title: Randomized, multicentre assessment of the efficacy and safety of ASAQ--a fixed-dose artesunate-amodiaquine combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria.
abstract: BACKGROUND
  The use of artemisinin derivative-based combination therapy (ACT) such as artesunate plus amodiaquine is currently recommended for the treatment of uncomplicated Plasmodium falciparum malaria. Fixed-dose combinations are more adapted to patients than regimens involving multiple tablets and improve treatment compliance. A fixed-dose combination of artesunate + amodiaquine (ASAQ) was recently developed. To assess the efficacy and safety of this new combination and to define its optimum dosage regimen (once or twice daily) in the treatment of uncomplicated P. falciparum malaria, a multicentre clinical study was conducted.
  
  
  METHODS
  A multicentre, randomized, controlled, investigator-blinded, parallel-group study was conducted in five African centers in Cameroon, Madagascar, Mali and Senegal from March to December 2006. Efficacy and safety of ASAQ were assessed compared to those of artemether + lumefantrine (AL). The WHO protocol with a 28-day follow-up for assessing the drug therapeutic efficacy was used. Patients suffering from uncomplicated P. falciparum malaria were randomized to receive ASAQ orally once daily (ASAQ1), ASAQ twice daily (ASAQ2) or AL twice daily (AL) for three days. The primary outcome was PCR-corrected parasitological cure rate and clinical response.
  
  
  RESULTS
  Of 941 patients initially randomized and stratified into two age groups (<5 years, and >or=5 years), 936 (99.5%) were retained for the intent to treat (ITT) analysis, and 859 (91.3%) patients for the per protocol (PP) analysis. Among ITT population, up to D28, PCR-corrected adequate parasitological and clinical response rates were 95.2% in the ASAQ1 group, 94.9% in the ASAQ2 group and 95.5% in the AL group. Moreover, the cure rate evaluated among PP population was >or=98.5% in both ASAQ therapeutic arms. Therapeutic response rates did not display any significant differences between age groups or between one geographical site and another. Altogether, this demonstrates the non-inferiority of ASAQ1 regimen compared to both ASAQ2 and AL regimens. During follow-up mild and moderate adverse events including gastrointestinal and/or nervous disorders were reported in 29.3% of patients, with no difference between groups in the nature, frequency or intensity of adverse events.
  
  
  CONCLUSIONS
  The non-inferiority of ASAQ compared with AL was demonstrated. The fixed-dose combination artesunate + amodiaquine (ASAQ) is safe and efficacious even in young children under 5 years of age. Whilst administration on a twice-a-day basis does not improve the efficacy of ASAQ significantly, a once-a-day intake of this new combination clearly appears as an effective and safe therapy in the treatment of uncomplicated P. falciparum malaria both in adults and children. Implications of such findings are of primary importance in terms of public health especially in African countries. As most national policies plan to strengthen malaria control to reach the elimination of this disease, anti-malarial drugs such as the artesunate + amodiaquine fixed-dose ACT will play a pivotal role in this process.
  
  
  BACKGROUND
  The protocol was registered with the www.clinicaltrials.gov open clinical trial registry under the identifier number NCT00316329.
authors.affiliation: Department of Parasitology, Université Cheikh Anta Diop, Dakar, Senegal. jlndiaye@yahoo.com
authors.forename: Jean Louis
authors.initials: JL
authors.lastname: Ndiaye
authors.forename: Milijaona
authors.initials: M
authors.lastname: Randrianarivelojosia
authors.forename: Issaka
authors.initials: I
authors.lastname: Sagara
authors.forename: Philippe
authors.initials: P
authors.lastname: Brasseur
authors.forename: Ibrahima
authors.initials: I
authors.lastname: Ndiaye
authors.forename: Babacar
authors.initials: B
authors.lastname: Faye
authors.forename: Laurence
authors.initials: L
authors.lastname: Randrianasolo
authors.forename: Arsène
authors.initials: A
authors.lastname: Ratsimbasoa
authors.forename: Doris
authors.initials: D
authors.lastname: Forlemu
authors.forename: Vicky Ama
authors.initials: VA
authors.lastname: Moor
authors.forename: Aminata
authors.initials: A
authors.lastname: Traore
authors.forename: Yahia
authors.initials: Y
authors.lastname: Dicko
authors.forename: Niawanlou
authors.initials: N
authors.lastname: Dara
authors.forename: Valérie
authors.initials: V
authors.lastname: Lameyre
authors.forename: Mouctar
authors.initials: M
authors.lastname: Diallo
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Djimde
authors.forename: Albert
authors.initials: A
authors.lastname: Same-Ekobo
authors.forename: Oumar
authors.initials: O
authors.lastname: Gaye
mesh_terms: D000293:Adolescent; D000328:Adult; D000349:Africa; D000368:Aged; D000369:Aged, 80 and over; D000655:Amodiaquine / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D037621:Artemisinins / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000187:drug effects; D011247:Pregnancy; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; C515299:amodiaquine, artesunate drug combination; D000655:Amodiaquine