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

Michael Hawkes12, Robert O Opoka3, Sophie Namasopo4, Christopher Miller5, Kevin E Thorpe67, James V Lavery89, Andrea L Conroy10, W Conrad Liles111121314, Chandy C John15 and Kevin C Kain11011121314*

Author Affiliations

1 Institute of Medical Sciences, University of Toronto, Canada

2 Division of Infectious Diseases, Department of Pediatrics, The Hospital for Sick Children, Toronto, Canada

3 Department of Paediatrics and Child Health, Mulago Hospital and Makerere University, Kampala, Uganda

4 Department of Paediatrics, Jinja Regional Referral Hospital, Jinja, Uganda

5 Department of Respiratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, Canada

6 Dalla Lana School of Public Health, University of Toronto, Canada

7 Applied Health Research Centre, St Michael's Hospital, Toronto, Ontario, Canada

8 Centre for Global Health Research, The Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

9 Department of Public Health Sciences and Joint Centre for Bioethics at the University of Toronto, Canada

10 Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada

11 Department of Medicine, University of Toronto, Toronto, Canada

12 Sandra A. Rotman Laboratories, McLaughlin-Rotman Centre for Global Health, Toronto, Canada

13 McLaughlin Centre for Molecular Medicine, Toronto, Canada

14 Tropical Disease Unit, Toronto General Hospital, Toronto, Canada

15 Division of Global Pediatrics, Department of Pediatrics, University of Minnesota, Minnesota, USA

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Trials 2011, 12:176  doi:10.1186/1745-6215-12-176

Published: 13 July 2011



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.


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.

Trial Registration Identifier: NCT01255215