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

This study has been completed.
Sponsor:
Collaborators:
Makerere University
University of Toronto
Information provided by (Responsible Party):
University Health Network, Toronto
ClinicalTrials.gov Identifier:
NCT01255215
First received: December 5, 2010
Last updated: February 19, 2014
Last verified: December 2012
  Purpose

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.


Condition Intervention Phase
Severe Malaria
Drug: Inhaled Nitric Oxide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Inhaled Nitric Oxide for the Adjunctive Therapy of Severe Malaria: a Randomized Controlled Trial

Resource links provided by NLM:


Further study details as provided by University Health Network, Toronto:

Primary Outcome Measures:
  • Change in serum angiopoietin-2 level [ Time Frame: Admission through 72 hours ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Mortality [ Time Frame: 48 hours and 14 days after admission ] [ Designated as safety issue: Yes ]
  • Time to hospital discharge [ Time Frame: From admission to approximately 72 hours ] [ Designated as safety issue: No ]
    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.

  • Time to parasite clearance. [ Time Frame: From admission to approximately 72 hours ] [ Designated as safety issue: No ]
    Parasitological efficacy outcome; quantitative assessment of parasite density by light microscopy of Giemsa-stained thin smears.

  • Biomarkers and genetic determinants of endothelial activation, inflammation and coagulopathy, to be determined. [ Time Frame: From admission to approximately 72 hours ] [ Designated as safety issue: No ]
    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.


Enrollment: 180
Study Start Date: July 2011
Study Completion Date: January 2014
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: NO, nitrogen monoxide

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

Ages Eligible for Study:   1 Year to 10 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01255215

Locations
Uganda
Jinja Regional Referral Hospital
Jinja, Uganda
Sponsors and Collaborators
University Health Network, Toronto
Makerere University
University of Toronto
Investigators
Study Director: Michael Hawkes, MD University of Toronto
  More Information

Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: University Health Network, Toronto
ClinicalTrials.gov Identifier: NCT01255215     History of Changes
Other Study ID Numbers: iNO RCT
Study First Received: December 5, 2010
Last Updated: February 19, 2014
Health Authority: Uganda: Makerere University Research and Ethics Committee
Uganda: Uganda National Council on Science and Technology
Uganda: National Drug Authority
Canada: University Health Network Research Ethics Board

Keywords provided by University Health Network, Toronto:
malaria
children

Additional relevant MeSH terms:
Malaria
Protozoan Infections
Parasitic Diseases
Nitric Oxide
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Asthmatic Agents
Respiratory System Agents
Therapeutic Uses
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Endothelium-Dependent Relaxing Factors
Vasodilator Agents
Cardiovascular Agents
Gasotransmitters
Protective Agents

ClinicalTrials.gov processed this record on August 28, 2014