Malaria, CerebralPhase 1/2NCT05478720
DON in Pediatric Cerebral Malaria
A Phase 1/2 study testing 6-diazo-5-oxo-L-norleucine (DON) in people with Malaria, Cerebral, run by Douglas Postels, MD, MS at 2 sites in Malawi.
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 12 months-14 years old with clinically defined Cerebral Malaria. Read more about this study
- Who is it for?
- Ages 12 months to 14 years
- Conditions the study is for
- Malaria, Cerebral
- What is being tested?
- 6-diazo-5-oxo-L-norleucine (DON)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 152 participants
- Where
- 2 sitesMalawi
- Study dates
- 16 Aug 2022to 30 Nov 2028
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 months to 14 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- For Healthy Adults (Part 1):
- 18 years and older
- Informed consent obtained and ICF signed
- Temperature ≤ 37.5 °C
- BMI 18.5-25 kg/m2
- Creatinine ≤ 110 mmol/L (≤ 1.2 mg/dL; males) or ≤ 90 mmol/L (≤ 1.0 mg/dL; females)
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- Hemoglobin ≥ 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 child-bearing potential
- 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
- Aspartate aminotransferase (AST) < 280 IU/L
- Alanine aminotransferase (ALT) < 195 IU/L
Who cannot join
- 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
- Allergy to ondansetron or ceftriaxone
- Additional Exclusion Criteria for Children with Cerebral Malaria (Part 2):
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- 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 CYP3A4 inhibitor within 7 days of enrollment
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Malawi2 sites, 1 recruiting
- Completed
Ndirande Research Clinic
Blantyre
- Recruiting
Queen Elizabeth Central Hospital
Blantyre
Yamikani Chimalizeni, MD, +265 992 23 32 21, ychimalizeni@medcol.mw
Douglas Postels, MD, +265 995 83 32 73, dpostels@childrensnational.org
About this study
Official title: DON in Pediatric Cerebral Malaria: A Phase I/IIa Dose-Escalation Safety Study
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
Read more
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.
- Conditions
- Malaria, Cerebral
- Being tested
- 6-diazo-5-oxo-L-norleucine (DON), Placebo
- Keywords
- malaria, Plasmodium falciparum
- Medical subject headings
- Malaria, Cerebral, Malaria, Malaria, Falciparum
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
6-diazo-5-oxo-L-norleucine (DON)Drug
Also called NSC 7365
Single intravenous dose ranging from 0.1-10 mg/kg per dose
PlaceboDrug
Also called Saline
Single intravenous dose of saline
6-diazo-5-oxo-L-norleucine (DON)Drug
Also called NSC 7365
Single intravenous dose ranging from 0.1-1.0 mg/kg per dose
| Study group | Role | What they receive |
|---|---|---|
| Dose escalation in healthy Malawian adults - 0.1 mg/kg IV DON | Experimental | 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. Receives: Drug: 6-diazo-5-oxo-L-norleucine (DON) |
| Dose escalation in healthy Malawian adults - 1.0 mg/kg IV DON | Experimental | 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. Receives: Drug: 6-diazo-5-oxo-L-norleucine (DON) |
| Dose escalation in healthy Malawian adults - 5.0 mg/kg IV DON | Experimental | 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. Receives: Drug: 6-diazo-5-oxo-L-norleucine (DON) |
| Dose escalation in healthy Malawian adults - 10.0 mg/kg IV DON | Experimental | 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. Receives: Drug: 6-diazo-5-oxo-L-norleucine (DON) |
| Dose escalation in Malawian adults with uncomplicated malaria - 0.1 mg/kg IV DON | Experimental | 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. Receives: Drug: 6-diazo-5-oxo-L-norleucine (DON) |
| Dose escalation in Malawian adults with uncomplicated malaria - 1.0 mg/kg IV DON | Experimental | 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. Receives: Drug: 6-diazo-5-oxo-L-norleucine (DON) |
