DON in Pediatric Cerebral Malaria

Malaria, Cerebral Clinical Trial

Official title: DON in Pediatric Cerebral Malaria: A Phase I/IIa Dose-Escalation Safety Study

Status Recruiting

Clinical Trial Summary

The goal of this clinical trial is to evaluate the safety of a single intravenous dose of DON in healthy adults, adults with uncomplicated malaria, and children 6 months-14 years old with clinically defined Cerebral Malaria. The main objectives are:

• Determine the pharmacokinetic (PK) profile of a single dose of DON in children with CM

• Determine if administration of a single intravenous dose of DON as an adjunctive therapy in children with CM is associated with improved intracerebral blood flow dynamics on transcranial doppler (TCD)

• Determine if administration of a single intravenous dose of DON as an adjunctive therapy in children with CM is associated with a reduction in brain volume score on magnetic resonance imaging (MRI)

• Determine if administration of a single intravenous dose of DON as an adjunctive therapy in children with cerebral malaria is associated with changes in electroencephalogram (EEG) pattern

• Exploratory: Explore the metabolic mechanisms of action of adjunctive DON in children with CM

Healthy adult participants will receive:

• anti-emetic ondansetron

• one dose of DON

Adults with uncomplicated malaria will receive:

• anti-emetic ondansetron

• one dose of DON

• artemisinin-combination therapies per Malawi Ministry of Health guidelines

Pediatric participants will receive:

• one dose of DON

• anti-emetic ondansetron and per Malawi Ministry of Health guidelines

• enteral lumefantrine therapy, and

• artesunate therapy

Clinical Trial Description

The initial study to be conducted under this IND is a 2 part dose escalation study. The first part contains 2 groups that will be open-label, dose escalation, and will define the safety of 6-diazo-5-oxo-L-norleucine (DON) in African adults (>18 years old), who are healthy or who have uncomplicated malaria.

Each of the two adult groups will enroll 40 participants broken down into 4 dosage groups with safety evaluations before each dose increase. The first 10 participants enrolled will receive 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, the dose will be increased to 1.0 mg/kg IV DON, and then 5.0 mg/kg IV DON, and then the final group will receive 10.0 mg/kg IV DON. Each adult dosage group contains 10 healthy participants and 10 participants with uncomplicated malaria. The total number of adult participants enrolled is 80 (20 participants at 4 doses). All participants will receive only one dose of DON.

Adult participants will receive a premedication dose of the antiemetic ondansetron, 5 mg IV, administered 30 minutes prior to DON, and repeated 8 and 16 hours later. The duration of study participation for all adult participants is six months.

Part 2 of the study will be a randomized, placebo-controlled, dose-escalation study in children ages 6 months to 14 years with cerebral malaria to determine safety. Pediatric enrollments will span three malaria seasons, which will be carried out in Study Years 3-5, with a planned interim analysis after cohort 3. In cohort 1 we will first enroll 6 sentinel pediatric participants who will receive intravenous artesunate therapy, enteral lumefantrine therapy, and either adjunctive DON 0.1 mg/kg or placebo randomized 2:1). Cohort 2 will enroll 12 participants who will receive intravenous artesunate therapy, enteral lumefantrine therapy, and either adjunctive DON 0.1 mg/kg or placebo randomized 5:1.Cohort 3 will enroll 18 participants who will receive intravenous artesunate therapy, enteral lumefantrine therapy, and either adjunctive DON 1.0 mg/kg or placebo randomized 7:1. If DON has a promising risk-benefit profile, the study will continue to cohort 4 (n=36) with similar or higher doses of DON (up to 1 mg/kg) or placebo in combination with IV artesunate, and enteral lumefantrine therapy. Pediatric participation in the study will be 6 months. ;

Related Conditions & MeSH terms

• Malaria
• Malaria, Cerebral

• NCT number: NCT05478720
• Study type: Interventional
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: Jane Mallewa, MD
• Phone: +265 993 71 12 74
• Email: jmallewa@medcol.mw
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: August 16, 2022
• Completion date: December 2025