title: Artemisinin-naphthoquine versus artemether-lumefantrine for uncomplicated malaria in Papua New Guinean children: an open-label randomized trial.
abstract: BACKGROUND
  Artemisinin combination therapies (ACTs) with broad efficacy are needed where multiple Plasmodium species are transmitted, especially in children, who bear the brunt of infection in endemic areas. In Papua New Guinea (PNG), artemether-lumefantrine is the first-line treatment for uncomplicated malaria, but it has limited efficacy against P. vivax. Artemisinin-naphthoquine should have greater activity in vivax malaria because the elimination of naphthoquine is slower than that of lumefantrine. In this study, the efficacy, tolerability, and safety of these ACTs were assessed in PNG children aged 0.5-5 y.
  
  
  RESULTS
  An open-label, randomized, parallel-group trial of artemether-lumefantrine (six doses over 3 d) and artemisinin-naphthoquine (three daily doses) was conducted between 28 March 2011 and 22 April 2013. Parasitologic outcomes were assessed without knowledge of treatment allocation. Primary endpoints were the 42-d P. falciparum PCR-corrected adequate clinical and parasitologic response (ACPR) and the P. vivax PCR-uncorrected 42-d ACPR. Non-inferiority and superiority designs were used for falciparum and vivax malaria, respectively. Because the artemisinin-naphthoquine regimen involved three doses rather than the manufacturer-specified single dose, the first 188 children underwent detailed safety monitoring. Of 2,542 febrile children screened, 267 were randomized, and 186 with falciparum and 47 with vivax malaria completed the 42-d follow-up. Both ACTs were safe and well tolerated. P. falciparum ACPRs were 97.8% and 100.0% in artemether-lumefantrine and artemisinin-naphthoquine-treated patients, respectively (difference 2.2% [95% CI -3.0% to 8.4%] versus -5.0% non-inferiority margin, p = 0.24), and P. vivax ACPRs were 30.0% and 100.0%, respectively (difference 70.0% [95% CI 40.9%-87.2%], p<0.001). Limitations included the exclusion of 11% of randomized patients with sub-threshold parasitemias on confirmatory microscopy and direct observation of only morning artemether-lumefantrine dosing.
  
  
  CONCLUSIONS
  Artemisinin-naphthoquine is non-inferior to artemether-lumefantrine in PNG children with falciparum malaria but has greater efficacy against vivax malaria, findings with implications in similar geo-epidemiologic settings within and beyond Oceania.
  
  
  BACKGROUND
  Australian New Zealand Clinical Trials Registry ACTRN12610000913077. Please see later in the article for the Editors' Summary.
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia; Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea.
authors.forename: Moses
authors.initials: M
authors.lastname: Laman
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia; Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea.
authors.forename: Brioni R
authors.initials: BR
authors.lastname: Moore
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea.
authors.forename: John M
authors.initials: JM
authors.lastname: Benjamin
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea.
authors.forename: Gumul
authors.initials: G
authors.lastname: Yadi
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea.
authors.forename: Cathy
authors.initials: C
authors.lastname: Bona
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Warrel
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea; Infection and Immunity Division, Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
authors.forename: Johanna H
authors.initials: JH
authors.lastname: Kattenberg
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea.
authors.forename: Tamarah
authors.initials: T
authors.lastname: Koleala
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia.
authors.forename: Laurens
authors.initials: L
authors.lastname: Manning
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea.
authors.forename: Bernadine
authors.initials: B
authors.lastname: Kasian
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea; Infection and Immunity Division, Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
authors.forename: Leanne J
authors.initials: LJ
authors.lastname: Robinson
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea.
authors.forename: Naomi
authors.initials: N
authors.lastname: Sambale
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea.
authors.forename: Lina
authors.initials: L
authors.lastname: Lorry
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia; Infection and Immunity Division, Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
authors.forename: Stephan
authors.initials: S
authors.lastname: Karl
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Davis
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea.
authors.forename: Anna
authors.initials: A
authors.lastname: Rosanas-Urgell
authors.affiliation: Infection and Immunity Division, Walter and Eliza Hall Institute, Parkville, Victoria, Australia; Center de Recerca en Salut Internacional de Barcelona, Barcelona, Spain.
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siba
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea.
authors.forename: Inoni
authors.initials: I
authors.lastname: Betuela
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia.
authors.forename: Timothy M E
authors.initials: TM
authors.lastname: Davis
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000627:therapeutic use*; D000077549:Artemether; D037621:Artemisinins / Q000627:therapeutic use*; D004983:Ethanolamines / Q000627:therapeutic use*; D005260:Female; D005449:Fluorenes / Q000627:therapeutic use*; D006801:Humans; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; C031327:artemisinin; D000077549:Artemether; D000078102:Lumefantrine