| Dose escalation in Malawian adults with uncomplicated malaria - 5.0 mg/kg IV DON | Experimental | 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. Receives: Drug: 6-diazo-5-oxo-L-norleucine (DON) |
| Dose escalation in Malawian adults with uncomplicated malaria - 10.0 mg/kg IV DON | Experimental | 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. Receives: Drug: 6-diazo-5-oxo-L-norleucine (DON) |
| Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 1 | Experimental | 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. Receives: Drug: 6-diazo-5-oxo-L-norleucine (DON) |
| Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 2 | Experimental | 10 participants will receive 0.1 mg/kg IV DON, and 2 will receive placebo. Receives: Drug: 6-diazo-5-oxo-L-norleucine (DON) |
| Dose escalation in Malawian children with cerebral malaria - 1.0 mg/kg IV DON - Cohort 3 | Experimental | 14 participants will receive 1.0 mg/kg IV DON, and 4 will receive placebo. Receives: Drug: 6-diazo-5-oxo-L-norleucine (DON) |
| Dose escalation in Malawian children with cerebral malaria - 0.1 or 1.0 mg/kg IV DON - Cohort 4 | Experimental | 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. Receives: Drug: 6-diazo-5-oxo-L-norleucine (DON) |
| Dose escalation in Malawian children with cerebral malaria - placebo | Placebo comparator | 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 Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of local AEs occurring within 14 days after the administration of DON
Number of AEs
Measured: 14 days
Incidence of systemic AEs occurring within 14 days after the administration of DON
Number of AEs
Measured: 14 days
Incidence of systemic SAEs occurring within 14 days after the administration of DON
Number of SAEs - pediatric arms only
Measured: 14 days
Assessment of Blantyre Coma Score
Time to Blantyre Coma Score of 5
Measured: 14 days
Secondary outcomes (8)
PK measurement of DON in sera of recipients measured by half life
Measurement of half life
Measured: Measured through 18 hours post infusion
PK measurement of DON in sera of recipients measured by volume of distribution
Measurement of Vd
Measured: Measured through 18 hours post infusion
PK measurement of DON in sera of recipients measure by maximum concentration (Cmax)
Measurement of Cmax
Measured: Measured through 18 hours post infusion
PK measurement of DON in sera of recipients measure by time of maximal concentration (Tmax)
Measurement of Tmax
Measured: Measured through 18 hours post infusion
PK measurement of DON in sera of recipients measure by area under the concentrations vs. time curve (AUC)
Measurement of AUC
Measured: Measured through 18 hours post infusion
PK measurement of DON in sera of recipients measure by clearance
Clearance measured over time
Measured: Measured through 18 hours post infusion
PK measurement of DON in sera of recipients measure by elimination rate
Elimination over time
Measured: Measured through 18 hours post infusion
PK measurement of DON in sera of recipients measure by terminal T1/2
Measurement of terminal T1/2
Measured: Measured through 18 hours post infusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jul 2022
- Study start16 Aug 2022
- Primary completion30 Nov 2028 (estimated)
- Study completion30 Nov 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Malaria, CerebralStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Model description
- Part 1: Adult groups Healthy / Uncomplicated Malaria - Groups of 10 adult participants will be enrolled sequentially, with safety assessment and dose escalation for each group if safety criteria are satisfied in the previous group. Pediatric Arm: Enrollment of pediatric participants will begin if safety criteria are satisfied in adults previously enrolled. The pediatric study will be randomized and placebo-controlled with DON or Placebo doses added to standard of care therapy. Interim assessments are planned to determine dosing for subsequent participants.
