title: A multi-center, open-label trial to compare the efficacy and pharmacokinetics of Artemether-Lumefantrine in children with severe acute malnutrition versus children without severe acute malnutrition: study protocol for the MAL-NUT study.
abstract: BACKGROUND
  Malnutrition and malaria frequently coexist in sub-Saharan African countries. Studies on efficacy of antimalarial treatments usually follow the WHO standardized protocol in which severely malnourished children are systematically excluded. Few studies have assessed the efficacy of chloroquine, sulfadoxine-pyrimethamine and quinine in severe acute malnourished children. Overall, efficacy of these treatments appeared to be reduced, attributed to lower immunity and for some antimalarials altered pharmacokinetic profiles and lower drug concentrations. However, similar research on the efficacy and pharmacokinetic profiles of artemisinin-combination therapies (ACTs) and especially artemether-lumefantrine in malnourished children is currently lacking. The main objective of this study is to assess whether artemether-lumefantrine is less efficacious in children suffering from severe acute malnutrition (SAM) compared to non-SAM children, and if so, to what extent this can be attributed to a sub-optimal pharmacokinetic profile.
  
  
  METHODS
  In two sites, Ouelessebougou, Mali and Maradi, Niger, children with uncomplicated microscopically-confirmed P. falciparum malaria aged between 6 and 59 months will be enrolled. Two non-SAM children will be enrolled after the enrolment of each SAM case. Children with severe manifestations of malaria or complications of acute malnutrition needing intensive treatment will be excluded. Treatment intakes will be supervised and children will be followed-up for 42 days, according to WHO guidance for surveillance of antimalarial drug efficacy. Polymerase Chain Reaction genotyping will be used to distinguish recrudescence from re-infection. SAM children will also benefit from the national nutritional rehabilitation program. Outcomes will be compared between the SAM and non-SAM populations. The primary outcome will be adequate clinical and parasitological response at day 28 after PCR correction, estimated by Kaplan-Meier analysis. To assess the pharmacokinetic profile of lumefantrine, a sparse sampling approach will be used with randomized allocation of sampling times (5 per child). A total of 180 SAM children and 360 non-SAM children will be recruited during the 2013 and 2014 malaria seasons.
  
  
  CONCLUSIONS
  This study will provide important information that is currently lacking on the effect of SAM on therapeutic efficacy and pharmacokinetic profile of artemether-lumefantrine. If it shows lower therapeutic efficacy and decreased lumefantrine concentrations, it would inform dose optimization studies in SAM children.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT01958905.
authors.affiliation: Epicentre, Paris, France. lise.denoeud@epicentre.msf.org.
authors.forename: Lise
authors.initials: L
authors.lastname: Denoeud-Ndam
authors.affiliation: Malaria Research and Training Center, Faculte de Médecine, Pharmacie et d'Odonto-stomatologie, Université des Sciences Techniques et Technologies de Bamako, Bamako, Mali. adicko@icermali.org.
authors.forename: Alassane
authors.initials: A
authors.lastname: Dicko
authors.affiliation: Epicentre, Paris, France. elisabeth.baudin@epicentre.msf.org.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Baudin
authors.affiliation: Epicentre, Paris, France. ousmane.guindo@epicentre.msf.org.
authors.forename: Ousmane
authors.initials: O
authors.lastname: Guindo
authors.affiliation: Epicentre, Paris, France. francesco.grandesso@epicentre.msf.org.
authors.forename: Francesco
authors.initials: F
authors.lastname: Grandesso
authors.affiliation: Malaria Research and Training Center, Faculte de Médecine, Pharmacie et d'Odonto-stomatologie, Université des Sciences Techniques et Technologies de Bamako, Bamako, Mali. isagara@icermali.org.
authors.forename: Issaka
authors.initials: I
authors.lastname: Sagara
authors.affiliation: Medecins sans Frontieres, Paris, France. Estrella.Lasry@newyork.msf.org.
authors.forename: Estrella
authors.initials: E
authors.lastname: Lasry
authors.affiliation: Medecins sans Frontieres, Barcelona, Spain. palma.pp2013@gmail.com.
authors.forename: Pedro Pablo
authors.initials: PP
authors.lastname: Palma
authors.affiliation: Medecins sans Frontieres, Barcelona, Spain. nines.lima@barcelona.msf.org.
authors.forename: Angeles M Lima
authors.initials: AM
authors.lastname: Parra
authors.affiliation: Worldwide Antimalarial Resistance Network (WWARN), Oxford, UK. kasia.stepniewska@wwarn.org.|Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. kasia.stepniewska@wwarn.org.
authors.forename: Kasia
authors.initials: K
authors.lastname: Stepniewska
authors.affiliation: Malaria Research and Training Center, Faculte de Médecine, Pharmacie et d'Odonto-stomatologie, Université des Sciences Techniques et Technologies de Bamako, Bamako, Mali. adjimde@icermali.org.
authors.forename: Abdoulaye A
authors.initials: AA
authors.lastname: Djimde
authors.affiliation: Worldwide Antimalarial Resistance Network (WWARN), Oxford, UK. karen.barnes@uct.ac.za.|Division of Clinical Pharmacology, University of Cape Town, Cape Town, South Africa. karen.barnes@uct.ac.za.
authors.forename: Karen I
authors.initials: KI
authors.lastname: Barnes
authors.affiliation: Malaria Research and Training Center, Faculte de Médecine, Pharmacie et d'Odonto-stomatologie, Université des Sciences Techniques et Technologies de Bamako, Bamako, Mali. okd@icermali.org.
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
authors.affiliation: Epicentre, Paris, France. jean-francois.etard@epicentre.msf.org.|TransVIHMI UMI 233, Institut de recherche pour le développement (IRD) - Inserm U 1175 - Montpellier 1 University, Montpellier, France. jean-francois.etard@epicentre.msf.org.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Etard
mesh_terms: D000962:Antimalarials / Q000493:pharmacokinetics*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000493:pharmacokinetics*; D002675:Child, Preschool; D004338:Drug Combinations; D004983:Ethanolamines / Q000493:pharmacokinetics*; D005260:Female; D005449:Fluorenes / Q000493:pharmacokinetics*; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D008302:Mali; D009548:Niger; D012008:Recurrence; D012107:Research Design; D000067011:Severe Acute Malnutrition; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes