DON in Pediatric Cerebral Malaria

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:

• 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-artemether therapy, and
• artesunate therapy

Study Overview

• Status: Recruiting
• Conditions: Malaria, Cerebral
• Intervention / Treatment: Drug: 6-diazo-5-oxo-L-norleucine (DON); Drug: Placebo; Drug: 6-diazo-5-oxo-L-norleucine (DON)

Detailed 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 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 Type: Interventional
• Enrollment (Estimated): 152
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Yamikani Chimalizeni, MD; Phone Number: +265 992 23 32 21; Email: ychimalizeni@medcol.mw
• Study Contact Backup: Name: Alice Liomba; Phone Number: +265 888 36 57 58; Email: wanguialice@gmail.com

Study Locations

• Malawi
  • Blantyre, Malawi
    • Recruiting
    • Queen Elizabeth Central Hospital
    • Contact: Yamikani Chimalizeni, MD; Phone Number: +265 992 23 32 21; Email: ychimalizeni@medcol.mw
    • Contact: Douglas Postels, MD; Phone Number: +265 995 83 32 73; Email: dpostels@childrensnational.org
  • Blantyre, Malawi
    • Completed
    • Ndirande Research Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

For Healthy Adults (Arm 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)
• 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 (Arm 2):

• 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 (Arm 3):

• 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

Exclusion Criteria (All Participants):

• 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

Additional Exclusion Criteria for Children with Cerebral Malaria (Arm 3):

• Cloudy cerebrospinal fluid (indicative of a probable bacterial central nervous system infection)
• Malnutrition defined as a more than or equal to two standard deviations below the mean weight for height and/ or MUAC ≤ 12.5 cm (due to inability to adequately care for children with severe malnutrition on the PRW)
• Allergy to ondansetron or ceftriaxone
• Coma for > 72 hours
• Have taken a CYP3A4 inhibitor within 7 days of enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

