Intramuscular Artesunate for Severe Malaria in African Children: A Multicenter Randomized Controlled Trial

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%). methods and findings: 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 ≤ 7g/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. trial registration: pan african clinical trials registry pactr201102000277177 © 2016 kremsner et al.