Host and parasite factors influencing the pharmacokinetics of artesunate
Final Report Abstract
Background: Current artesunate regimens for severe malaria are complex. Once daily intramuscular (im) injection would be simpler and more appropriate for remote health facilities. We compared both a 3-dose im and a 3-dose intravenous (iv) parenteral artesunate regimen with the standard 5-dose regimen using a non-inferiority design (with non-inferiority margins of 10%). Methods: This randomized, controlled trial included children (0·5 – 10 years) with severe malaria at 7 sites in 5 African countries to assess whether efficacy of simplified 3-dose regimens is noninferior to a 5-dose regimen. We randomly allocated 1047 children to receive a total dose of 12 mg/kg artesunate as either a control regimen of 5 im injections of 2·4 mg/kg (at 0, 12, 24, 48, 72 hours) (n = 348), or 3 injections of 4 mg/kg (0, 24, 48 hours) either im (n = 348) or iv (n =351) both of which were intervention arms. The primary endpoint was the proportion of children with ≤ 1 % parasitemia of admission values at 24 h, 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 host and parasite genotypes as risks for prolongation in parasite clearance kinetics measured 6 hourly 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 days or more after admission. The trial is registered at PACTR201102000277177. Results: The per-protocol population was 1002 children (5-dose im: n = 331; 3-dose im: n = 338; 3- dose iv: n = 333). 139 participants were lost to follow-up. In the 3-dose im arm 266/338 (79%) children met the primary endpoint compared to 264/331 (80%) receiving the 5-dose im regimen, showing non-inferiority of the simplified 3-dose over the conventional 5-dose regimen (95% Confidence Interval of the difference: -7 – 5; p = 0·02, with the non-inferiority margin of 10%). In the 3-dose iv arm, 248/333 (74%) met the primary endpoint, hence noninferiority to the 5-dose control arm 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 out of 885 (22%) of 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 primary outcome measures were assessed in a blinded manner. Conclusions: A simplified im regimen for severe malaria in African children is non-inferior to the more complex WHO-recommended regimen. Parenteral artesunate is associated with a risk of delayed anemia in African children.
