Evaluation of the Efficacy and Safety of Inhaled Nitric Oxide as Adjunctive Treatment for Cerebral Malaria in Children

Evaluation of the Efficacy and Safety of Inhaled Nitric Oxide (iNO) as Adjunctive Treatment for Cerebral Malaria in Children: A Randomized Open Label Phase II Clinical Trial

The purpose of this study is to assess if adding inhaled Nitric Oxide to other malaria treatments can improve the outcome of cerebral malaria in children aged 2months to 12 years.

Study Overview

• Status: Completed
• Conditions: Malaria, Cerebral
• Intervention / Treatment: Drug: Placebo; Drug: inhaled nitric oxide

Detailed Description

Despite very effective antimalarial treatment, there is a residual and unacceptable high mortality rate of malaria, especially amongst young children. Recent progress has been made in understanding the role of Nitric Oxide (NO) in severe malaria, indicating that NO supplementation is likely to have a beneficial action in severe malaria possibly through down-regulation of inflammatory cytokines like TNF. Of the various ways to supplement NO, iNO appears to be the safest since it is very well studied in critically ill patients and does not cause systemic vasodilation. The safety of NO inhalation has been clearly demonstrated through its wide use in the treatment of persistent pulmonary hypertension in neonates and pulmonary hypertension in children and adults. Extensive data on its safety has been collected. This study is a phase 2 clinical trial that aims at demonstrating the efficacy of iNO when added to antimalarial treatment to treat cerebral malaria. This study will also provide a better understanding of the pathophysiological mechanisms involved in severe malaria.

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 2

Contacts and Locations

Study Locations

• Uganda
  • Mbarara, Uganda
    • Mbarara Regional Referral Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 months to 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age between 2 months and 12 years.
• With malaria infection confirmed by a malaria antigen test and/or a positive blood smear examination
• AND sustained coma: achieving a Blantyre Coma Score less than 3 for 2, or more, hours after ruling out and treating hypoglycemia (blood glucose less than 2.2 mmol/l), ruling out meningitis, and ruling out and treating active clinical seizures.

Exclusion Criteria:

• Refusal to participate
• Other cause of coma (toxic or pre-existing severe neurological disease)
• Terminal respiratory failure (due to brainstem coning)
• Coagulopathic
• Clinically unstable enough to preclude venipuncture and phlebotomy
• Severe malnutrition defined by edema or a weight-for-height minus 3 SD;
• Evidence of pre-existing brain injury
• Advanced AIDS defined by WHO clinical staging 4;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Controls will receive small pulses of placebo study drug via the INOpulse delivery system. Oxygen saturation will be maintained above 94% by adding oxygen to inspired gas via a loose fitting mask when necessary.	Drug: Placebo; The placebo will be administered using an INOpulse delivery system that delivers small pulses of study drug to the patient via a nasal cannula. Subjects randomized to the placebo arm will receive nitrogen in air for 24 hours per day for a minimum of two days and until clinical improvement (coma recovery), death or a maximum of 5 days.; Other Names: Nitrogen in air
Experimental: inhaled nitric oxide; Subjects randomized to the intervention arm will receive a dose equivalent to 80 ppm iNO in air using an INOpulse delivery system for 24 hours per day for a minimum of two days and until clinical improvement (coma recovery), death or a maximum of 5 days. Oxygen saturation will be maintained above 94% by adding oxygen to inspired gas via a loose fitting mask when necessary.	Drug: inhaled nitric oxide; Study drug will be administered using an INOpulse delivery system that delivers small pulses of study drug to the patient via a nasal cannula. Subjects randomized to the intervention arm will receive a dose equivalent to 80 ppm iNO in air for 24 hours per day for a minimum of two days and until clinical improvement (coma recovery), death or a maximum of 5 days.; Other Names: INOmax (nitric oxide) for inhalation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Angiopoietin 1 (Ang-1)	Increase in Ang-1 between inclusion and 48 hours of combined therapy (iNO or placebo plus antimalarial chemotherapy)	48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Reduction in mortality at 48 hours	48 hours
coma score	normalisation of coma score (Blantyre coma scale)	48 hours
retinopathy	Normalisation of malaria retinopathy measured by indirect fundoscopy	every 6 hours
tone	Improvement of posture and tone	48 hours
Measure of occurrence of neurological sequelae in children	Reduction of incidence of neurological sequelae, including motor dysfunction, behavioral disorders, hearing, speech and sight disorders and seizure disorders.	months 1, 3 and 6
Vital signs	Improvement of vital signs: Systolic and diastolic blood pressure, pulse rate, temperature	every 6 hours
oxygen saturation	Both Hb Oxygen saturation (SpO2) and total MetHb levels continuously measured by pulse oximetry (Rascal Model 7, Massimo Corp.)	every 6 hours

Collaborators and Investigators

• Sponsor: Epicentre
• Collaborators: Harvard Medical School (HMS and HSDM); Massachusetts General Hospital; Mbarara University of Science and Technology; Medecins Sans Frontieres, Netherlands
• Investigators: Principal Investigator: Juliet Mwanga-Amumpaire, Dr, Epicentre

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: November 23, 2010
• First Submitted That Met QC Criteria: July 5, 2011
• First Posted (Estimate): July 7, 2011

Study Record Updates

• Last Update Posted (Estimate): March 2, 2016
• Last Update Submitted That Met QC Criteria: February 29, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: children; adjunctive treatment; severe malaria
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Central Nervous System Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Central Nervous System Parasitic Infections; Central Nervous System Protozoal Infections; Malaria; Malaria, Cerebral; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Antioxidants; Free Radical Scavengers; Endothelium-Dependent Relaxing Factors; Gasotransmitters; Nitric Oxide
• Other Study ID Numbers: Epicentre/MBA/2011/NO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO