title: Effectiveness of Seasonal Malaria Chemoprevention in Children under Ten Years of Age in Senegal: A Stepped-Wedge Cluster-Randomised Trial.
abstract: BACKGROUND
  Seasonal Malaria Chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ), given each month during the transmission season, is recommended for children living in areas of the Sahel where malaria transmission is highly seasonal. The recommendation for SMC is currently limited to children under five years of age, but, in many areas of seasonal transmission, the burden in older children may justify extending this age limit. This study was done to determine the effectiveness of SMC in Senegalese children up to ten years of age.
  
  
  RESULTS
  SMC was introduced into three districts over three years in central Senegal using a stepped-wedge cluster-randomised design. A census of the population was undertaken and a surveillance system was established to record all deaths and to record all cases of malaria seen at health facilities. A pharmacovigilance system was put in place to detect adverse drug reactions. Fifty-four health posts were randomised. Nine started implementation of SMC in 2008, 18 in 2009, and a further 18 in 2010, with 9 remaining as controls. In the first year of implementation, SMC was delivered to children aged 3-59 months; the age range was then extended for the latter two years of the study to include children up to 10 years of age. Cluster sample surveys at the end of each transmission season were done to measure coverage of SMC and the prevalence of parasitaemia and anaemia, to monitor molecular markers of drug resistance, and to measure insecticide-treated net (ITN) use. Entomological monitoring and assessment of costs of delivery in each health post and of community attitudes to SMC were also undertaken. About 780,000 treatments were administered over three years. Coverage exceeded 80% each month. Mortality, the primary endpoint, was similar in SMC and control areas (4.6 and 4.5 per 1000 respectively in children under 5 years and 1.3 and 1.2 per 1000 in children 5-9 years of age; the overall mortality rate ratio [SMC: no SMC] was 0.90, 95% CI 0.68-1.2, p = 0.496). A reduction of 60% (95% CI 54%-64%, p < 0.001) in the incidence of malaria cases confirmed by a rapid diagnostic test (RDT) and a reduction of 69% (95% CI 65%-72%, p < 0.001) in the number of treatments for malaria (confirmed and unconfirmed) was observed in children. In areas where SMC was implemented, incidence of confirmed malaria in adults and in children too old to receive SMC was reduced by 26% (95% CI 18%-33%, p < 0.001) and the total number of treatments for malaria (confirmed and unconfirmed) in these older age groups was reduced by 29% (95% CI 21%-35%, p < 0.001). One hundred and twenty-three children were admitted to hospital with a diagnosis of severe malaria, with 64 in control areas and 59 in SMC areas, showing a reduction in the incidence rate of severe disease of 45% (95% CI 5%-68%, p = 0.031). Estimates of the reduction in the prevalence of parasitaemia at the end of the transmission season in SMC areas were 68% (95% CI 35%-85%) p = 0.002 in 2008, 84% (95% CI 58%-94%, p < 0.001) in 2009, and 30% (95% CI -130%-79%, p = 0.56) in 2010. SMC was well tolerated with no serious adverse reactions attributable to SMC drugs. Vomiting was the most commonly reported mild adverse event but was reported in less than 1% of treatments. The average cost of delivery was US$0.50 per child per month, but varied widely depending on the size of the health post. Limitations included the low rate of mortality, which limited our ability to detect an effect on this endpoint.
  
  
  CONCLUSIONS
  SMC substantially reduced the incidence of outpatient cases of malaria and of severe malaria in children, but no difference in all-cause mortality was observed. Introduction of SMC was associated with an overall reduction in malaria incidence in untreated age groups. In many areas of Africa with seasonal malaria, there is a substantial burden in older children that could be prevented by SMC. SMC in older children is well tolerated and effective and can contribute to reducing malaria transmission.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00712374.
authors.affiliation: Université Cheikh Anta Diop, Dakar, Sénégal.|London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Badara
authors.initials: B
authors.lastname: Cissé
authors.affiliation: London School of Hygiene & Tropical Medicine, London, United Kingdom.|Institut de Recherche pour le Développement, Dakar, Sénégal.
authors.forename: El Hadj
authors.identifier: http://orcid.org/0000-0001-8935-6529
authors.initials: EH
authors.lastname: Ba
authors.affiliation: Institut de Recherche pour le Développement, Dakar, Sénégal.
