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

February 19, 2014 updated by: University Health Network, Toronto
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

180

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Uganda
      • Jinja, Uganda
        • Jinja Regional Referral Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 10 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Inhaled Nitric Oxide
iNO, a gaseous molecule, will be administered by inhalational route over a maximum period of 72 hours.
Drug: Inhaled Nitric Oxide
Form: Gas (inhalational) Dose: 80 ppm Dosing schedule: Continuous Treatment period: Maximum 72 hours (may be discontinued earlier if patient recovers and no longer tolerates face mask)
Other Names:
  • NO, nitrogen monoxide
Placebo Comparator: Room air
Room air will be delivered by air compressor through an indistinguishable mask system.
Drug: Inhaled Nitric Oxide
Form: Gas (inhalational) Dose: 80 ppm Dosing schedule: Continuous Treatment period: Maximum 72 hours (may be discontinued earlier if patient recovers and no longer tolerates face mask)
Other Names:
  • NO, nitrogen monoxide

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in serum angiopoietin-2 level
Time Frame: Admission through 72 hours
Daily Ang-2 measurements over the first 72 hours of hospital admission will be the primary efficacy outcome. Elevated Ang-2 levels are associated with poor clinical outcome in severe malaria and Ang-2 has been used to follow disease progression and recovery in previous studies of malaria. Thus, Ang-2 is an objective, quantitative surrogate marker of disease severity, validated for longitudinal follow-up of patients with malaria.
Admission through 72 hours

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mortality
Time Frame: 48 hours and 14 days after admission
48 hours and 14 days after admission
Time to hospital discharge
Time Frame: From admission to approximately 72 hours
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.
From admission to approximately 72 hours
Time to parasite clearance.
Time Frame: From admission to approximately 72 hours
Parasitological efficacy outcome; quantitative assessment of parasite density by light microscopy of Giemsa-stained thin smears.
From admission to approximately 72 hours
Biomarkers and genetic determinants of endothelial activation, inflammation and coagulopathy, to be determined.
Time Frame: From admission to approximately 72 hours
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.
From admission to approximately 72 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Health Network, Toronto

Collaborators

University of Toronto
Makerere University

Investigators

  • Study Director: Michael Hawkes, MD, University of Toronto

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2011

Primary Completion (Actual)

July 1, 2013

Study Completion (Actual)

January 1, 2014

Study Registration Dates

First Submitted

December 5, 2010

First Submitted That Met QC Criteria

December 5, 2010

First Posted (Estimate)

December 7, 2010

Study Record Updates

Last Update Posted (Estimate)

February 20, 2014

Last Update Submitted That Met QC Criteria

February 19, 2014

Last Verified

December 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • iNO RCT

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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