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 6 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 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 6 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 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 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 therapy, and either adjunctive DON 1.0 mg/kg or placebo randomized 7:1. If DON has a promising risk-benefit profile, the study will continue to cohort 4 (n=36) with similar or higher doses of DON (up to 1 mg/kg) or placebo in combination with IV artesunate, and enteral lumefantrine therapy. 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 60-110 mmol/L (0.7-1.2 mg/dL; males) or 45-90 mmol/L (0.5-1.0 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 person 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 60-110 mmol/L (0.7-1.2 mg/dL; males) or 45-90 mmol/L (0.5-1.0 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 6 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 of Glasgow Coma Score ≤ 10.
- No other explanation for coma by history or physical exam
- Greater than 1 hour from last clinical seizure
- Hematocrit or PCV ≥ 18%
- Negative pregnancy test for persons of child-bearing potential
Exclusion Criteria (All Participants):
- Pregnancy or lactation (female participants 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
Additional Exclusion criteria for Children with Cerebral Malaria (Arm 3):
- Positive Kernig or Brudzinski sign
- CSF white blood cell count ≥ 10 /μL
- 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