title: Inhaled nitric oxide for the adjunctive therapy of severe malaria: protocol for a randomized controlled trial.
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
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier: NCT01255215.
authors.affiliation: Institute of Medical Sciences, University of Toronto, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Hawkes
authors.forename: Robert O
authors.initials: RO
authors.lastname: Opoka
authors.forename: Sophie
authors.initials: S
authors.lastname: Namasopo
authors.forename: Christopher
authors.initials: C
authors.lastname: Miller
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Thorpe
authors.forename: James V
authors.initials: JV
authors.lastname: Lavery
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Conroy
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.forename: Chandy C
authors.initials: CC
authors.lastname: John
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
mesh_terms: D000280:Administration, Inhalation; D042702:Angiopoietin-2 / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002648:Child; D002675:Child, Preschool; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007223:Infant; D016014:Linear Models; D008288:Malaria / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000009:adverse effects; D015990:Placebo Effect; D011446:Prospective Studies; D012107:Research Design; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D014454:Uganda; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D042702:Angiopoietin-2; D015415:Biomarkers; D014665:Vasodilator Agents; D009569:Nitric Oxide