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

Michael Hawkes, Robert O. Opoka, Sophie Namasopo, Christopher Miller, Kevin E. Thorpe, James V. Lavery, Andrea L. Conroy, W. Conrad Liles, Chandy C. John, Kevin C. Kain

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Background: Severe malaria 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 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.

Original languageEnglish (US)
Article number176
JournalTrials
Volume12
DOIs
StatePublished - Jul 13 2011

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology (medical)

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    Hawkes, M., Opoka, R. O., Namasopo, S., Miller, C., Thorpe, K. E., Lavery, J. V., Conroy, A. L., Liles, W. C., John, C. C., & Kain, K. C. (2011). Inhaled nitric oxide for the adjunctive therapy of severe malaria: Protocol for a randomized controlled trial. Trials, 12, [176]. https://doi.org/10.1186/1745-6215-12-176