Clinical trial NCT01255215: Inhaled Nitric Oxide for the Adjunctive Therapy of Severe Malaria: a Randomized Controlled Trial
Official title: Inhaled Nitric Oxide for the Adjunctive Therapy of Severe Malaria: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Severe Malaria
Keywords: malaria
children
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: Makerere University
name: University of Toronto
First posted: 2010-12-07
Enrollment: 180
Sex: ALL
Minimum age (years): 1
Maximum age (years): 10
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in serum angiopoietin-2 level
timeFrame: Admission through 72 hours
Secondary outcomes:
measure: Mortality
timeFrame: 48 hours and 14 days after admission
measure: Time to hospital discharge
timeFrame: From admission to approximately 72 hours
measure: Time to parasite clearance.
timeFrame: From admission to approximately 72 hours
measure: Biomarkers and genetic determinants of endothelial activation, inflammation and coagulopathy, to be determined.
timeFrame: From admission to approximately 72 hours
Other outcomes:
Locations:
city: Jinja
country: Uganda
facility: Jinja Regional Referral Hospital
Study officials:
affiliation: University of Toronto
name: Michael Hawkes, MD
role: STUDY_DIRECTOR
References:
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