13

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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); Single intravenous dose ranging from 0.1-10 mg/kg per dose; Other Names: NSC 7365; Drug: 6-diazo-5-oxo-L-norleucine (DON); Single intravenous dose ranging from 0.1-1.0 mg/kg per dose; Other Names: NSC 7365
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); Single intravenous dose ranging from 0.1-10 mg/kg per dose; Other Names: NSC 7365; Drug: 6-diazo-5-oxo-L-norleucine (DON); Single intravenous dose ranging from 0.1-1.0 mg/kg per dose; Other Names: NSC 7365
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); Single intravenous dose ranging from 0.1-10 mg/kg per dose; Other Names: NSC 7365; Drug: 6-diazo-5-oxo-L-norleucine (DON); Single intravenous dose ranging from 0.1-1.0 mg/kg per dose; Other Names: NSC 7365
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); Single intravenous dose ranging from 0.1-10 mg/kg per dose; Other Names: NSC 7365; Drug: 6-diazo-5-oxo-L-norleucine (DON); Single intravenous dose ranging from 0.1-1.0 mg/kg per dose; Other Names: NSC 7365
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); Single intravenous dose ranging from 0.1-10 mg/kg per dose; Other Names: NSC 7365; Drug: 6-diazo-5-oxo-L-norleucine (DON); Single intravenous dose ranging from 0.1-1.0 mg/kg per dose; Other Names: NSC 7365
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); Single intravenous dose ranging from 0.1-10 mg/kg per dose; Other Names: NSC 7365; Drug: 6-diazo-5-oxo-L-norleucine (DON); Single intravenous dose ranging from 0.1-1.0 mg/kg per dose; Other Names: NSC 7365
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); Single intravenous dose ranging from 0.1-10 mg/kg per dose; Other Names: NSC 7365; Drug: 6-diazo-5-oxo-L-norleucine (DON); Single intravenous dose ranging from 0.1-1.0 mg/kg per dose; Other Names: NSC 7365
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); Single intravenous dose ranging from 0.1-10 mg/kg per dose; Other Names: NSC 7365; Drug: 6-diazo-5-oxo-L-norleucine (DON); Single intravenous dose ranging from 0.1-1.0 mg/kg per dose; Other Names: NSC 7365
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); Single intravenous dose ranging from 0.1-10 mg/kg per dose; Other Names: NSC 7365; Drug: 6-diazo-5-oxo-L-norleucine (DON); Single intravenous dose ranging from 0.1-1.0 mg/kg per dose; Other Names: NSC 7365
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); Single intravenous dose ranging from 0.1-10 mg/kg per dose; Other Names: NSC 7365; Drug: 6-diazo-5-oxo-L-norleucine (DON); Single intravenous dose ranging from 0.1-1.0 mg/kg per dose; Other Names: NSC 7365
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); Single intravenous dose ranging from 0.1-10 mg/kg per dose; Other Names: NSC 7365; Drug: 6-diazo-5-oxo-L-norleucine (DON); Single intravenous dose ranging from 0.1-1.0 mg/kg per dose; Other Names: NSC 7365
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); Single intravenous dose ranging from 0.1-10 mg/kg per dose; Other Names: NSC 7365; Drug: 6-diazo-5-oxo-L-norleucine (DON); Single intravenous dose ranging from 0.1-1.0 mg/kg per dose; Other Names: NSC 7365
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; Single intravenous dose of saline; Other Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of local AEs occurring within 14 days after the administration of DON	Number of AEs	14 days
Incidence of systemic AEs occurring within 14 days after the administration of DON	Number of AEs	14 days
Incidence of systemic SAEs occurring within 14 days after the administration of DON	Number of SAEs - pediatric arms only	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK measurement of DON in sera of recipients measured by half life	Measurement of half life	Measured through 18 hours post infusion
PK measurement of DON in sera of recipients measured by volume of distribution	Measurement of Vd	Measured through 18 hours post infusion
PK measurement of DON in sera of recipients measure by maximum concentration (Cmax)	Measurement of Cmax	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 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 through 18 hours post infusion
PK measurement of DON in sera of recipients measure by clearance	Clearance measured over time	Measured through 18 hours post infusion
PK measurement of DON in sera of recipients measure by elimination rate	Elimination over time	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 through 18 hours post infusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pediatric participants: Brain volume score on MRI at admission and 24 hours (+/- 6 hours) post-randomization, if MRI is available	Detected by MRI	Measured at baseline and 24 hours post randomization
Pediatric participants: 2. Number of minutes of electrographic seizures within the first 12 hours after DON administration	Detected by continuous EEG monitoring	Measured through 12 hours post infusion
Pediatric participants: EEG power analysis	Detected by 30 minute EEG samples analyzing power at baseline and 3, 6, and 12 hours post infusion	Measured at baseline and through 12 hours post infusion
Pediatric participants: EEG amplitude analysis	Detected by 30 minute EEG samples analyzing amplitude at baseline and 3, 6, and 12 hours post infusion	Measured at baseline and through 12 hours post infusion
Pediatric participants: EEG frequency analysis	Detected by 30 minute EEG samples analyzing frequency at baseline and 3, 6, and 12 hours post infusion	Measured at baseline and through 12 hours post infusion
Pediatric participants: Transcranial Doppler (TCD) phenotype flow velocities	Detected by TCD at 4H and 24H post infusion	Measured through 24 hours post infusion
Pediatric participants: Cerebrospinal Fluid Metabolic Profile	Detected by LP at baseline and 4H (+ or - 2H) post DON infusion	Measured through 4 hours post infusion

Collaborators and Investigators

• Sponsor: Douglas Postels, MD, MS
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Douglas Postels, MD, Children's National Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): August 16, 2022
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: July 26, 2022
• First Submitted That Met QC Criteria: July 26, 2022
• First Posted (Actual): July 28, 2022

Study Record Updates

• Last Update Posted (Actual): July 31, 2025
• Last Update Submitted That Met QC Criteria: July 28, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Plasmodium falciparum; malaria
• Additional Relevant MeSH Terms: Vector Borne Diseases; Mosquito-Borne Diseases; Central Nervous System Diseases; Nervous System Diseases; Infections; Protozoan Infections; Parasitic Diseases; Central Nervous System Infections; Central Nervous System Parasitic Infections; Central Nervous System Protozoal Infections; Malaria; Malaria, Cerebral; Antibiotics, Antineoplastic; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Diazooxonorleucine
• Other Study ID Numbers: 21/04/2676; 21-0005 (Other Identifier: DMID); PAR-18-633 (Other Grant/Funding Number: DMID)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No