Abstract Background Severe malaria click here remains a major cause of global morbidity and mortality.Despite the use of potent anti-parasitic agents, the mortality rate in severe malaria remains high.Adjunctive therapies that target the underlying pathophysiology of severe malaria may further reduce morbidity and mortality.Endothelial activation plays a central role in the pathogenesis of severe malaria, of which angiopoietin-2 (Ang-2) has recently been shown to function as a key regulator.
Nitric oxide (NO) is a major inhibitor of Ang-2 release from endothelium and has been shown to decrease endothelial inflammation and reduce the adhesion of parasitized erythrocytes.Low-flow inhaled nitric oxide (iNO) gas is a US FDA-approved treatment for hypoxic respiratory failure in neonates.Methods/Design This prospective, parallel arm, randomized, placebo-controlled, blinded clinical trial compares adjunctive continuous inhaled nitric oxide at 80 ppm to placebo (both arms receiving standard anti-malarial therapy), among Ugandan children aged 1-10 years of age with severe malaria.The primary endpoint is the longitudinal change in read more Ang-2, an objective and quantitative biomarker of malaria severity, which will be analysed using a mixed-effects linear model.
Secondary endpoints include mortality, recovery time, parasite clearance and neurocognitive sequelae.Discussion Noteworthy aspects of this trial design include its efficient sample size supported by a computer simulation study to evaluate statistical power, meticulous attention to complex ethical issues in a cross-cultural setting, and innovative strategies for safety monitoring and blinding to treatment allocation in a resource-constrained setting in sub-Saharan Africa.Trial Registration ClinicalTrials.gov Identifier: NCT01255215.