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 152 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Douglas Postels, MD, MS
- Responsible party
- Principal investigator, Douglas Postels, Children's National Research Institute
- Investigators
- Douglas Postels, MD, Principal investigator, Children's National Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05478720
- Sponsor's protocol ID
- 21/04/2676
- Other IDs
- PAR-18-633, PAR-25-305, 21-0005
- Status last verified
- Oct 2026
- First submitted
- 26 Jul 2022
- Last updated
- 23 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
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 41748157Nampota-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
Study at a glance
From the registry record, last updated by the sponsor on 23 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- DON in Pediatric Cerebral Malaria: A Phase I/IIa Dose-Escalation Safety Study
- ClinicalTrials.gov ID
- NCT05478720
- Acronym / sponsor ID
- 21/04/2676
- Conditions
- Malaria, Cerebral
- Keywords
- malaria, Plasmodium falciparum
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 152 participants (estimated)
- Lead sponsor
- Douglas Postels, MD, MS
- Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID)
- Study start
- 16 Aug 2022 (actual)
- Primary completion
- 30 Nov 2028 (estimated)
- Study completion
- 30 Nov 2028 (estimated)
- First posted
- 28 Jul 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- Single blind (participant)
- Number of arms
- 13
- Model description
- Part 1: Adult groups Healthy / Uncomplicated Malaria - Groups of 10 adult participants will be enrolled sequentially, with safety assessment and dose escalation for each group if safety criteria are satisfied in the previous group. Pediatric Arm: Enrollment of pediatric participants will begin if safety criteria are satisfied in adults previously enrolled. The pediatric study will be randomized and placebo-controlled with DON or Placebo doses added to standard of care therapy. Interim assessments are planned to determine dosing for subsequent participants.
| Arm | Type | Receives |
|---|---|---|
| Dose escalation in healthy Malawian adults - 0.1 mg/kg IV DON | Experimental | Drug: 6-diazo-5-oxo-L-norleucine (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. |
| Dose escalation in healthy Malawian adults - 1.0 mg/kg IV DON | Experimental | Drug: 6-diazo-5-oxo-L-norleucine (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. |
| Dose escalation in healthy Malawian adults - 5.0 mg/kg IV DON | Experimental | Drug: 6-diazo-5-oxo-L-norleucine (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. |
| Dose escalation in healthy Malawian adults - 10.0 mg/kg IV DON | Experimental | Drug: 6-diazo-5-oxo-L-norleucine (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. |
| Dose escalation in Malawian adults with uncomplicated malaria - 0.1 mg/kg IV DON | Experimental | Drug: 6-diazo-5-oxo-L-norleucine (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. |
| Dose escalation in Malawian adults with uncomplicated malaria - 1.0 mg/kg IV DON | Experimental | Drug: 6-diazo-5-oxo-L-norleucine (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. |
| Dose escalation in Malawian adults with uncomplicated malaria - 5.0 mg/kg IV DON | Experimental | Drug: 6-diazo-5-oxo-L-norleucine (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. |
| Dose escalation in Malawian adults with uncomplicated malaria - 10.0 mg/kg IV DON | Experimental | Drug: 6-diazo-5-oxo-L-norleucine (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. |
| Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 1 | Experimental | Drug: 6-diazo-5-oxo-L-norleucine (DON)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. |
| Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 2 | Experimental | Drug: 6-diazo-5-oxo-L-norleucine (DON)10 participants will receive 0.1 mg/kg IV DON, and 2 will receive placebo. |
| Dose escalation in Malawian children with cerebral malaria - 1.0 mg/kg IV DON - Cohort 3 | Experimental | Drug: 6-diazo-5-oxo-L-norleucine (DON)14 participants will receive 1.0 mg/kg IV DON, and 4 will receive placebo. |
| Dose escalation in Malawian children with cerebral malaria - 0.1 or 1.0 mg/kg IV DON - Cohort 4 | Experimental | Drug: 6-diazo-5-oxo-L-norleucine (DON)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. |
| Dose escalation in Malawian children with cerebral malaria - placebo | Placebo comparator | Drug: PlaceboCohort 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 |
