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

Phase 2

Completed

Brief Summary: 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.

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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Placebo	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.
inhaled nitric oxide	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.

Primary Outcome Measures

Name	Time	Method
Angiopoietin 1 (Ang-1)	48 hours	Increase in Ang-1 between inclusion and 48 hours of combined therapy (iNO or placebo plus antimalarial chemotherapy)

Secondary Outcome Measures

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