Health Trials

DON in Pediatric Cerebral Malaria

ConditionMalaria, Cerebral
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age12+
SponsorDouglas Postels, MD, MS

About this trial

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 12 months-14 years old with clinically defined Cerebral Malaria. The main objectives are:

* Evaluate the safety of a single intravenous dose of DON in healthy adults and adults with uncomplicated malaria ( Part 1) * Determine the safety of a single dose of DON in children 12 months-14 years old with World Health Organization (WHO) clinically defined CM (Part 2 :Cohort 1-4) * Determine the pharmacokinetic (PK) profile of a single dose of DON in healthy adults, adults with uncomplicated malaria and children with CM (Part 1, and Cohorts 1-4 of Part 2) * 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) (Part 2 :Cohort 1-4) * 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) (Part 2 :Cohort 1-4) * 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 (Part 2 :Cohort 1-4) * 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-artemether therapy, and * artesunate therapy

Eligibility criteria

This trial accepts healthy volunteers

Qualifiers

18 years and older

Informed consent obtained and ICF signed

Temperature ≤ 37.5 °C

BMI 18.5-25 kg/m2

Disqualifiers

Pregnancy or lactation (participants of child-bearing potential ages 9-59 years will undergo pregnancy testing prior to administration of the intervention)

Participants attempting to become pregnant

Currently taking highly active antiretroviral therapy (HAART)

Currently taking anti-tuberculosis medications

Trial design

Design model

Sequential

Treatments tested in this trial

  • 6-diazo-5-oxo-L-norleucine (DON)

    Drug

    Single intravenous dose ranging from 0.1-10 mg/kg per dose

  • Placebo

    Drug

    Single intravenous dose of saline

  • 6-diazo-5-oxo-L-norleucine (DON)

    Drug

    Single intravenous dose ranging from 0.1-1.0 mg/kg per dose

Treatment groups

152 Participants
are divided into 13 treatment groups

13

Treatment groups

See each treatment group below.

Group A: Dose escalation in healthy Malawian adults - 0.1 mg/kg IV DONExperimental treatment 1 intervention
Group B: Dose escalation in healthy Malawian adults - 1.0 mg/kg IV DONExperimental treatment 1 intervention
Group C: Dose escalation in healthy Malawian adults - 5.0 mg/kg IV DONExperimental treatment 1 intervention
Group D: Dose escalation in healthy Malawian adults - 10.0 mg/kg IV DONExperimental treatment 1 intervention
Group E: Dose escalation in Malawian adults with uncomplicated malaria - 0.1 mg/kg IV DONExperimental treatment 1 intervention
Group F: Dose escalation in Malawian adults with uncomplicated malaria - 1.0 mg/kg IV DONExperimental treatment 1 intervention
Group G: Dose escalation in Malawian adults with uncomplicated malaria - 5.0 mg/kg IV DONExperimental treatment 1 intervention
Group H: Dose escalation in Malawian adults with uncomplicated malaria - 10.0 mg/kg IV DONExperimental treatment 1 intervention
Group I: Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 1Experimental treatment 1 intervention
Group J: Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 2Experimental treatment 1 intervention
Group K: Dose escalation in Malawian children with cerebral malaria - 1.0 mg/kg IV DON - Cohort 3Experimental treatment 1 intervention
Group L: Dose escalation in Malawian children with cerebral malaria - 0.1 or 1.0 mg/kg IV DON - Cohort 4Experimental treatment 1 intervention
Group M: Dose escalation in Malawian children with cerebral malaria - placeboPlacebo comparator 1 intervention

Trial outcomes

Primary outcomes

1

Incidence of local AEs occurring within 14 days after the administration of DON

Number of AEs

Time frame
14 days
2

Incidence of systemic AEs occurring within 14 days after the administration of DON

Number of AEs

Time frame
14 days
3

Incidence of systemic SAEs occurring within 14 days after the administration of DON

Number of SAEs - pediatric arms only

Time frame
14 days
4

Assessment of Blantyre Coma Score

Time to Blantyre Coma Score of 5

Time frame
14 days

Secondary outcomes

1

PK measurement of DON in sera of recipients measured by half life

Measurement of half life

Time frame
Measured through 18 hours post infusion
2

PK measurement of DON in sera of recipients measured by volume of distribution

Measurement of Vd

Time frame
Measured through 18 hours post infusion
3

PK measurement of DON in sera of recipients measure by maximum concentration (Cmax)

Measurement of Cmax

Time frame
Measured through 18 hours post infusion
4

PK measurement of DON in sera of recipients measure by time of maximal concentration (Tmax)

Measurement of Tmax

Time frame
Measured through 18 hours post infusion

Other outcomes

1

Pediatric participants: Brain volume score on MRI at admission and 24 hours (+/- 6 hours) post-randomization, if MRI is available

Detected by MRI

Time frame
Measured at baseline and 24 hours post randomization
2

Pediatric participants: Number of minutes of electrographic seizures within the first 12 hours after DON administration

Detected by continuous EEG monitoring

Time frame
Measured through 12 hours post infusion
3

Pediatric participants: EEG power analysis

Detected by 30 minute EEG samples analyzing power at baseline and 3, 6, and 12 hours post infusion

Time frame
Measured at baseline and through 12 hours post infusion
4

Pediatric participants: EEG amplitude analysis

Detected by 30 minute EEG samples analyzing amplitude at baseline and 3, 6, and 12 hours post infusion

Time frame
Measured at baseline and through 12 hours post infusion

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Douglas Postels, MD, MS

Lead sponsor

Children's National Research Institute

Sponsor institution

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborator

Source ClinicalTrials.gov
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