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

ABSTRACT: 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.ClinicalTrials.gov Identifier: NCT01255215.

SUBMITTER: Hawkes M

PROVIDER: S-EPMC3151218 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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

Hawkes Michael M Opoka Robert O RO Namasopo Sophie S Miller Christopher C Thorpe Kevin E KE Lavery James V JV Conroy Andrea L AL Liles W Conrad WC John Chandy C CC Kain Kevin C KC

Trials 20110713

<h4>Background</h4>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 ...[more]

PMID: 21752262

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Project description:Background: Severe malaria is a leading cause of acquired neurodisability in Africa and is associated with reduced nitric oxide (NO) bioavailability. A neuroprotective role for inhaled NO has been reported in animal studies, and administration of inhaled NO in preterm neonates with respiratory distress syndrome is associated with a 47% reduced risk of cognitive impairment at two years of age.Methods: A randomized double-blind placebo-controlled trial of inhaled NO versus placebo as an adjunctive therapy for severe malaria was conducted in Uganda between 2011 and 2013. Children received study gas for a maximum 72 hours (inhaled NO, 80 parts per million; room air placebo). Neurocognitive testing was performed on children<5 years at 6 month follow-up. The neurocognitive outcomes assessed were overall cognition (a composite of fine motor, visual reception, receptive language, and expressive language), attention, associative memory, and the global executive composite. Main outcomes were attention, associative memory, and overall cognitive ability.Results: Sixty-one children receiving iNO and 59 children receiving placebo were evaluated. Forty-two children (35.0%) were impaired in at least one neurocognitive domain. By intention-to-treat analysis, there were no differences in unadjusted or unadjusted age-adjusted z-scores for overall cognition (? (95% CI): 0.26 (-0.19, 0.72), p = 0.260), attention (0.18 (-0.14, 0.51), p = 0.267), or memory (0.14 (-0.02, 0.30), p = 0.094) between groups by linear regression. Children receiving inhaled NO had a 64% reduced relative risk of fine motor impairment than children receiving placebo (relative risk, 95% CI: 0.36, 0.14-0.96) by log binomial regression following adjustment for anticonvulsant use.Conclusions: Severe malaria is associated with high rates of neurocognitive impairment. Treatment with inhaled NO was associated with reduced risk of fine motor impairment. These results need to be prospectively validated in a larger study powered to assess cognitive outcomes in order to evaluate whether strategies to increase bioavailable NO are neuroprotective in children with severe malaria.Trial registration: ClinicalTrials.gov Identifier: NCT01255215.

Project description:the current worldwide outbreak of Coronavirus disease 2019 (COVID-19) due to a novel coronavirus (SARS-CoV-2) is seriously threatening the public health. The number of infected patients is continuously increasing and the need for Intensive Care Unit admission ranges from 5 to 26%. The mortality is reported to be around 3.4% with higher values for the elderly and in patients with comorbidities. Moreover, this condition is challenging the healthcare system where the outbreak reached its highest value. To date there is still no available treatment for SARS-CoV-2. Clinical and preclinical evidence suggests that nitric oxide (NO) has a beneficial effect on the coronavirus-mediated acute respiratory syndrome, and this can be related to its viricidal effect. The time from the symptoms' onset to the development of severe respiratory distress is relatively long. We hypothesize that high concentrations of inhaled NO administered during early phases of COVID-19 infection can prevent the progression of the disease. This is a multicenter randomized controlled trial. Spontaneous breathing patients admitted to the hospital for symptomatic COVID-19 infection will be eligible to enter the study. Patients in the treatment group will receive inhaled NO at high doses (140-180 parts per million) for 30 minutes, 2 sessions every day for 14 days in addition to the hospital care. Patient in the control group will receive only hospital care. The primary outcome is the percentage of patients requiring endotracheal intubation due to the progression of the disease in the first 28 days from enrollment in the study. Secondary outcomes include mortality at 28 days, proportion of negative test for SARS-CoV-2 at 7 days and time to clinical recovery. The trial protocol has been approved at the Investigation Review Boards of Xijing Hospital (Xi'an, China) and The Partners Human Research Committee of Massachusetts General Hospital (Boston, USA) is pending. Recruitment is expected to start in March 2020. Results of this study will be published in scientific journals, presented at scientific meetings, and on related website or media in fighting this widespread contagious disease.

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

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

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