DON in Pediatric Cerebral Malaria

NCT05478720 | Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: 21/04/267621-0005PAR-18-633
• Study Type: interventional
• Target: 152
• Locations: 1 country
• Sites: 2

Brief 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:

• 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

Conditions

Malaria, Cerebral

Keywords

malaria; Plasmodium falciparum

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (8)

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

  Measured through 18 hours post infusion

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

  Measured through 18 hours post infusion

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

  Measured through 18 hours post infusion

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

  Measured through 18 hours post infusion

Other Outcomes (7)

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

  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

  Measured through 12 hours post infusion

• Pediatric participants: EEG power analysis

  Measured at baseline and through 12 hours post infusion

Study Arms (13)

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

Drug: Placebo

Interventions

6-diazo-5-oxo-L-norleucine (DON) DRUG

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

Also known as: NSC 7365

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

Placebo DRUG

Single intravenous dose of saline

Also known as: Saline

Dose escalation in Malawian children with cerebral malaria - placebo

Eligibility Criteria

• Age: 12 Months+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• For Healthy Adults (Arm 1):
• 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):
• 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%

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Douglas Postels, MD, MS: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (2)

Ndirande Research Clinic

Blantyre, Malawi

COMPLETED

Queen Elizabeth Central Hospital

Blantyre, Malawi

RECRUITING

Related Publications (1)

• 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.

  PMID: 38279124 DERIVED

MeSH Terms

Conditions

Malaria, Cerebral; Malaria; Malaria, Falciparum

Interventions

Diazooxonorleucine; Sodium Chloride

Condition Hierarchy (Ancestors)

Central Nervous System Protozoal Infections; Central Nervous System Parasitic Infections; Central Nervous System Infections; Infections; Parasitic Diseases; Protozoan Infections; Mosquito-Borne Diseases; Vector Borne Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Azo Compounds; Organic Chemicals; Norleucine; Aminocaproates; Amino Acids; Amino Acids, Peptides, and Proteins; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Douglas Postels, MD

  Children's National Research Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Yamikani Chimalizeni, MD

CONTACT

+265 992 23 32 21; ychimalizeni@medcol.mw

Alice Liomba

CONTACT

+265 888 36 57 58; wanguialice@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: Part 1: None (Open Label) Part 2: Blinded (Participants/ Caregivers, Study Staff)
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: UNKNOWN
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Pediatric Neurology

Model Details: 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.

Study Record Dates

• First Submitted: July 26, 2022
• First Posted: July 28, 2022
• Study Start: August 16, 2022
• Primary Completion: December 1, 2025
• Study Completion: December 1, 2025
• Last Updated: July 31, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

MA (2)