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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2013 by Epicentre
Sponsor:
Collaborators:
Mbarara University of Science and Technology
Massachusetts General Hospital
Harvard University
Medecins Sans Frontieres
Information provided by (Responsible Party):
Epicentre
ClinicalTrials.gov Identifier:
NCT01388842
First received: November 23, 2010
Last updated: February 16, 2013
Last verified: February 2013
  Purpose

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

Condition Intervention Phase
Cerebral Malaria
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.)


Estimated Enrollment: 92
Study Start Date: September 2011
Estimated Study Completion Date: December 2013
Estimated Primary Completion Date: December 2013 (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
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.

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
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

Contacts
Contact: Juliet Mwanga, Dr juliet.mwanga@epicentre.msf.org

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

No publications provided

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 16, 2013
Health Authority: France: Committee for the Protection of Personnes
United States: Institutional Review Board

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
Malaria, Falciparum
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
Pharmacologic Actions
Anti-Asthmatic Agents
Respiratory System Agents
Therapeutic Uses
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Endothelium-Dependent Relaxing Factors
Vasodilator Agents
Cardiovascular Agents
Gasotransmitters
Protective Agents

ClinicalTrials.gov processed this record on October 02, 2014