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

Primary Purpose

Malaria, Cerebral

Status
Completed
Phase
Phase 2
Locations
Uganda
Study Type
Interventional
Intervention
inhaled nitric oxide
Placebo
Sponsored by
Epicentre
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malaria, Cerebral focused on measuring severe malaria, children, adjunctive treatment

Eligibility Criteria

2 Months - 12 Years (Child)All SexesDoes not accept healthy volunteers

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;

Sites / Locations

  • Mbarara Regional Referral Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

inhaled nitric oxide

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Mortality
Reduction in mortality at 48 hours
coma score
normalisation of coma score (Blantyre coma scale)
retinopathy
Normalisation of malaria retinopathy measured by indirect fundoscopy
tone
Improvement of posture and tone
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.
Vital signs
Improvement of vital signs: Systolic and diastolic blood pressure, pulse rate, temperature
oxygen saturation
Both Hb Oxygen saturation (SpO2) and total MetHb levels continuously measured by pulse oximetry (Rascal Model 7, Massimo Corp.)

Full Information

First Posted
November 23, 2010
Last Updated
February 29, 2016
Sponsor
Epicentre
Collaborators
Mbarara University of Science and Technology, Massachusetts General Hospital, Harvard Medical School (HMS and HSDM), Medecins Sans Frontieres, Netherlands
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1. Study Identification

Unique Protocol Identification Number
NCT01388842
Brief Title
Evaluation of the Efficacy and Safety of Inhaled Nitric Oxide as Adjunctive Treatment for Cerebral Malaria in Children
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
Study Type
Interventional

2. Study Status

Record Verification Date
February 2016
Overall Recruitment Status
Completed
Study Start Date
September 2011 (undefined)
Primary Completion Date
February 2014 (Actual)
Study Completion Date
February 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Epicentre
Collaborators
Mbarara University of Science and Technology, Massachusetts General Hospital, Harvard Medical School (HMS and HSDM), Medecins Sans Frontieres, Netherlands

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria, Cerebral
Keywords
severe malaria, children, adjunctive treatment

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
92 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
inhaled nitric oxide
Arm Type
Experimental
Arm Description
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 Type
Drug
Intervention Name(s)
inhaled nitric oxide
Other Intervention Name(s)
INOmax (nitric oxide) for inhalation
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Nitrogen in air
Intervention Description
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.
Primary Outcome Measure Information:
Title
Angiopoietin 1 (Ang-1)
Description
Increase in Ang-1 between inclusion and 48 hours of combined therapy (iNO or placebo plus antimalarial chemotherapy)
Time Frame
48 hours
Secondary Outcome Measure Information:
Title
Mortality
Description
Reduction in mortality at 48 hours
Time Frame
48 hours
Title
coma score
Description
normalisation of coma score (Blantyre coma scale)
Time Frame
48 hours
Title
retinopathy
Description
Normalisation of malaria retinopathy measured by indirect fundoscopy
Time Frame
every 6 hours
Title
tone
Description
Improvement of posture and tone
Time Frame
48 hours
Title
Measure of occurrence of neurological sequelae in children
Description
Reduction of incidence of neurological sequelae, including motor dysfunction, behavioral disorders, hearing, speech and sight disorders and seizure disorders.
Time Frame
months 1, 3 and 6
Title
Vital signs
Description
Improvement of vital signs: Systolic and diastolic blood pressure, pulse rate, temperature
Time Frame
every 6 hours
Title
oxygen saturation
Description
Both Hb Oxygen saturation (SpO2) and total MetHb levels continuously measured by pulse oximetry (Rascal Model 7, Massimo Corp.)
Time Frame
every 6 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Months
Maximum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility 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;
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Juliet Mwanga-Amumpaire, Dr
Organizational Affiliation
Epicentre
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mbarara Regional Referral Hospital
City
Mbarara
Country
Uganda

12. IPD Sharing Statement

Plan to Share IPD
No

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

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