title: Intramuscular Artesunate for Severe Malaria in African Children: A Multicenter Randomized Controlled Trial.
abstract: BACKGROUND
  Current artesunate (ARS) regimens for severe malaria are complex. Once daily intramuscular (i.m.) injection for 3 d would be simpler and more appropriate for remote health facilities than the current WHO-recommended regimen of five intravenous (i.v.) or i.m. injections over 4 d. We compared both a three-dose i.m. and a three-dose i.v. parenteral ARS regimen with the standard five-dose regimen using a non-inferiority design (with non-inferiority margins of 10%).
  
  
  RESULTS
  This randomized controlled trial included children (0.5-10 y) with severe malaria at seven sites in five African countries to assess whether the efficacy of simplified three-dose regimens is non-inferior to a five-dose regimen. We randomly allocated 1,047 children to receive a total dose of 12 mg/kg ARS as either a control regimen of five i.m. injections of 2.4 mg/kg (at 0, 12, 24, 48, and 72 h) (n = 348) or three injections of 4 mg/kg (at 0, 24, and 48 h) either i.m. (n = 348) or i.v. (n = 351), both of which were the intervention arms. The primary endpoint was the proportion of children with ≥ 99% reduction in parasitemia at 24 h from admission values, measured by microscopists who were blinded to the group allocations. Primary analysis was performed on the per-protocol population, which was 96% of the intention-to-treat population. Secondary analyses included an analysis of host and parasite genotypes as risks for prolongation of parasite clearance kinetics, measured every 6 h, and a Kaplan-Meier analysis to compare parasite clearance kinetics between treatment groups. A post hoc analysis was performed for delayed anemia, defined as hemoglobin ≤ 7 g/dl 7 d or more after admission. The per-protocol population was 1,002 children (five-dose i.m.: n = 331; three-dose i.m.: n = 338; three-dose i.v.: n = 333); 139 participants were lost to follow-up. In the three-dose i.m. arm, 265/338 (78%) children had a ≥ 99% reduction in parasitemia at 24 h compared to 263/331 (79%) receiving the five-dose i.m. regimen, showing non-inferiority of the simplified three-dose regimen to the conventional five-dose regimen (95% CI -7, 5; p = 0.02). In the three-dose i.v. arm, 246/333 (74%) children had ≥ 99% reduction in parasitemia at 24 h; hence, non-inferiority of this regimen to the five-dose control regimen was not shown (95% CI -12, 1; p = 0.24). Delayed parasite clearance was associated with the N86YPfmdr1 genotype. In a post hoc analysis, 192/885 (22%) children developed delayed anemia, an adverse event associated with increased leukocyte counts. There was no observed difference in delayed anemia between treatment arms. A potential limitation of the study is its open-label design, although the primary outcome measures were assessed in a blinded manner.
  
  
  CONCLUSIONS
  A simplified three-dose i.m. regimen for severe malaria in African children is non-inferior to the more complex WHO-recommended regimen. Parenteral ARS is associated with a risk of delayed anemia in African children.
  
