Inhaled Nitric Oxide for the Adjunctive Therapy of Severe Malaria: a Randomized Controlled Trial

• Change in serum angiopoietin-2 level [ Time Frame: Admission through 72 hours ] [ Designated as safety issue: No ]
  Daily Ang-2 measurements over the first 72 hours of hospital admission will be the primary efficacy outcome. Elevated Ang-2 levels are associated with poor clinical outcome in severe malaria and Ang-2 has been used to follow disease progression and recovery in previous studies of malaria. Thus, Ang-2 is an objective, quantitative surrogate marker of disease severity, validated for longitudinal follow-up of patients with malaria.
  
  

• Mortality [ Time Frame: 48 hours and 14 days after admission ] [ Designated as safety issue: Yes ]
  
• Time to hospital discharge [ Time Frame: From admission to approximately 72 hours ] [ Designated as safety issue: No ]
  Recovery times (time to fever resolution, time to sit unsupported, and time to hospital discharge) are standard, clinically relevant outcomes in other therapeutic trials for malaria.
  
  
• Time to parasite clearance. [ Time Frame: From admission to approximately 72 hours ] [ Designated as safety issue: No ]
  Parasitological efficacy outcome; quantitative assessment of parasite density by light microscopy of Giemsa-stained thin smears.
  
  
• Biomarkers and genetic determinants of endothelial activation, inflammation and coagulopathy, to be determined. [ Time Frame: From admission to approximately 72 hours ] [ Designated as safety issue: No ]
  Biomarkers and genetic determinants of severe malaria pathogenesis may provide additional insight into the pathways and processes altered in cerebral malaria and affected by iNO delivery. We plan to examine biomarkers of endothelial activation, inflammation including cytokines, and coagulopathy which are central to the pathophysiology of severe malaria. In addition, genetic pathways involved in severe malaria and response to iNO will be investigated.
  
  

Severe malaria remains a major cause of global morbidity and mortality. While the use of artemisinin-based antimalarial therapy has improved outcomes in severe malaria, the mortality rate 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 the angiogenic factors angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) have recently been shown to function as key regulators. 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 gas (iNO) is a US FDA-approved treatment for hypoxic respiratory failure in neonates. Based on compelling data on the efficacy of iNO in experimental cerebral malaria in animal models, coupled with the documented safety of iNO in clinical practice and trials for other diseases, we propose a randomized clinical trial of iNO for the adjunctive treatment of severe malaria in Ugandan children.