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RecruitingNCT05478720Updated Oct 23, 2026

DON in Pediatric Cerebral Malaria

A Phase 1/2 interventional study of 6-diazo-5-oxo-L-norleucine (DON) and Placebo in Malaria, Cerebral, sponsored by Douglas Postels, MD, MS. Recruiting at 2 sites in Malawi. Open to participants aged 12 Months to 14 Years. Per ClinicalTrials.gov, last updated 2026-10-23.

Sponsored by Douglas Postels, MD, MS · Phase 1/2, Interventional, and Treatment

From the registry’s dates

  • Started Aug 2022; still recruiting 4 years 2 months later.
Updated Oct 23, 2026Primary completion movedStudy completion moved+1 moreGo to Updates ↓
Phase
Phase 1/2
Study type
Interventional
Enrollment
152
Allocation
Randomized
Ages
12 Months to 14 Years
Sex
All
01

Study 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 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
Read the detailed description

The initial study to be conducted under this IND is a 2-part dose escalation study. The first part (Adults) 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 (pediatric) of the study will be a randomized, placebo-controlled, dose-escalation study in children ages 12 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-artemether 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-artemether 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-artemether therapy, and either adjunctive DON 1.0 mg/kg or placebo randomized 7:1.

Cohort 4 will enroll 36 participants who will receive intravenous artesunate therapy, enteral lumefantrine-artemether therapy, and either adjunctive DON 0.1 mg/kg, DON 1.0 mg/kg or placebo randomized 1:1:1. Pediatric participation in the study will be 6 months.

02

Conditions studied

  • Malaria, Cerebral

Keywords

  • malaria
  • Plasmodium falciparum
03

In context

Malaria

1,184 studies on the registry are indexed under Malaria; 79 are open to participants now.

This study's planned enrollment of 152 is below the median of 252 across 937 interventional studies indexed under Malaria.

Browse Malaria studies →

Lead sponsor

This is the only study on the registry with Douglas Postels, MD, MS as lead sponsor.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
12 Months to 14 Years
Sexes eligible
All
Accepts healthy volunteers
No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

For Healthy Adults (Part 1):

  • 18 years and older
  • obtained and ICF signed
  • Temperature ≤ 37.5 °C
  • 18.5-25 kg/m2
  • Creatinine ≤ 110 mmol/L (≤ 1.2 mg/dL; males) or ≤ 90 mmol/L (≤ 1.0 mg/dL; females)
  • ≥ 7 g/dL or hematocrit/ packed-cell volume (PCV) ≥ 20%
  • Thick or thin blood smear negative for asexual forms of P. falciparum
  • Negative pregnancy test for persons of

For Adults with Uncomplicated Malaria (Part 1):

  • 18 years and older
  • Informed consent obtained and ICF signed
  • Temperature ≥ 38 °C or history of fever in the past 24 hours
  • Thick or thin blood smear positive for asexual forms of P. falciparum (parasite count and speciation documented)
  • Hemoglobin ≥ 7 g/dL or hematocrit/ PCV ≥ 20%
  • BMI 18.5-25 kg/m2
  • Creatinine ≤ 110 mmol/L (≤ 1.2 mg/dL; males) or ≤ 90 mmol/L (≤ 1.0 mg/dL; females)
  • Glasgow coma score of 15
  • Respiratory rate ≤ 20 breaths/ minute
  • Oxygen saturation ≥ 90% on room air
  • Negative pregnancy test for person of child-bearing potential

For Children with Cerebral Malaria (Part 2):

  • Age 12 months-14 years old
  • Informed consent obtained and ICF signed by parent or guardian
  • Temperature ≥ 38 °C or history of fever in the last 24 hours
  • Thick or thin blood smear positive for asexual forms of P. falciparum
  • Blantyre coma score ≤ 2
  • No other explanation for coma by history or physical exam
  • Hematocrit or PCV ≥ 18%
  • Negative pregnancy test for persons of child-bearing potential
  • Creatinine ≤ 1.5 mg/dL
  • (AST) \< 280 IU/L
  • Alanine aminotransferase (ALT) \< 195 IU/L

