DON in Pediatric Cerebral Malaria
DON in Pediatric Cerebral Malaria: A Phase I/IIa Dose-Escalation Safety Study
Douglas Postels, MD, MS
152 participants
Aug 16, 2022
INTERVENTIONAL
Conditions
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
Eligibility
Inclusion Criteria33
- 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%
- 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 Criteria10
- 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
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Interventions
Single intravenous dose ranging from 0.1-10 mg/kg per dose
Single intravenous dose of saline
Single intravenous dose ranging from 0.1-1.0 mg/kg per dose
Locations(2)
View Full Details on ClinicalTrials.gov
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NCT05478720