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

• 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.

Despite the use of highly effective anti-malarial medications, 10-30% of African children with severe malaria will die, underscoring the need for adjunctive therapies that can be applied in endemic areas. A clinical trial of adjunctive inhaled nitric oxide (iNO) in severe malaria is warranted on the basis of firm proof of concept from animal studies and a human study using the NO donor L-arginine, together with evidence of safety from clinical experience and trials of iNO for other conditions. Our objective is to determine whether supplemental iNO (80 ppm) in addition to Ugandan Standard of Care treatment reduces levels of Angiopoietin-2 (Ang-2), a quantitative biomarker of malaria severity, in children with severe malaria compared to Standard of Care treatment alone. We will conduct a randomized placebo-controlled trial among children 1-10 years of age admitted to Jinja Hospital (Uganda) with severe malaria to test the efficacy of inhaled nitric oxide in severe malaria.

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.

• Experimental: Inhaled Nitric Oxide
  iNO, a gaseous molecule, will be administered by inhalational route over a maximum period of 72 hours.
  Intervention: Drug: Inhaled Nitric Oxide
• Placebo Comparator: Room air
  Room air will be delivered by air compressor through an indistinguishable mask system.
  Intervention: Drug: Inhaled Nitric Oxide

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Inclusion Criteria:

• Age 1-10 years
• Positive malaria rapid diagnostic test in the presence of any of the features of severe malaria
• Willing and able to complete follow up schedules for the study - 14 day and 6 months after hospital discharge

Exclusion Criteria:

• Baseline methemoglobinemia
• Known renal, cardiac, or hepatic disease or other chronic illnesses like diabetes, epilepsy, cerebral palsy, clinical AIDS
• Severe malnutrition
• Severe malarial anemia without other signs of severe malaria

• Makerere University
• University of Toronto