title: 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.
abstract: 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-mefloquine tablets (25 mg artesunate and 55 mg mefloquine) 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 difference 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.
  
  
  RESULTS
  945 children were enrolled and randomised, 473 to artesunate-mefloquine 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-mefloquine group and 89·7% (365 patients) in the artemether-lumefantrine group (treatment difference 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-mefloquine group vs 24 in the artemether-lumefantrine group). The safety profiles 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 five [1·1%] of 465), and no detectable psychiatric adverse events.
  
  
  CONCLUSIONS
  Artesunate-mefloquine is effective and safe, and an important treatment option, for children younger than 5 years with uncomplicated P falciparum malaria in Africa.
  
  
  BACKGROUND
  Agence Française de Développement, France; Department for International Development, UK; Dutch Ministry of Foreign Affairs, Netherlands; European and Developing Countries Clinical Trials Partnership; Fondation Arpe, Switzerland; Médecins Sans Frontières; Swiss Agency for Development and Cooperation, Switzerland.
authors.affiliation: Centre National de Recherche et de Formation sur le Paludisme (CNRFP), Ouagadougou, Burkina Faso.
authors.forename: Sodiomon B
authors.initials: SB
authors.lastname: Sirima
authors.affiliation: Kenya Medical Research Institute (CCR-KEMRI), Kisumu, Kenya.
authors.forename: Bernhards
authors.initials: B
authors.lastname: Ogutu
authors.affiliation: National Institute for Medical Research (NIMR), Korogwe, Tanzania.
authors.forename: John P A
authors.initials: JPA
authors.lastname: Lusingu
authors.affiliation: Ifakara Health Institute (IHI), Bagamoyo, Tanzania.
authors.forename: Ali
authors.initials: A
authors.lastname: Mtoro
authors.affiliation: National Institute for Medical Research (NIMR), Kilosa, Tanzania.
authors.forename: Zakayo
authors.initials: Z
authors.lastname: Mrango
authors.affiliation: Centre National de Recherche et de Formation sur le Paludisme (CNRFP), Ouagadougou, Burkina Faso.
authors.forename: Alphonse
authors.initials: A
authors.lastname: Ouedraogo
authors.affiliation: Centre National de Recherche et de Formation sur le Paludisme (CNRFP), Ouagadougou, Burkina Faso.
authors.forename: Jean Baptiste
authors.initials: JB
authors.lastname: Yaro
authors.affiliation: Kenya Medical Research Institute (CCR-KEMRI), Kisumu, Kenya.
authors.forename: Kevin Omondi
authors.initials: KO
authors.lastname: Onyango
authors.affiliation: National Institute for Medical Research (NIMR), Korogwe, Tanzania.
authors.forename: Samwel
authors.initials: S
authors.lastname: Gesase
authors.affiliation: Ifakara Health Institute (IHI), Bagamoyo, Tanzania.
authors.forename: Ernest
authors.initials: E
authors.lastname: Mnkande
authors.affiliation: National Institute for Medical Research (NIMR), Kilosa, Tanzania.
authors.forename: James Samwel
authors.initials: JS
authors.lastname: Ngocho
authors.affiliation: Venn Life Sciences, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ackermann
authors.affiliation: Venn Life Sciences, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Aubin
authors.affiliation: Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.
authors.forename: Joelle
authors.initials: J
authors.lastname: Vanraes
authors.affiliation: Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Strub
authors.affiliation: Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland. Electronic address: gwen.carn@gmail.com.
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Carn
mesh_terms: D017954:Africa South of the Sahara / Q000453:epidemiology; D000962:Antimalarials / Q000008:administration & dosage* / Q000009:adverse effects; D000077549:Artemether; D037621:Artemisinins / Q000008:administration & dosage*; D000077332:Artesunate; D002675:Child, Preschool; D004983:Ethanolamines / Q000008:administration & dosage*; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage*; D006801:Humans; D007223:Infant; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology; D008297:Male; D015767:Mefloquine / Q000008:administration & dosage*; D061214:Patient Safety; D016133:Polymerase Chain Reaction
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D000077332:Artesunate; C031327:artemisinin; D000077549:Artemether; D000078102:Lumefantrine; D015767:Mefloquine