Exclusion criteria

Exclusion Criteria (All Participants):

  • Pregnancy or lactation (participants of 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
  • Allergy to ondansetron or ceftriaxone

Additional Exclusion Criteria for Children with Cerebral Malaria (Part 2):

  • Cloudy cerebrospinal fluid (indicative of a probable bacterial central nervous system infection)
  • Severe malnutrition (>3 standard deviations below the mean weight for height and/ or mid-upper arm circumference (MUAC) ≤11.5 cm
  • Allergy to ondansetron or ceftriaxone
  • Coma for > 72 hours
  • Have taken a inhibitor within 7 days of enrollment
Terms in these criteria, in plain language(6)

Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.

Informed consent

Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.

You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.

BMI (body mass index)

Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.

What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.

Hemoglobin (Hb)

The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).

Childbearing potential

Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).

Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.

ALT and AST (liver enzymes)

Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.

Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.

CYP3A (CYP3A4) inhibitors and inducers

CYP3A is a group of enzymes, mainly CYP3A4, in the liver and gut that break down many medicines. Some medicines, supplements and foods (grapefruit, St John’s wort) slow them down or speed them up, which changes how much of a study drug stays in the body.

Studies list them so they can be avoided or switched; bring a list of everything you take, including supplements.

05

Study design

Phase
Phase 1 / Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Sequential assignment
Masking
Single (Participant)
Enrollment
152 participants (estimated)

Study arms

  • Experimental
    Dose escalation in healthy Malawian adults - 0.1 mg/kg IV DON

    The first 10 healthy adult participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON the final group will receive 10.0 mg/kg IV DON.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)

  • Experimental
    Dose escalation in healthy Malawian adults - 1.0 mg/kg IV DON

    The first 10 healthy adult participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON the final group will receive 10.0 mg/kg IV DON.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)

  • Experimental
    Dose escalation in healthy Malawian adults - 5.0 mg/kg IV DON

    The first 10 healthy adult participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON the final group will receive 10.0 mg/kg IV DON.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)

  • Experimental
    Dose escalation in healthy Malawian adults - 10.0 mg/kg IV DON

    The first 10 healthy adult participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON the final group will receive 10.0 mg/kg IV DON.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)

  • Experimental
    Dose escalation in Malawian adults with uncomplicated malaria - 0.1 mg/kg IV DON

    The first 10 adults with uncomplicated malaria participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, 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.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)

  • Experimental
    Dose escalation in Malawian adults with uncomplicated malaria - 1.0 mg/kg IV DON

    The first 10 adults with uncomplicated malaria participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, 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.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)

  • Experimental
    Dose escalation in Malawian adults with uncomplicated malaria - 5.0 mg/kg IV DON

    The first 10 adults with uncomplicated malaria participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, 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.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)

  • Experimental
    Dose escalation in Malawian adults with uncomplicated malaria - 10.0 mg/kg IV DON

    The first 10 adults with uncomplicated malaria participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, 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.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)

  • Experimental
    Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 1

    After adult doses are shown to be safe. Of the first 6 children with cerebral malaria enrolled, 4 will receive 0.1 mg/kg IV DON, and 2 will receive placebo.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)

  • Experimental
    Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 2

    10 participants will receive 0.1 mg/kg IV DON, and 2 will receive placebo.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)

  • Experimental
    Dose escalation in Malawian children with cerebral malaria - 1.0 mg/kg IV DON - Cohort 3

    14 participants will receive 1.0 mg/kg IV DON, and 4 will receive placebo.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)

  • Experimental
    Dose escalation in Malawian children with cerebral malaria - 0.1 or 1.0 mg/kg IV DON - Cohort 4

    36 participants will receive 0.1 mg/kg IV DON (n=12) or 1.0 mg/kg IV DON (n=12), and 12 will receive placebo.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)

  • Placebo comparator
    Dose escalation in Malawian children with cerebral malaria - placebo

    Cohort 1 will dose 2 participants to receive placebo Cohort 2 will dose 2 participants to receive placebo Cohort 3 will dose 4 participants to receive placebo Cohort 4 will dose 12 participants to receive placebo

