DON in Pediatric Cerebral Malaria: A Phase I/IIa Dose-Escalation Safety Study: Part 1-Adult Arm

• Status: Not yet recruiting
• Trial end date: 2023-12-01
• Target enrollment: 0
• Participant gender: All

Summary

The initial study to be conducted under this IND is a 2-arm dose escalation study. The two arms 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 arms 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, 8 mg IV, administered 30 minutes prior to DON, and repeated once 6 hours later. The duration of study participation for all adult participants is six months.

Once the safety profile in adults is completed, a second protocol is planned in children with Cerebral Malaria.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Douglas Postels, MD, MS
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID)
• Treatments: Diazooxonorleucine

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 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

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