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

21/04/2676

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

2022-08-16

2025-12-01

2025-12-01

Recruiting

Early phase I

152

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

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE1', 'PHASE2'], 'designInfo': {'allocation': 'NON_RANDOMIZED', 'interventionModel': 'SEQUENTIAL', 'interventionModelDescription': 'Part 1: Adult groups Healthy / Uncomplicated Malaria - Groups of 10 adult participants will be enrolled sequentially, with safety assessment and dose escalation for each group if safety criteria are satisfied in the previous group.\n\nPediatric Arm: Enrollment of pediatric participants will begin if safety criteria are satisfied in adults previously enrolled. The pediatric study will be randomized and placebo-controlled with DON or Placebo doses added to standard of care therapy. Interim assessments are planned to determine dosing for subsequent participants.', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'NONE', 'maskingDescription': 'Part 1: None (Open Label) Part 2: Blinded (Participants/ Caregivers, Study Staff)'}}, 'enrollmentInfo': {'count': 152, 'type': 'ESTIMATED'}}

2023-11-13