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

NCT01255215 | Completed Phase 1 DMC

• 1 other identifier: iNO RCT
• Study Type: interventional
• Target: 180
• Locations: 1 country
• Sites: 1

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.

Conditions

Severe Malaria

Keywords

malaria; children

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (4)

• Mortality

  48 hours and 14 days after admission

• Time to hospital discharge

  From admission to approximately 72 hours

• Time to parasite clearance.

  From admission to approximately 72 hours

• Biomarkers and genetic determinants of endothelial activation, inflammation and coagulopathy, to be determined.

  From admission to approximately 72 hours

Study Arms (2)

Inhaled Nitric Oxide

EXPERIMENTAL

iNO, a gaseous molecule, will be administered by inhalational route over a maximum period of 72 hours.

Drug: Inhaled Nitric Oxide

Room air

PLACEBO COMPARATOR

Room air will be delivered by air compressor through an indistinguishable mask system.

Drug: Inhaled Nitric Oxide

Interventions

Inhaled Nitric Oxide DRUG

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)

Also known as: NO, nitrogen monoxide

Inhaled Nitric Oxide; Room air

Eligibility Criteria

• Age: 1 Year - 10 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Health Network, Toronto: lead
• Makerere University: collaborator
• University of Toronto: collaborator

Study Sites (1)

Jinja Regional Referral Hospital

Jinja, Uganda

Location

Related Publications (15)

• 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. doi: 10.1056/NEJM199702273360901.

  PMID: 9036320 RESULT

• 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-response, multicenter study. The I-NO/PPHN Study Group. Pediatrics. 1998 Mar;101(3 Pt 1):325-34. doi: 10.1542/peds.101.3.325.

  PMID: 9480993 RESULT

• 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 hypoxemic respiratory failure. J Pediatr. 1999 Apr;134(4):406-12. doi: 10.1016/s0022-3476(99)70196-4.

  PMID: 10190913 RESULT

• 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 oxygenation in ARDS. Am J Respir Crit Care Med. 1998 May;157(5 Pt 1):1372-80. doi: 10.1164/ajrccm.157.5.96-10089.

  PMID: 9603111 RESULT

• 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 in ARDS Study Group. Crit Care Med. 1998 Jan;26(1):15-23. doi: 10.1097/00003246-199801000-00011.

  PMID: 9428538 RESULT

• 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. doi: 10.1164/ajrccm.157.5.9707090.

  PMID: 9603127 RESULT

• 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. doi: 10.1007/s001340050982.

  PMID: 10501745 RESULT

• 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, controlled study. Am J Respir Crit Care Med. 2003 Apr 1;167(7):1008-15. doi: 10.1164/rccm.2108121.

  PMID: 12663340 RESULT

• 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 Apr 7;291(13):1603-9. doi: 10.1001/jama.291.13.1603.

  PMID: 15069048 RESULT

• Conroy AL, Hawkes MT, Elphinstone R, Opoka RO, Namasopo S, Miller C, John CC, Kain KC. Chitinase-3-like 1 is a biomarker of acute kidney injury and mortality in paediatric severe malaria. Malar J. 2018 Feb 15;17(1):82. doi: 10.1186/s12936-018-2225-5.

  PMID: 29448936 DERIVED

• Bangirana P, Conroy AL, Opoka RO, Hawkes MT, Hermann L, Miller C, Namasopo S, Liles WC, John CC, Kain KC. Inhaled nitric oxide and cognition in pediatric severe malaria: A randomized double-blind placebo controlled trial. PLoS One. 2018 Jan 25;13(1):e0191550. doi: 10.1371/journal.pone.0191550. eCollection 2018.

  PMID: 29370261 DERIVED

• Conroy AL, Hawkes M, Hayford K, Hermann L, McDonald CR, Sharma S, Namasopo S, Opoka RO, John CC, Liles WC, Miller C, Kain KC. Methemoglobin and nitric oxide therapy in Ugandan children hospitalized for febrile illness: results from a prospective cohort study and randomized double-blind placebo-controlled trial. BMC Pediatr. 2016 Nov 4;16(1):177. doi: 10.1186/s12887-016-0719-2.

  PMID: 27814710 DERIVED

• Hawkes MT, Conroy AL, Opoka RO, Hermann L, Thorpe KE, McDonald C, Kim H, Higgins S, Namasopo S, John C, Miller C, Liles WC, Kain KC. Inhaled nitric oxide as adjunctive therapy for severe malaria: a randomized controlled trial. Malar J. 2015 Oct 29;14:421. doi: 10.1186/s12936-015-0946-2.

  PMID: 26510464 DERIVED

• Hawkes M, Opoka RO, Namasopo S, Miller C, Thorpe KE, Lavery JV, Conroy AL, Liles WC, John CC, Kain KC. Inhaled nitric oxide for the adjunctive therapy of severe malaria: protocol for a randomized controlled trial. Trials. 2011 Jul 13;12:176. doi: 10.1186/1745-6215-12-176.

  PMID: 21752262 DERIVED

• Hawkes M, Opoka RO, Namasopo S, Miller C, Conroy AL, Serghides L, Kim H, Thampi N, Liles WC, John CC, Kain KC. Nitric oxide for the adjunctive treatment of severe malaria: hypothesis and rationale. Med Hypotheses. 2011 Sep;77(3):437-44. doi: 10.1016/j.mehy.2011.06.003. Epub 2011 Jul 13.

  PMID: 21745716 DERIVED

MeSH Terms

Conditions

Malaria

Interventions

Nitric Oxide

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Reactive Nitrogen Species; Free Radicals; Inorganic Chemicals; Nitrogen Oxides; Nitrogen Compounds; Oxides; Oxygen Compounds; Organic Chemicals

Study Officials

• Michael Hawkes, MD

  University of Toronto

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 5, 2010
• First Posted: December 7, 2010
• Study Start: July 1, 2011
• Primary Completion: July 1, 2013
• Study Completion: January 1, 2014
• Last Updated: February 20, 2014

Record last verified: 2012-12

Locations

UG (1)