Who may qualify
- Ages
- 12 months to 14 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (33 listed)
- 18 years and older
- Informed consent obtained and ICF signed
- Temperature ≤ 37.5 °C
- BMI 18.5-25 kg/m2
- Creatinine ≤ 110 mmol/L (≤ 1.2 mg/dL; males) or ≤ 90 mmol/L (≤ 1.0 mg/dL; females)
Key exclusion criteria (11 listed)
- 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
- Allergy to ondansetron or ceftriaxone
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 6-diazo-5-oxo-L-norleucine (DON)Also: NSC 7365Single intravenous dose ranging from 0.1-10 mg/kg per dose | Drug | Dose escalation in Malawian adults with uncomplicated malaria - 0.1 mg/kg IV DON, Dose escalation in Malawian adults with uncomplicated malaria - 1.0 mg/kg IV DON, Dose escalation in Malawian adults with uncomplicated malaria - 10.0 mg/kg IV DON, Dose escalation in Malawian adults with uncomplicated malaria - 5.0 mg/kg IV DON, Dose escalation in healthy Malawian adults - 0.1 mg/kg IV DON, Dose escalation in healthy Malawian adults - 1.0 mg/kg IV DON, Dose escalation in healthy Malawian adults - 10.0 mg/kg IV DON, Dose escalation in healthy Malawian adults - 5.0 mg/kg IV DON |
| PlaceboAlso: SalineSingle intravenous dose of saline | Drug | Dose escalation in Malawian children with cerebral malaria - placebo |
| 6-diazo-5-oxo-L-norleucine (DON)Also: NSC 7365Single intravenous dose ranging from 0.1-1.0 mg/kg per dose | Drug | Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 1, Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 2, Dose escalation in Malawian children with cerebral malaria - 0.1 or 1.0 mg/kg IV DON - Cohort 4, Dose escalation in Malawian children with cerebral malaria - 1.0 mg/kg IV DON - Cohort 3 |
Primary outcome
Incidence of local AEs occurring within 14 days after the administration of DON
Time frame: 14 days
Number of AEs
Incidence of systemic AEs occurring within 14 days after the administration of DON
Time frame: 14 days
Number of AEs
Incidence of systemic SAEs occurring within 14 days after the administration of DON
Time frame: 14 days
Number of SAEs - pediatric arms only
Assessment of Blantyre Coma Score
Time frame: 14 days
Time to Blantyre Coma Score of 5
8 secondary outcomes
PK measurement of DON in sera of recipients measured by half life
Time frame: Measured through 18 hours post infusion
PK measurement of DON in sera of recipients measured by volume of distribution
Time frame: Measured through 18 hours post infusion
PK measurement of DON in sera of recipients measure by maximum concentration (Cmax)
Time frame: Measured through 18 hours post infusion
PK measurement of DON in sera of recipients measure by time of maximal concentration (Tmax)
Time frame: Measured through 18 hours post infusion
PK measurement of DON in sera of recipients measure by area under the concentrations vs. time curve (AUC)
Time frame: Measured through 18 hours post infusion
PK measurement of DON in sera of recipients measure by clearance
Time frame: Measured through 18 hours post infusion
PK measurement of DON in sera of recipients measure by elimination rate
Time frame: Measured through 18 hours post infusion
PK measurement of DON in sera of recipients measure by terminal T1/2
Time frame: Measured through 18 hours post infusion
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Oct 2026.
- Results publication: PubMed 41748157Riggle 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.
- Derived from this study: PubMed 38279124Nampota-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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Douglas Postels, MD principal investigator
Children's National Research Institute
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing 6-diazo-5-oxo-L-norleucine (DON) in people with Malaria, Cerebral, run by Douglas Postels, MD, MS at 2 sites in Malawi.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 33 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 23 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Malawi. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Yamikani Chimalizeni, MD (+265 992 23 32 21, ychimalizeni@medcol.mw), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of local AEs occurring within 14 days after the administration of DON (time frame: 14 days). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05478720, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Oct 2026.