DON in Pediatric Cerebral Malaria

Malaria, Cerebral Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05478720
• Other study ID #: 21/04/2676
• Secondary ID: 21-0005PAR-18-63
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: August 16, 2022
• Est. completion date: December 2025

Study information

• Verified date: November 2023
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: Jane Mallewa, MD
• Phone: +265 993 71 12 74
• Email: jmallewa[@]medcol.mw
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 152
• Est. completion date: December 2025
• Est. primary completion date: December 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 6 Months and older

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

Related Conditions & MeSH terms

• Malaria
• Malaria, Cerebral

Intervention

Drug:
• 6-diazo-5-oxo-L-norleucine (DON)
Single intravenous dose ranging from 0.1-10 mg/kg per dose
• Placebo
Single intravenous dose of saline
• 6-diazo-5-oxo-L-norleucine (DON)
Single intravenous dose ranging from 0.1-1.0 mg/kg per dose

Locations

Country	Name	City	State
Malawi	Ndirande Research Clinic	Blantyre
Malawi	Queen Elizabeth Central Hospital	Blantyre

Sponsors (2)

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

Country where clinical trial is conducted

Malawi, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Pediatric participants: Brain volume score on MRI at admission and 24 hours (+/- 6 hours) post-randomization, if MRI is available	Detected by MRI	Measured at baseline and 24 hours post randomization
Other	Pediatric participants: 2. Number of minutes of electrographic seizures within the first 12 hours after DON administration	Detected by continuous EEG monitoring	Measured through 12 hours post infusion
Other	Pediatric participants: EEG power analysis	Detected by 30 minute EEG samples analyzing power at baseline and 3, 6, and 12 hours post infusion	Measured at baseline and through 12 hours post infusion
Other	Pediatric participants: EEG amplitude analysis	Detected by 30 minute EEG samples analyzing amplitude at baseline and 3, 6, and 12 hours post infusion	Measured at baseline and through 12 hours post infusion
Other	Pediatric participants: EEG frequency analysis	Detected by 30 minute EEG samples analyzing frequency at baseline and 3, 6, and 12 hours post infusion	Measured at baseline and through 12 hours post infusion
Other	Pediatric participants: Transcranial Doppler (TCD) phenotype flow velocities	Detected by TCD at 4H and 24H post infusion	Measured through 24 hours post infusion
Primary	Incidence of local AEs occurring within 14 days after the administration of DON	Number of AEs	14 days
Primary	Incidence of systemic AEs occurring within 14 days after the administration of DON	Number of AEs	14 days
Primary	Incidence of systemic SAEs occurring within 14 days after the administration of DON	Number of SAEs - pediatric arms only	14 days
Secondary	PK measurement of DON in sera of recipients measured by half life	Measurement of half life	Measured through 18 hours post infusion
Secondary	PK measurement of DON in sera of recipients measured by volume of distribution	Measurement of Vd	Measured through 18 hours post infusion
Secondary	PK measurement of DON in sera of recipients measure by maximum concentration (Cmax)	Measurement of Cmax	Measured through 18 hours post infusion
Secondary	PK measurement of DON in sera of recipients measure by time of maximal concentration (Tmax)	Measurement of Tmax	Measured through 18 hours post infusion
Secondary	PK measurement of DON in sera of recipients measure by area under the concentrations vs. time curve (AUC)	Measurement of AUC	Measured through 18 hours post infusion
Secondary	PK measurement of DON in sera of recipients measure by clearance	Clearance measured over time	Measured through 18 hours post infusion
Secondary	PK measurement of DON in sera of recipients measure by elimination rate	Elimination over time	Measured through 18 hours post infusion
Secondary	PK measurement of DON in sera of recipients measure by terminal T1/2	Measurement of terminal T1/2	Measured through 18 hours post infusion