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

Severe Malaria Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01255215
• Other study ID #: iNO RCT
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: December 5, 2010
• Last updated: February 19, 2014
• Start date: July 2011
• Est. completion date: January 2014

Study information

• Verified date: December 2012
• Source: University Health Network, Toronto
• Contact: n/a
• Is FDA regulated: No
• Health authority: Uganda: Makerere University Research and Ethics CommitteeUganda: Uganda National Council on Science and TechnologyUganda: National Drug AuthorityCanada: University Health Network Research Ethics Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 180
• Est. completion date: January 2014
• Est. primary completion date: July 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 10 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Malaria
• Severe Malaria

Intervention

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)

Locations

Country	Name	City	State
Uganda	Jinja Regional Referral Hospital	Jinja

Sponsors (3)

Lead Sponsor	Collaborator
University Health Network, Toronto	Makerere University, University of Toronto

Country where clinical trial is conducted

Uganda, 

References & Publications (9)

Davidson D, Barefield ES, Kattwinkel J, Dudell G, Damask M, Straube R, Rhines J, Chang CT. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose-respons — View Citation

Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, Davis K Jr, Hyers TM, Papadakos P. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide — View Citation

Dobyns EL, Cornfield DN, Anas NG, Fortenberry JD, Tasker RC, Lynch A, Liu P, Eells PL, Griebel J, Baier M, Kinsella JP, Abman SH. Multicenter randomized controlled trial of the effects of inhaled nitric oxide therapy on gas exchange in children with acute — View Citation

Gerlach H, Keh D, Semmerow A, Busch T, Lewandowski K, Pappert DM, Rossaint R, Falke KJ. Dose-response characteristics during long-term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, contr — View Citation

Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. The European Study Group of Inhaled Nitric Oxide. Intensive Care Med. 1999 Sep;25(9):911-9. — View Citation

Michael JR, Barton RG, Saffle JR, Mone M, Markewitz BA, Hillier K, Elstad MR, Campbell EJ, Troyer BE, Whatley RE, Liou TG, Samuelson WM, Carveth HJ, Hinson DM, Morris SE, Davis BL, Day RW. Inhaled nitric oxide versus conventional therapy: effect on oxygen — View Citation

Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med. 1997 Feb 27;336(9):597-604. Erratum in: N Engl J Med 1997 Aug 7;337(6):434. — View Citation

Taylor RW, Zimmerman JL, Dellinger RP, Straube RC, Criner GJ, Davis K Jr, Kelly KM, Smith TC, Small RJ; Inhaled Nitric Oxide in ARDS Study Group. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA. 2004 A — View Citation

Troncy E, Collet JP, Shapiro S, Guimond JG, Blair L, Ducruet T, Francoeur M, Charbonneau M, Blaise G. Inhaled nitric oxide in acute respiratory distress syndrome: a pilot randomized controlled study. Am J Respir Crit Care Med. 1998 May;157(5 Pt 1):1483-8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in serum angiopoietin-2 level	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	No
Secondary	Mortality		48 hours and 14 days after admission	Yes
Secondary	Time to hospital discharge	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	No
Secondary	Time to parasite clearance.	Parasitological efficacy outcome; quantitative assessment of parasite density by light microscopy of Giemsa-stained thin smears.	From admission to approximately 72 hours	No
Secondary	Biomarkers and genetic determinants of endothelial activation, inflammation and coagulopathy, to be determined.	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	No