authors.forename: Cheikh
authors.initials: C
authors.lastname: Sokhna
authors.affiliation: Université Cheikh Anta Diop, Dakar, Sénégal.
authors.forename: Jean Louis
authors.initials: JL
authors.lastname: NDiaye
authors.affiliation: Université Cheikh Anta Diop, Dakar, Sénégal.
authors.forename: Jules F
authors.initials: JF
authors.lastname: Gomis
authors.affiliation: Ministère de la Santé et de la Prévention, Sénégal.
authors.forename: Yankhoba
authors.initials: Y
authors.lastname: Dial
authors.affiliation: London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Pitt
authors.affiliation: Université Cheikh Anta Diop, Dakar, Sénégal.
authors.forename: Mouhamed
authors.initials: M
authors.lastname: NDiaye
authors.affiliation: London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Cairns
authors.affiliation: Université Cheikh Anta Diop, Dakar, Sénégal.
authors.forename: Ernest
authors.initials: E
authors.lastname: Faye
authors.affiliation: Université Cheikh Anta Diop, Dakar, Sénégal.
authors.forename: Magatte
authors.initials: M
authors.lastname: NDiaye
authors.affiliation: Université Cheikh Anta Diop, Dakar, Sénégal.
authors.forename: Aminata
authors.identifier: http://orcid.org/0000-0002-9724-3724
authors.initials: A
authors.lastname: Lo
authors.affiliation: Université Cheikh Anta Diop, Dakar, Sénégal.
authors.forename: Roger
authors.initials: R
authors.lastname: Tine
authors.affiliation: Université Cheikh Anta Diop, Dakar, Sénégal.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Faye
authors.affiliation: Université Cheikh Anta Diop, Dakar, Sénégal.
authors.forename: Babacar
authors.initials: B
authors.lastname: Faye
authors.affiliation: Université Cheikh Anta Diop, Dakar, Sénégal.
authors.forename: Ousmane
authors.initials: O
authors.lastname: Sy
authors.affiliation: Université Cheikh Anta Diop, Dakar, Sénégal.
authors.forename: Lansana
authors.initials: L
authors.lastname: Konate
authors.affiliation: Institut de Recherche pour le Développement, Dakar, Sénégal.
authors.forename: Ekoue
authors.initials: E
authors.lastname: Kouevijdin
authors.affiliation: London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Clare
authors.initials: C
authors.lastname: Flach
authors.affiliation: Université Cheikh Anta Diop, Dakar, Sénégal.
authors.forename: Ousmane
authors.initials: O
authors.lastname: Faye
authors.affiliation: Institut de Recherche pour le Développement, Dakar, Sénégal.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Trape
authors.affiliation: London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Colin
authors.initials: C
authors.lastname: Sutherland
authors.affiliation: Ministère de la Santé et de la Prévention, Sénégal.
authors.forename: Fatou Ba
authors.initials: FB
authors.lastname: Fall
authors.affiliation: Ministère de la Santé et de la Prévention, Sénégal.
authors.forename: Pape M
authors.initials: PM
authors.lastname: Thior
authors.affiliation: Ministère de la Santé et de la Prévention, Sénégal.
authors.forename: Oumar K
authors.initials: OK
authors.lastname: Faye
authors.affiliation: London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Brian
authors.initials: B
authors.lastname: Greenwood
authors.affiliation: Université Cheikh Anta Diop, Dakar, Sénégal.
authors.forename: Oumar
authors.initials: O
authors.lastname: Gaye
authors.affiliation: London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Milligan
mesh_terms: D000655:Amodiaquine / Q000627:therapeutic use*; D000962:Antimalarials / Q000627:therapeutic use*; D018890:Chemoprevention / Q000592:standards; D002648:Child; D002675:Child, Preschool; D004338:Drug Combinations; D006801:Humans; D007223:Infant; D008288:Malaria / Q000188:drug therapy* / Q000517:prevention & control*; D011739:Pyrimethamine / Q000627:therapeutic use*; D012621:Seasons; D012675:Senegal; D013413:Sulfadoxine / Q000627:therapeutic use*
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D000655:Amodiaquine; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D011739:Pyrimethamine