Safety and tolerability of adjunctive rosiglitazone treatment for children with uncomplicated malaria

Rosauro Varo, Valerie M Crowley, Antonio Sitoe, Lola Madrid, Lena Serghides, Rubao Bila, Helio Mucavele, Alfredo Mayor, Quique Bassat, Kevin C Kain, Rosauro Varo, Valerie M Crowley, Antonio Sitoe, Lola Madrid, Lena Serghides, Rubao Bila, Helio Mucavele, Alfredo Mayor, Quique Bassat, Kevin C Kain

Abstract

Background: Despite 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.

Methods: In 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.

Results: Thirty 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.

Conclusions: Adjunctive 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.

Figures

Fig. 1
Fig. 1
Study profile of 33 patients screened for eligibility for a randomized, placebo-controlled, phase IIa trial of adjunctive rosiglitazone for the treatment of uncomplicated malaria in children
Fig. 2
Fig. 2
Median glucose levels of study participants on admission (AD) and at each measured time point. Bars represent interquartile range
Fig. 3
Fig. 3
Mean hematocrit and hemoglobin levels according to study group on admission (AD) and at each measured time point
Fig. 4
Fig. 4
Log mean parasite load in Mozambican children with uncomplicated malaria according to study group

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