title: Efficacy and safety of re-treatment with the same artemisinin-based combination treatment (ACT) compared with an alternative ACT and quinine plus clindamycin after failure of first-line recommended ACT (QUINACT): a bicentre, open-label, phase 3, randomised controlled trial.
abstract: Quinine or alternative artemisinin-based combination treatment (ACT) is the recommended rescue treatment for uncomplicated malaria. However, patients are often re-treated with the same ACT though it is unclear whether this is the most suitable approach. We assessed the efficacy and safety of re-treating malaria patients with uncomplicated failures with the same ACT used for the primary episode, compared with other rescue treatments.
  
  
  
  This was a bicentre, open-label, randomised, three-arm phase 3 trial done in Lisungi health centre in DR Congo, and Kazo health centre in Uganda in 2012-14. Children aged 12-60 months with recurrent malaria infection after treatment with the first-line ACT were randomly assigned to either re-treatment with the same first-line ACT, an alternative ACT, which were given for 3 days, or quinine-clindamycin (QnC), which was given for 5-7 days, following a 2:2:1 ratio. Randomisation was done by computer-generated randomisation list in a block design by country. The three treatment groups were assumed to have equivalent efficacy above 90%. Both the research team and parents or guardians were aware of treatment allocation. The primary outcome was the proportion of patients with an adequate clinical and parasitological response (ACPR) at day 28, in the per-protocol population. This trial was registered under the numbers NCT01374581 in ClinicalTrials.gov and PACTR201203000351114 in the Pan African Clinical Trials Registry.
  
  
  
  From May 22, 2012, to Jan 31, 2014, 571 children were included in the trial. 240 children were randomly assigned to the re-treatment ACT group, 233 to the alternative ACT group, and 98 to the QnC group. 500 children were assessed for the primary outcome. 71 others were not included because they did not complete the follow-up or PCR genotyping result was not conclusive. The ACPR response was similar in the three groups: 91·4% (95% CI 87·5-95·2) for the re-treatment ACT, 91·3% (95% CI 87·4-95·1) for the alternative ACT, and 89·5% (95% CI 83·0-96·0) for QnC. The estimates for rates of malaria recrudescence in the three treatment groups were similar (log-rank test: χ2=0·22, p=0·894). Artemether-lumefantrine was better tolerated than QnC (p=0·0005) and artesunate-amodiaquine (p<0·0001) in the modified intention-to-treat analysis. No serious adverse events were observed. The most common adverse events reported in the re-treatment ACT group were anorexia (31 [13%] of 240 patients), asthenia (20 [8%]), coughing (16 [7%]), abnormal behaviour (13 [5%]), and diarrhoea (12 [5%]). Anorexia (13 [6%] of 233 patients) was the most frequently reported adverse event in the alternative ACT group. The most commonly reported adverse events in the QnC group were anorexia (12 [12%] of 98 patients), abnormal behaviour (6 [6%]), asthenia (6 [6%]), and pruritus (5 [5%]).
  
  
  
  Re-treatment with the same ACT shows similar efficacy as recommended rescue treatments and could be considered for rescue treatment for Plasmodium falciparum malaria. However, the effect of this approach on the selection of resistant strains should be monitored to ensure that re-treatment with the same ACT does not contribute to P falciparum resistance.
  
  
  
  Fonds Wetenschappelijk Onderzoek, Vlaamse Interuniversitaire Raad-Universitaire Ontwikkelings Samenwerking, European and Developing Countries Clinical Trials Partnership, and the Belgian Technical Cooperation-Programme d'Etudes et d'Expertises-in the Democratic Republic of Congo.
authors.affiliation: Département de Médecine Tropicale, Faculté de Médecine, Université de Kinshasa, Kinshasa, DR Congo; Epidemiology for Global Health Institute, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium. Electronic address: mavoko@yahoo.com.
authors.forename: Hypolite Muhindo
authors.initials: HM
authors.lastname: Mavoko
authors.affiliation: Epidemiology for Global Health Institute, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Infectious Disease Institute, University of Makerere, Kampala, Uganda; Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Nabasumba
authors.affiliation: Epidemiology for Global Health Institute, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Raquel Inocêncio
authors.initials: RI
authors.lastname: da Luz
authors.affiliation: Centre Muraz/Institut de Recherche en Sciences de la Santé, Bobo Dioulasso, Burkina Faso.
authors.forename: Halidou
authors.initials: H
authors.lastname: Tinto
authors.affiliation: Institute of Tropical Medicine, Antwerp, Belgium; London School of Hygiene & Tropical Medicine, London, UK; Medical Research Council, The Gambia Unit, Banjul, The Gambia.
authors.forename: Umberto
authors.initials: U
authors.lastname: D'Alessandro
authors.affiliation: Infectious Disease Institute, University of Makerere, Kampala, Uganda.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kambugu
authors.affiliation: Epidemiology for Global Health Institute, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; National Institute for Medical Research, Tanga Research Centre, Tanga, Tanzania.
authors.forename: Vito
authors.initials: V
authors.lastname: Baraka
authors.affiliation: Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Anna
authors.initials: A
authors.lastname: Rosanas-Urgell
authors.affiliation: Département de Médecine Tropicale, Faculté de Médecine, Université de Kinshasa, Kinshasa, DR Congo.
authors.forename: Pascal
authors.initials: P
authors.lastname: Lutumba
authors.affiliation: Epidemiology for Global Health Institute, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Van Geertruyden
mesh_terms: D000655:Amodiaquine / Q000627:therapeutic use*; D000855:Anorexia; D000962:Antimalarials / Q000627:therapeutic use*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000627:therapeutic use*; D002675:Child, Preschool; D002981:Clindamycin / Q000627:therapeutic use*; D015023:Democratic Republic of the Congo; D004338:Drug Combinations; D004983:Ethanolamines / Q000627:therapeutic use*; D005260:Female; D005449:Fluorenes / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy; D008297:Male; D011803:Quinine / Q000627:therapeutic use*; D016896:Treatment Outcome; D014454:Uganda
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; C515299:amodiaquine, artesunate drug combination; D000655:Amodiaquine; D002981:Clindamycin; D011803:Quinine