mefl oquine) once a day or one or two artemether–lumefantrine tablets (20 mg artemether and 120 mg lumefantrine) twice a day. Parasitological assessments were done independently by two microscopists who were blinded to treatment allocation. The primary outcome was the PCR-corrected rate of adequate clinical and parasitological response (ACPR) at day 63 in the per-protocol population. Non-inferiority was shown if the lower limit of the 95% CI for the diff erence between groups was greater than –5%. Early vomiting was monitored and neuropsychiatric status assessed regularly during follow-up. This study is registered with ISRCTN, number ISRCTN17472707, and the Pan African Clinical Trials Registry, number PACTR201202000278282.
 
Findings
945 children were enrolled and randomised, 473 to artesunate–mefl oquine and 472 to artemether–lumefantrine. The per-protocol population consisted of 407 children in each group. The PCR-corrected ACPR rate at day 63 was 90·9% (370 patients) in the artesunate–mefl oquine group and 89·7% (365 patients) in the artemether– lumefantrine group (treatment diff erence 1·23%, 95% CI –2·84% to 5·29%). At 72 h after the start of treatment, no child had detectable parasitaemia and less than 6% had fever, with a similar number in each group (21 in the artesunate–mefl oquine group vs 24 in the artemether–lumefantrine group). The safety profi les of artesunate–mefloquine and artemether–lumefantrine were similar, with low rates of early vomiting (71 [15·3%] of 463 patients in the artesunate–mefloquine group vs 79 [16·8%] of 471 patients in the artemether–lumefantrine group in any of the three dosing days), few neurological adverse events (ten [2·1%] of 468 vs fi ve [1·1%] of 465), and no detectable psychiatric adverse events.
 
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