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:
- 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
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.
Eligibility
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
