While the incidence of Plasmodium falciparum malaria declines (1) the proportion of cases with severe malaria (SM) may increase (2). The mortality associated with SM in endemic countries remains high despite the use of artesunate (AS) (3). Safe, cheap, and effective adjunct therapies preventing the development of, or reducing the mortality from, SM could have considerable and rapid public health impact. We discovered that oral administration of activated charcoal (oAC), a safe treatment for acute poisoning (4), protects mice from experimental cerebral malaria and demonstrated in a randomized controlled trial (RCT) in African adults that oAC is safe and does not interfere with the pharmacokinetics of AS (5). Here, we propose the next step to evaluate the efficacy of adjunct treatment with oAC in Malian children and to explore its mode of action. Before testing adjunct treatment with oAC in children with SM, we will perform an open-label RCT in children with uncomplicated malaria (UM) to demonstrate non-inferiority of intravenous (IV) AS plus adjunct oAC vs. IV AS alone with regards to parasite clearance rate. This study will be conducted in African children, because they are the primary target population for such an intervention. Although the adequate standard-of-care treatment for UM is oral (PO) administration of an artemisinin-based combination therapy (ACT), we will treat participants with IV AS. Like ACT treatment of UM, AS is the WHO-recommended first-line treatment for SM (1). In order for the data obtained from UM cases to be meaningful for our future studies in children with SM, we will administer AS to the UM cases in this trial via the same IV route that is used to administer AS to SM cases. Exploratory objectives include: (i) to compare the kinetics of plasma cytokines in both groups, and (ii) to preserve RNA for gene transcription analysis for future studies into the mode of action of oAC. The study will be nested within an NIAID-funded study (Principal Investigators Drs. Fairhurst, Diakite) that assesses parasite clearance rates in response to AS treatment in Kenieroba (6). Children aged 2-10 years with UM and initial parasite densities 10,000 70,000 parasites per micro L will be enrolled. Parasite clearance rates will be expressed as the parasite half-life (Ph), estimated from parasite clearance curves using a formula that has been validated in this cohort (7). Children will be randomized 1:1 to receive IV AS+oAC or IV AS only, respectively, until complete specimen and data sets for 35 children per group are obtained. oAC will be administered as Actidose Aqua\[registered\] at 0, 6, 12, and 18 hours. AS will be administered IV following WHO recommendations for use of AS in SM (8), followed by 3 daily doses of amodiaquine (AQ). Subsequently and in a separate study, we plan a proof-of-concept RCT to determine whether adjunct oAC reduces disease severity and morbidity (assessed by scoring systems (9)) in hospitalized children with SM and to define the mode of action of oAC. Since oAC is a licensed, inexpensive drug without sophisticated storage requirements, which has an extremely long shelf life at room temperature and can be given orally or via nasogastric tube at high doses without major side effects (4, 10), this drug has an ideal profile for use at the primary health-care level to reduce mortality from SM, or even prevent the development of SM.