    Drug: Placebo

Interventions

  • Drug6-diazo-5-oxo-L-norleucine (DON)

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

    Also known as: NSC 7365

  • DrugPlacebo

    Single intravenous dose of saline

    Also known as: Saline

  • Drug6-diazo-5-oxo-L-norleucine (DON)

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

    Also known as: NSC 7365

06

What researchers measure

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

  5. PK measurement of DON in sera of recipients measure by area under the concentrations vs. time curve (AUC)

    Measurement of AUC

    Time frame: Measured through 18 hours post infusion

  6. PK measurement of DON in sera of recipients measure by clearance

    Clearance measured over time

    Time frame: Measured through 18 hours post infusion

  7. PK measurement of DON in sera of recipients measure by elimination rate

    Elimination over time

    Time frame: Measured through 18 hours post infusion

  8. PK measurement of DON in sera of recipients measure by terminal T1/2

    Measurement of terminal T1/2

    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

  5. Pediatric participants: EEG frequency analysis

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

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

  6. Pediatric participants: Transcranial Doppler (TCD) phenotype flow velocities

    Detected by TCD at 4H and 24H post infusion

    Time frame: Measured through 24 hours post infusion

  7. Pediatric participants: Cerebrospinal Fluid Metabolic Profile

    Detected by LP at baseline and 4H (+ or - 2H) post DON infusion

    Time frame: Measured through 4 hours post infusion

07

Study locations

1 of 2 sites recruiting
08

References and documents

Publications

  • Riggle BA, Chamzas A, Gopalakrishnan M, Nyirenda OM, Nampota-Nkomba N, Mallewa JE, Masonga R, Manyozo C, Zuze K, Liomba AM, Alt J, Rais R, Slusher B, Moodley N, Miller LH, Pierce SK, O'Brien NF, Laurens MB, Postels DG. Safety, Tolerability, and Pharmacokinetics of 6-Diazo-5-Oxo-L-Norleucine in Malawian Adults With and Without Malaria: A Phase 1 Dose-Escalation Clinical Trial. J Infect Dis. 2026 May 15;233(5):e1226-e1237. doi: 10.1093/infdis/jiag121. PubMed 41748157 ↗
  • Nampota-Nkomba N, Nyirenda OM, Mallewa J, Chimalizeni Y, Dzabala N, Fay MP, Gopalakrishnan M, Laurens MB, O'Brien NF, Miller LH, Pierce SK, Riggle BA, Postels DG. DON in pediatric cerebral malaria, a phase I/IIA dose-escalation safety study: study protocol for a clinical trial. Trials. 2024 Jan 26;25(1):87. doi: 10.1186/s13063-023-07808-w. PubMed 38279124 ↗

Individual participant data

Plan to share: No

09

Updates

1 registry update since Sep 25, 2026
Primary completion
Dec 2026→Nov 30, 2028
Oct 23, 2026
Study completion
Dec 2026→Nov 30, 2028
Oct 23, 2026
Eligibility
Maximum age none→14 Years
Oct 23, 2026
Show all 1 update
  1. Oct 23, 2026
    Primary completion Dec 2026→Nov 30, 2028
    Study completion Dec 2026→Nov 30, 2028
    Eligibility Maximum age none→14 Years
    + 2 other changes: verification date and design details

From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗

10

Registry details

Key details

Study ID
NCT05478720
Lead sponsor
Douglas Postels, MD, MS
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Responsible party
Douglas Postels (Professor of Pediatric Neurology, Children's National Research Institute) — Principal investigator
First posted
Jul 28, 2022
Start date
Aug 16, 2022
Primary completion
Nov 30, 2028 (estimated)
Completion
Nov 30, 2028 (estimated)
Last update
Oct 23, 2026

Study contacts

Yamikani Chimalizeni, MD
Contact
ychimalizeni@medcol.mw
+265 992 23 32 21
Alice Liomba
Contact
wanguialice@gmail.com
+265 888 36 57 58
Douglas Postels, MD
principal investigator · Children's National Research Institute

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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