Abstract
BackgroundDespite the widespread use and availability of rapidly acting anti-malarials, the fatality rate of severe malaria in sub-Saharan Africa remains high. Adjunctive therapies that target the host response to malaria infection may further decrease mortality over that of anti-malarial agents alone. Peroxisome proliferator-activated receptor-gamma agonists (e.g. rosiglitazone) have been shown to act on several pathways implicated in the pathogenesis of severe malaria and may improve clinical outcome as an adjunctive intervention.MethodsIn this study, the safety and tolerability of adjunctive rosiglitazone in paediatric uncomplicated malaria infection was evaluated in Mozambique, as a prelude to its evaluation in a randomized controlled trial in paediatric severe malaria. The study was a prospective, randomized, double-blind, placebo-controlled, phase IIa trial of rosiglitazone (0.045 mg/kg/dose) twice daily for 4 days versus placebo as adjunctive treatment in addition to Mozambican standard of care (artemisinin combination therapy Coartem®) in children with uncomplicated malaria. The primary outcomes were tolerability and safety, including clinical, haematological, biochemical, and electrocardiographic evaluations.ResultsThirty children were enrolled: 20 were assigned to rosiglitazone and 10 to placebo. Rosiglitazone treatment did not induce hypoglycaemia nor significantly alter clinical, biochemical, haematological, or electrocardiographic parameters.ConclusionsAdjunctive rosiglitazone was safe and well-tolerated in children with uncomplicated malaria, permitting the extension of its evaluation as adjunctive therapy for severe malaria.The trial is registered with Clinicaltrials.gov, NCT02694874
Highlights
Despite the widespread use and availability of rapidly acting anti-malarials, the fatality rate of severe malaria in sub-Saharan Africa remains high
The trial is registered with Clinicaltrials.gov, NCT02694874
Rosiglitazone acts by increasing insulin sensitivity rather than increasing insulin levels, does not induce hypoglycaemia, and has an established safety profile in adults [25,26,27,28,29]
Summary
Study design and participants This was a prospective, parallel arm, unequally randomized, placebo-controlled, double-blind trial of rosiglitazone versus placebo, in 30 Mozambican children with uncomplicated malaria. Children received either rosiglitazone (0.045 mg/kg/dose) or placebo twice daily for 4 days [36]. A blood sample was taken at baseline and prior to the administration of the study intervention, for malaria diagnosis by microscopy, and haematological (haemoglobin, haematocrit, platelets, white cell full blood count) and biochemical (renal and liver function, glucose and lactate) evaluations. Biochemistry, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, creatinine, lactate dehydrogenase (LDH), and indirect and direct bilirubin, were assessed in venous blood every 24 h from admission until discharge and once again on day 7 follow-up. Venous blood extraction for haematology was performed every 24 h from admission until discharge and again on day 7 and 14 follow-up. A p value
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