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
⁃ 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