  
  BACKGROUND
  Pan African Clinical Trials Registry PACTR201102000277177.
authors.affiliation: Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Tübingen, Germany.|Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kremsner
authors.affiliation: Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Tübingen, Germany.|Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon.
authors.forename: Akim A
authors.initials: AA
authors.lastname: Adegnika
authors.affiliation: Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Tübingen, Germany.|Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon.
authors.forename: Aurore B
authors.initials: AB
authors.lastname: Hounkpatin
authors.affiliation: Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Tübingen, Germany.|Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon.
authors.forename: Jeannot F
authors.initials: JF
authors.lastname: Zinsou
authors.affiliation: Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Taylor
authors.affiliation: Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: Yamikani
authors.initials: Y
authors.lastname: Chimalizeni
authors.affiliation: Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: Alice
authors.initials: A
authors.lastname: Liomba
authors.affiliation: Department of Parasitology Mycology, Faculty of Medicine, Université des Sciences de la Santé, Libreville, Gabon.
authors.forename: Maryvonne
authors.initials: M
authors.lastname: Kombila
authors.affiliation: Department of Parasitology Mycology, Faculty of Medicine, Université des Sciences de la Santé, Libreville, Gabon.
authors.forename: Marielle K
authors.initials: MK
authors.lastname: Bouyou-Akotet
authors.affiliation: Department of Parasitology Mycology, Faculty of Medicine, Université des Sciences de la Santé, Libreville, Gabon.
authors.forename: Denise P
authors.initials: DP
authors.lastname: Mawili Mboumba
authors.affiliation: Department of Physiology, University of Science and Technology, School of Medical Sciences, Kumasi, Ghana.|Departments of Child Health and Medicine, Komfo Anokye Teaching Hospital, Kumasi, Ghana.
authors.forename: Tsiri
authors.initials: T
authors.lastname: Agbenyega
authors.affiliation: Department of Physiology, University of Science and Technology, School of Medical Sciences, Kumasi, Ghana.|Departments of Child Health and Medicine, Komfo Anokye Teaching Hospital, Kumasi, Ghana.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ansong
authors.affiliation: Department of Physiology, University of Science and Technology, School of Medical Sciences, Kumasi, Ghana.|Departments of Child Health and Medicine, Komfo Anokye Teaching Hospital, Kumasi, Ghana.
authors.forename: Justice
authors.initials: J
authors.lastname: Sylverken
authors.affiliation: Centre for Clinical Research, Kenya Medical Research Institute, Kisumu, Kenya.
authors.forename: Bernhards R
authors.initials: BR
authors.lastname: Ogutu
authors.affiliation: Centre for Clinical Research, Kenya Medical Research Institute, Kisumu, Kenya.
authors.forename: Godfrey A
authors.initials: GA
authors.lastname: Otieno
authors.affiliation: Centre for Clinical Research, Kenya Medical Research Institute, Kisumu, Kenya.
authors.forename: Anne
authors.initials: A
authors.lastname: Wangwe
authors.affiliation: Medical Research Council Laboratories, Fajara, The Gambia.
authors.forename: Kalifa A
authors.initials: KA
authors.lastname: Bojang
authors.affiliation: Medical Research Council Laboratories, Fajara, The Gambia.
authors.forename: Uduak
authors.initials: U
authors.lastname: Okomo
authors.affiliation: Medical Research Council Laboratories, Fajara, The Gambia.
authors.forename: Frank
authors.initials: F
authors.lastname: Sanya-Isijola
authors.affiliation: Centre for Geographic Medicine Research-Coast, Kenya Medical Research Institute, Kilifi, Kenya.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Newton
authors.affiliation: Centre for Geographic Medicine Research-Coast, Kenya Medical Research Institute, Kilifi, Kenya.
authors.forename: Patricia
authors.initials: P
authors.lastname: Njuguna
authors.affiliation: Centre for Geographic Medicine Research-Coast, Kenya Medical Research Institute, Kilifi, Kenya.
authors.forename: Michael
authors.initials: M
authors.lastname: Kazungu
authors.affiliation: Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany.|Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kerb
authors.affiliation: Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany.|Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Geditz
authors.affiliation: Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany.|Abteilung Klinische Pharmakologie, Universitätsklinikum Tübingen, Tübingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Thirumalaisamy P
authors.initials: TP
authors.lastname: Velavan
authors.affiliation: Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Nguetse
authors.affiliation: Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Köhler
authors.affiliation: Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Tübingen, Germany.|Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon.
authors.forename: Saadou
authors.initials: S
authors.lastname: Issifou
authors.affiliation: Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bolte
authors.affiliation: Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Engleitner
authors.affiliation: Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Tübingen, Germany.|Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mordmüller
authors.affiliation: Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Tübingen, Germany.|Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon.|Institute for Infection and Immunity, St George's, University of London, London, United Kingdom.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Krishna
mesh_terms: D000349:Africa / Q000453:epidemiology; D000962:Antimalarials / Q000008:administration & dosage*; D037621:Artemisinins / Q000008:administration & dosage*; D000077332:Artesunate; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007273:Injections, Intramuscular; D016778:Malaria, Falciparum / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology*; D008297:Male; D012720:Severity of Illness Index
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate