Clinical trial NCT05478720: DON in Pediatric Cerebral Malaria
Official title: DON in Pediatric Cerebral Malaria: A Phase I/IIa Dose-Escalation Safety Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Malaria, Cerebral
Keywords: malaria
Plasmodium falciparum
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2022-07-28
Enrollment: 152
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 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.

Pediatric 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.
Primary purpose: TREATMENT

Brief 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

Detailed 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. If DON has a promising risk-benefit profile, the study will continue to cohort 4 (n=36) with similar doses of DON (up to 1 mg/kg) or placebo in combination with IV artesunate, and enteral lumefantrine-artemether therapy. Pediatric participation in the study will be 6 months.

Eligibility 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 ≤ 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

Primary outcomes:
measure: Incidence of local AEs occurring within 14 days after the administration of DON
timeFrame: 14 days
measure: Incidence of systemic AEs occurring within 14 days after the administration of DON
timeFrame: 14 days
measure: Incidence of systemic SAEs occurring within 14 days after the administration of DON
timeFrame: 14 days
Secondary outcomes:
measure: PK measurement of DON in sera of recipients measured by half life
timeFrame: Measured through 18 hours post infusion
measure: PK measurement of DON in sera of recipients measured by volume of distribution
timeFrame: Measured through 18 hours post infusion
measure: PK measurement of DON in sera of recipients measure by maximum concentration (Cmax)
timeFrame: Measured through 18 hours post infusion
measure: PK measurement of DON in sera of recipients measure by time of maximal concentration (Tmax)
timeFrame: Measured through 18 hours post infusion
measure: PK measurement of DON in sera of recipients measure by area under the concentrations vs. time curve (AUC)
timeFrame: Measured through 18 hours post infusion
measure: PK measurement of DON in sera of recipients measure by clearance
timeFrame: Measured through 18 hours post infusion
measure: PK measurement of DON in sera of recipients measure by elimination rate
timeFrame: Measured through 18 hours post infusion
measure: PK measurement of DON in sera of recipients measure by terminal T1/2
timeFrame: Measured through 18 hours post infusion
Other outcomes:
measure: Pediatric participants: Brain volume score on MRI at admission and 24 hours (+/- 6 hours) post-randomization, if MRI is available
timeFrame: Measured at baseline and 24 hours post randomization
measure: Pediatric participants: 2. Number of minutes of electrographic seizures within the first 12 hours after DON administration
timeFrame: Measured through 12 hours post infusion
measure: Pediatric participants: EEG power analysis
timeFrame: Measured at baseline and through 12 hours post infusion
measure: Pediatric participants: EEG amplitude analysis
timeFrame: Measured at baseline and through 12 hours post infusion
measure: Pediatric participants: EEG frequency analysis
timeFrame: Measured at baseline and through 12 hours post infusion
measure: Pediatric participants: Transcranial Doppler (TCD) phenotype flow velocities
timeFrame: Measured through 24 hours post infusion
measure: Pediatric participants: Cerebrospinal Fluid Metabolic Profile
timeFrame: Measured through 4 hours post infusion
Locations:
city: Blantyre
country: Malawi
facility: Ndirande Research Clinic
city: Blantyre
country: Malawi
facility: Queen Elizabeth Central Hospital
Study officials:
affiliation: Children's National Research Institute
name: Douglas Postels, MD
role: PRINCIPAL_INVESTIGATOR
References: