DON in Pediatric Cerebral Malaria

NCT ID: NCT05478720

Last Updated: 2025-07-31

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 152 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-08-16
• Study Completion Date: 2025-12-31

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

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.

Conditions

Malaria, Cerebral

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Single intravenous dose of saline

Interventions

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

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

Intervention Type: DRUG

Placebo

Single intravenous dose of saline

Intervention Type: DRUG

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

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

Intervention Type: DRUG

Other Intervention Names

NSC 7365; Saline; NSC 7365

Eligibility Criteria

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

• 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

• Minimum Eligible Age: 12 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

Douglas Postels, MD, MS

UNKNOWN

Sponsor Role: lead

Responsible Party

Douglas Postels

Professor of Pediatric Neurology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Douglas Postels, MD

Role: PRINCIPAL_INVESTIGATOR

Children's National Research Institute

Locations

Ndirande Research Clinic

Blantyre, , Malawi

Site Status: COMPLETED

Queen Elizabeth Central Hospital

Blantyre, , Malawi

Site Status: RECRUITING

Countries

Malawi

Central Contacts

Yamikani Chimalizeni, MD

Role: CONTACT

ychimalizeni@medcol.mw

+265 992 23 32 21

Alice Liomba

Role: CONTACT

wanguialice@gmail.com

+265 888 36 57 58

Facility Contacts

Yamikani Chimalizeni, MD

Role: primary

ychimalizeni@medcol.mw

+265 992 23 32 21

Douglas Postels, MD

Role: backup

dpostels@childrensnational.org

+265 995 83 32 73

References

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.

Reference Type: DERIVED

PMID: 38279124 (View on PubMed)

Other Identifiers

21-0005

Identifier Type: OTHER

Identifier Source: secondary_id

PAR-18-633

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

21/04/2676

Identifier Type: -

Identifier Source: org_study_id