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

This study has been completed.
Sponsor:
Collaborators:
Mbarara University of Science and Technology
Massachusetts General Hospital
Harvard Medical School
Medecins Sans Frontieres, Netherlands
Information provided by (Responsible Party):
Epicentre
ClinicalTrials.gov Identifier:
NCT01388842
First received: November 23, 2010
Last updated: February 29, 2016
Last verified: February 2016
  Purpose
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.

Condition Intervention Phase
Malaria, Cerebral
Drug: inhaled nitric oxide
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Epicentre:

Primary Outcome Measures:
  • Angiopoietin 1 (Ang-1) [ Time Frame: 48 hours ] [ Designated as safety issue: No ]
    Increase in Ang-1 between inclusion and 48 hours of combined therapy (iNO or placebo plus antimalarial chemotherapy)


Secondary Outcome Measures:
  • 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.)


Enrollment: 92
Study Start Date: September 2011
Study Completion Date: February 2014
Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: INOmax (nitric oxide) for inhalation

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.
  Eligibility

Ages Eligible for Study:   2 Months to 12 Years   (Child)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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;
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01388842

Locations
Uganda
Mbarara Regional Referral Hospital
Mbarara, Uganda
Sponsors and Collaborators
Epicentre
Mbarara University of Science and Technology
Massachusetts General Hospital
Harvard Medical School
Medecins Sans Frontieres, Netherlands
Investigators
Principal Investigator: Juliet Mwanga-Amumpaire, Dr Epicentre
  More Information

Responsible Party: Epicentre
ClinicalTrials.gov Identifier: NCT01388842     History of Changes
Other Study ID Numbers: Epicentre/MBA/2011/NO 
Study First Received: November 23, 2010
Last Updated: February 29, 2016
Health Authority: France: Committee for the Protection of Personnes
United States: Institutional Review Board
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by Epicentre:
severe malaria
children
adjunctive treatment

Additional relevant MeSH terms:
Malaria
Malaria, Cerebral
Protozoan Infections
Parasitic Diseases
Central Nervous System Protozoal Infections
Central Nervous System Parasitic Infections
Central Nervous System Infections
Central Nervous System Diseases
Nervous System Diseases
Nitric Oxide
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Endothelium-Dependent Relaxing Factors
Vasodilator Agents
Gasotransmitters
Protective Agents

ClinicalTrials.gov processed this record on July 26, 2016