DON in Pediatric Cerebral Malaria

Official title

DON in Pediatric Cerebral Malaria: A Phase I/IIa Dose-Escalation Safety Study

Overview

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.

Interventions

• Drug 6-diazo-5-oxo-L-norleucine (DON)
  Single intravenous dose ranging from 0.1-10 mg/kg per dose
• Drug Placebo
  Single intravenous dose of saline
• Drug 6-diazo-5-oxo-L-norleucine (DON)
  Single intravenous dose ranging from 0.1-1.0 mg/kg per dose

Primary outcome measures

• Incidence of local AEs occurring within 14 days after the administration of DON [Time frame: 14 days]
• Incidence of systemic AEs occurring within 14 days after the administration of DON [Time frame: 14 days]
• Incidence of systemic SAEs occurring within 14 days after the administration of DON [Time frame: 14 days]
• Assessment of Blantyre Coma Score [Time frame: 14 days]

Secondary outcome measures (8)

• 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]

Eligibility criteria

Inclusion criteria

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)
• 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

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 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 CYP3A4 inhibitor within 7 days of enrollment

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Malawi · 2 centers

• Ndirande Research Clinic — Blantyre
• Queen Elizabeth Central Hospital — Blantyre

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 Ma PMID 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. PMID 38279124

Identifiers

NCT: NCT05478720 · 21/04/2676 · PAR-18-633 · PAR-25-305 · 21-0005

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