Kremsner, PG;
Adegnika, AA;
Hounkpatin, AB;
Zinsou, JF;
Taylor, TE;
Chimalizeni, Y;
Liomba, A;
Kombila, M;
Bouyou-Akotet, MK;
Mawili Mboumba, DP;
et al.
Kremsner, PG; Adegnika, AA; Hounkpatin, AB; Zinsou, JF; Taylor, TE; Chimalizeni, Y; Liomba, A; Kombila, M; Bouyou-Akotet, MK; Mawili Mboumba, DP; Agbenyega, T; Ansong, D; Sylverken, J; Ogutu, BR; Otieno, GA; Wangwe, A; Bojang, KA; Okomo, U; Sanya-Isijola, F; Newton, CR; Njuguna, P; Kazungu, M; Kerb, R; Geditz, M; Schwab, M; Velavan, TP; Nguetse, C; Köhler, C; Issifou, S; Bolte, S; Engleitner, T; Mordmüller, B; Krishna, S
(2016)
Intramuscular Artesunate for Severe Malaria in African Children: A Multicenter Randomized Controlled Trial.
PLoS Med, 13 (1).
e1001938.
ISSN 1549-1676
https://doi.org/10.1371/journal.pmed.1001938
SGUL Authors: Krishna, Sanjeev
Abstract
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 ≤ 7 g/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.
Item Type: |
Article
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Additional Information: |
© 2016 Kremsner et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited |
Keywords: |
Africa, Antimalarials, Artemisinins, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Infant, Injections, Intramuscular, Malaria, Falciparum, Male, Severity of Illness Index, Humans, Malaria, Falciparum, Artemisinins, Antimalarials, Injections, Intramuscular, Severity of Illness Index, Follow-Up Studies, Child, Child, Preschool, Infant, Africa, Female, Male, General & Internal Medicine, 11 Medical And Health Sciences |
SGUL Research Institute / Research Centre: |
Academic Structure > Infection and Immunity Research Institute (INII) |
Journal or Publication Title: |
PLoS Med |
ISSN: |
1549-1676 |
Language: |
eng |
Dates: |
Date | Event |
---|
12 January 2016 | Published | 2 December 2015 | Accepted |
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Publisher License: |
Creative Commons: Attribution 4.0 |
Projects: |
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PubMed ID: |
26757276 |
Web of Science ID: |
WOS:000369370600007 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/109786 |
Publisher's version: |
https://doi.org/10.1371/journal.pmed.1001938 |
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