Inhaled nitric oxide for the adjunctive therapy of severe malaria: Protocol for a randomized controlled trial

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 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.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.ClinicalTrials.gov Identifier: NCT01255215Malaria is the leading parasitic cause of morbidity and mortality worldwide, causing an estimated 240 million clinical cases and 800,000 deaths annually [1]. Children in sub-Saharan Africa bear the greatest burden of disease, where one in every five childhood deaths is due to malaria and 25% of survivors of cerebral malaria develop long-term neurocognitive impairment [1,2]. Despite the use of highly effective anti-malarial medications, 10-30% patients with severe malaria will die [3-5], underscoring the need for adjunctive therapies that can be applied in endemic areas. To date, effective adjunctive treatments have been elusive despite numerous clinical trials [6]. New therapies, appropriate for use in endemic areas, are therefore urgently needed to address the unacceptably high residual mortality associated with severe malaria in pediatric populations.NO is a gaseous, lipid-soluble free radical that is produced in vivo by the enzymatic conversion of L-arginine and molecular oxygen to L-citrulline by members of the nitr