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

Malaria, Cerebral Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01388842
• Other study ID #: Epicentre/MBA/2011/NO
• Status: Completed
• Phase: Phase 2
• First received: November 23, 2010
• Last updated: February 29, 2016
• Start date: September 2011
• Est. completion date: February 2014

Study information

• Verified date: February 2016
• Source: Epicentre
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Committee for the Protection of PersonnesUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 92
• Est. completion date: February 2014
• Est. primary completion date: February 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Months to 12 Years

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:

• 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;

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Malaria
• Malaria, Cerebral

Intervention

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.
• 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.

Locations

Country	Name	City	State
Uganda	Mbarara Regional Referral Hospital	Mbarara

Sponsors (5)

Lead Sponsor	Collaborator
Epicentre	Harvard Medical School, Massachusetts General Hospital, Mbarara University of Science and Technology, Medecins Sans Frontieres

Country where clinical trial is conducted

Uganda, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Angiopoietin 1 (Ang-1)	Increase in Ang-1 between inclusion and 48 hours of combined therapy (iNO or placebo plus antimalarial chemotherapy)	48 hours	No
Secondary	Mortality	Reduction in mortality at 48 hours	48 hours	No
Secondary	coma score	normalisation of coma score (Blantyre coma scale)	48 hours	No
Secondary	retinopathy	Normalisation of malaria retinopathy measured by indirect fundoscopy	every 6 hours	No
Secondary	tone	Improvement of posture and tone	48 hours	No
Secondary	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.	months 1, 3 and 6	No
Secondary	Vital signs	Improvement of vital signs: Systolic and diastolic blood pressure, pulse rate, temperature	every 6 hours	Yes
Secondary	oxygen saturation	Both Hb Oxygen saturation (SpO2) and total MetHb levels continuously measured by pulse oximetry (Rascal Model 7, Massimo Corp.)	every 6 hours	Yes