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

• Mortality [ Time Frame: 48 hours ] [ Designated as safety issue: No ]
  Reduction in mortality at 48 hours
• coma score [ Time Frame: 48 hours ] [ Designated as safety issue: No ]
  normalisation of coma score (Blantyre coma scale)
• retinopathy [ Time Frame: every 6 hours ] [ Designated as safety issue: No ]
  Normalisation of malaria retinopathy measured by indirect fundoscopy
• tone [ Time Frame: 48 hours ] [ Designated as safety issue: No ]
  Improvement of posture and tone
• Measure of occurrence of neurological sequelae in children [ Time Frame: months 1, 3 and 6 ] [ Designated as safety issue: No ]
  Reduction of incidence of neurological sequelae, including motor dysfunction, behavioral disorders, hearing, speech and sight disorders and seizure disorders.
• Vital signs [ Time Frame: every 6 hours ] [ Designated as safety issue: Yes ]
  Improvement of vital signs: Systolic and diastolic blood pressure, pulse rate, temperature
• oxygen saturation [ Time Frame: every 6 hours ] [ Designated as safety issue: Yes ]
  Both Hb Oxygen saturation (SpO2) and total MetHb levels continuously measured by pulse oximetry (Rascal Model 7, Massimo Corp.)

• Mortality [ Time Frame: 48 hours ] [ Designated as safety issue: No ]
  Reduction in mortality at 48 hours
• coma score [ Time Frame: 48 hours ] [ Designated as safety issue: No ]
  normalisation of coma score (Blantyre coma scale)
• retinopathy [ Time Frame: every 6 hours ] [ Designated as safety issue: No ]
  Normalisation of malaria retinopathy measured by indirect fundoscopy
• tone [ Time Frame: 48 hours ] [ Designated as safety issue: No ]
  Improvement of posture and tone
• neurological sequelae [ Time Frame: months 1, 3 and 6 ] [ Designated as safety issue: No ]
  Reduction of incidence of neurological sequelae, including motor dysfunction, behavioral disorders, hearing, speech and sight disorders and seizure disorders.
• Vital signs [ Time Frame: every 6 hours ] [ Designated as safety issue: Yes ]
  Improvement of vital signs: Systolic and diastolic blood pressure, pulse rate, temperature
• oxygen saturation [ Time Frame: every 6 hours ] [ Designated as safety issue: Yes ]
  Both Hb Oxygen saturation (SpO2) and total MetHb levels continuously measured by pulse oximetry (Rascal Model 7, Massimo Corp.)

Primary objective:

To assess the efficacy of inhaled Nitric Oxide (iNO) as adjunctive treatment in cerebral malaria in children aged between 2 months and 12 years.

Main Secondary objectives:

• To determine the effect of iNO on long term neurological sequelae
• To determine the optimal duration of iNO therapy in children with severe malaria
• To determine the effects of iNO on circulating inflammatory biomarkers of severe malaria (Tumor Necrosis Factor, Interleukine IL6, Angiopoietin 1 and 2)
• To assess the safety of iNO as an adjunctive treatment in cerebral malaria

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.

• 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.
• Drug: Placebo

• 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.
  Intervention: Drug: Placebo
• 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.
  Intervention: Drug: inhaled nitric oxide

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;

• Mbarara University of Science and Technology
• Massachusetts General Hospital
• Harvard University
• Medecins Sans Frontieres