Role of Nitric Oxide in Malaria
|First Received Date ICMJE||September 7, 2007|
|Last Updated Date||March 31, 2015|
|Start Date ICMJE||September 2007|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE||Not Provided|
|Original Primary Outcome Measures ICMJE||Not Provided|
|Change History||Complete list of historical versions of study NCT00527163 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Role of Nitric Oxide in Malaria|
|Official Title ICMJE||Role of Nitric Oxide Scavenging by Plasma Hemoglobin and Identification of Hemolysis-Associated Pulmonary Hypertension in Malaria|
This study, conducted by NIH, the University of Bamako in Mali, Africa, and Tulane University will examine the relationships between hemolysis (breakdown of red blood cells), nitric oxide (a gas important in regulating blood vessel dilation and blood flow) and pulmonary hypertension in patients with malaria. Malaria is among the leading causes of death in many of the world s poorest countries. It is caused by a parasite that is transmitted to humans by mosquitoes.
Malian children ages 1-5 years are eligible for participation in this study. They include children with asymptomatic infection, uncomplicated disease, and severe disease. Uninfected controls are also included.
Upon enrollment, participants have a medical history and physical examination, echocardiogram (ultrasound test of heart function) and blood tests. In addition, all participants (infected children and controls) have repeat evaluations when healthy, approximately 7 to10 days following successful therapy.
Malaria is among the leading infectious causes of death in many of the world s poorest countries. This parasitic mosquito-borne illness produces massive hemolysis in many infected human hosts. While much is known about parasite replication and cytoadherence, very little is known about the impact of hemolysis per se on vascular tone and endothelial function. Crossing a number of medical disciplines beyond the scope of malaria, intriguing new research on inherited hemolytic disorders such as sickle cell disease (SCD) provides clues to pathogenic mechanisms that may be relevant to malaria. Dr. Gladwin (NHLBI) and colleagues have characterized a mechanism of disease, hemolysis-associated endothelial dysfunction, in which red blood cell hemoglobin spills into plasma and reacts with and oxidatively destroys nitric oxide (NO). Additionally, erythrocyte arginase I is released into plasma and catabolizes arginine, the substrate for endothelial NO synthesis. As a result, the profound reduction in NO bioavailability produces vasomotor instability, oxidant stress, inflammation, endothelial adhesion molecule expression, activation of tissue factor, and platelet aggregation. Consistent with shared mechanisms, these same pathways are found to be activated during malarial infection. Chronic hemolysis in hemoglobinopathies also leads to a disease syndrome, hemolysis associated pulmonary hypertension, which develops in all chronic hereditary and acquired hemolytic conditions and is associated with excessive morbidity and mortality. Despite the recent appreciation of these mechanisms, not one study can be found in the literature evaluating pulmonary hypertension in human malaria.
This protocol therefore aims to evaluate mechanisms governing interrelationships among malaria, intravascular hemolysis, NO bioavailability, endothelial function, pulmonary hypertension, and evolutionarily selected host polymorphisms that regulate the host response to hemolysis. We will correlate our clinical observations in the field with laboratory assays of hemolysis and nitric oxide bioavailability related to scavenging by cell-free hemoglobin and arginine catabolism. Using a candidate gene approach, we will identify and selectively characterize polymorphisms in genes important for endothelial function, vascular inflammation and disease phenotype. Finally, the characterization of this mechanism in malaria may catalyze the development of novel therapies targeting this pathway, such as sodium nitrite, inhaled nitric oxide gas, and/or recombinant haptoglobin infusions.
This international collaboration between scientists at the NIH, University of Bamako, and Tulane University will provide an exclusive opportunity for the rapid transfer of appropriate technology and expertise relevant to the provision of the highest quality care to malaria patients in Mali and the world.
|Study Type ICMJE||Observational|
|Study Design ICMJE||Time Perspective: Prospective|
|Target Follow-Up Duration||Not Provided|
|Sampling Method||Not Provided|
|Study Population||Not Provided|
|Intervention ICMJE||Not Provided|
|Study Group/Cohort (s)||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Estimated Enrollment ICMJE||650|
|Completion Date||March 2015|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
Malian children ages 1-5 years are eligible for participation in this study. We require a parent or legally authorized guardian to be present at enrollment to provide consent. Given the eligibility ages for children, incipient maturity and intelligence do not permit direct participant assent.
Inclusion criteria for Healthy Uninfected controls:
Inclusion criteria for Asymptomatic Parasitemia controls:
Inclusion criteria for Uncomplicated Malaria cases:
Inclusion criteria for Severe Malarial Anemia cases:
Exclusion criteria for Healthy Uninfected controls:
Exclusion criteria for Asymptomatic Parasitemia controls:
Exclusion criteria for Uncomplicated Malaria cases:
Exclusion criteria for Severe Malarial Anemia cases:
|Ages||1 Year to 5 Years (Child)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Mali|
|Removed Location Countries||United States|
|NCT Number ICMJE||NCT00527163|
|Other Study ID Numbers ICMJE||999907217, 07-H-N217|
|Has Data Monitoring Committee||Not Provided|
|Plan to Share Data||Not Provided|
|IPD Description||Not Provided|
|Responsible Party||National Heart, Lung, and Blood Institute (NHLBI)|
|Study Sponsor ICMJE||National Heart, Lung, and Blood Institute (NHLBI)|
|Collaborators ICMJE||Not Provided|
|Information Provided By||National Institutes of Health Clinical Center (CC)|
|Verification Date||March 2015|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP