Evaluating DON for treating pediatric cerebral malaria

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

This study is testing if a new treatment called DON is safe and can help children aged 12 months to 14 years with cerebral malaria by improving their blood flow and brain health.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 152 (estimated)
• Ages: 12 Months and up
• Sex: All
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (nih)
• Locations: 2 sites (Blantyre and 1 other locations)
• Trial ID: NCT05478720 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to assess the safety and pharmacokinetics of a single intravenous dose of 6-diazo-5-oxo-L-norleucine (DON) in children aged 12 months to 14 years diagnosed with cerebral malaria. The study will involve a dose escalation approach, where participants will receive varying doses of DON to determine its safety and potential benefits, including improved blood flow dynamics and reduced brain volume. Additionally, the trial will explore metabolic mechanisms of action and monitor changes in EEG patterns. The study will be conducted over three malaria seasons, with a planned interim analysis after the third cohort.

Who should consider this trial

Good fit: Ideal candidates for this study are children aged 12 months to 14 years who have been clinically diagnosed with cerebral malaria.

Not a fit: Patients with severe complications from cerebral malaria or those outside the specified age range may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly improve outcomes for children suffering from cerebral malaria.

How similar studies have performed: While there have been studies on treatments for malaria, the specific use of DON in this context is novel and has not been extensively tested.

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 (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

Where this trial is running

Blantyre and 1 other locations

• Ndirande Research Clinic — Blantyre, Malawi (COMPLETED)
• Queen Elizabeth Central Hospital — Blantyre, Malawi (RECRUITING)

Study contacts

• Principal investigator: Douglas Postels, MD — Children's National Research Institute
• Study coordinator: Yamikani Chimalizeni, MD

Conditions: Malaria, Cerebral, malaria, Plasmodium falciparum