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DON in Pediatric Cerebral Malaria

Primary Purpose

Malaria, Cerebral

Status
Recruiting
Phase
Phase 1
Locations
Malawi
Study Type
Interventional
Intervention
6-diazo-5-oxo-L-norleucine (DON)
Placebo
Sponsored by
Douglas Postels, MD, MS
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malaria, Cerebral focused on measuring malaria, Plasmodium falciparum

Eligibility Criteria

6 Months - undefined (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Ndirande Research ClinicRecruiting
  • Queen Elizabeth Central Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm 11

Arm 12

Arm 13

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

Dose escalation in healthy Malawian adults - 0.1 mg/kg IV DON

Dose escalation in healthy Malawian adults - 1.0 mg/kg IV DON

Dose escalation in healthy Malawian adults - 5.0 mg/kg IV DON

Dose escalation in healthy Malawian adults - 10.0 mg/kg IV DON

Dose escalation in Malawian adults with uncomplicated malaria - 0.1 mg/kg IV DON

Dose escalation in Malawian adults with uncomplicated malaria - 1.0 mg/kg IV DON

Dose escalation in Malawian adults with uncomplicated malaria - 5.0 mg/kg IV DON

Dose escalation in Malawian adults with uncomplicated malaria - 10.0 mg/kg IV DON

Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON

Dose escalation in Malawian children with cerebral malaria - 1.0 mg/kg IV DON

Dose escalation in Malawian children with cerebral malaria - 5.0 mg/kg IV DON

Dose escalation in Malawian children with cerebral malaria - 10.0 mg/kg IV DON

Dose escalation in Malawian children with cerebral malaria - placebo

Arm Description

The first 10 healthy adult participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON the final group will receive 10.0 mg/kg IV DON.

The first 10 healthy adult participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON the final group will receive 10.0 mg/kg IV DON.

The first 10 healthy adult participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON the final group will receive 10.0 mg/kg IV DON.

The first 10 healthy adult participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON the final group will receive 10.0 mg/kg IV DON.

The first 10 adults with uncomplicated malaria participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, 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.

The first 10 adults with uncomplicated malaria participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, 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.

The first 10 adults with uncomplicated malaria participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, 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.

The first 10 adults with uncomplicated malaria participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, 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.

During the 2nd year after adult doses are shown to be safe. The first 6 children with cerebral malaria enrolled will receive 0.1 mg/kg IV DON, and 2 will receive placebo. If this dose is proven safe, in the third year, 10 more patients will receive 0.1 mg/kg IV DON, 14 patients will receive 1.0 mg/kg IV DON, and 5 will receive placebo. Should promising risk-benefit ratio profile be shown in year 2 and 3, the study will continue with increased doses of 5.0 mg/kg IV DON, and 10.0 mg/kg IV DON, and 7 placebo patients.

During the 2nd year after adult doses are shown to be safe. The first 6 children with cerebral malaria enrolled will receive 0.1 mg/kg IV DON, and 2 will receive placebo. If this dose is proven safe, in the third year, 10 more patients will receive 0.1 mg/kg IV DON, 14 patients will receive 1.0 mg/kg IV DON, and 5 will receive placebo. Should promising risk-benefit ratio profile be shown in year 2 and 3, the study will continue with increased doses of 5.0 mg/kg IV DON, and 10.0 mg/kg IV DON, and 7 placebo patients.

During the 2nd year after adult doses are shown to be safe. The first 6 children with cerebral malaria enrolled will receive 0.1 mg/kg IV DON, and 2 will receive placebo. If this dose is proven safe, in the third year, 10 more patients will receive 0.1 mg/kg IV DON, 14 patients will receive 1.0 mg/kg IV DON, and 5 will receive placebo. Should promising risk-benefit ratio profile be shown in year 2 and 3, the study will continue with increased doses of 5.0 mg/kg IV DON, and 10.0 mg/kg IV DON, and 7 placebo patients.

During the 2nd year after adult doses are shown to be safe. The first 6 children with cerebral malaria enrolled will receive 0.1 mg/kg IV DON, and 2 will receive placebo. If this dose is proven safe, in the third year, 10 more patients will receive 0.1 mg/kg IV DON, 14 patients will receive 1.0 mg/kg IV DON, and 5 will receive placebo. Should promising risk-benefit ratio profile be shown in year 2 and 3, the study will continue with increased doses of 5.0 mg/kg IV DON, and 10.0 mg/kg IV DON, and 7 placebo patients.

During the 2nd year after adult doses are shown to be safe. The first 6 children with cerebral malaria enrolled will receive 0.1 mg/kg IV DON, and 2 will receive placebo. If this dose is proven safe, in the third year, 10 more patients will receive 0.1 mg/kg IV DON, 14 patients will receive 1.0 mg/kg IV DON, and 5 will receive placebo. Should promising risk-benefit ratio profile be shown in year 2 and 3, the study will continue with increased doses of 5.0 mg/kg IV DON, and 10.0 mg/kg IV DON, and 7 placebo patients.

Outcomes

Primary Outcome Measures

Incidence of local AEs occurring within 14 days after the administration of DON
Number of AEs
Incidence of systemic AEs occurring within 14 days after the administration of DON
Number of AEs
Incidence of systemic SAEs occurring within 14 days after the administration of DON
Number of SAEs - pediatric arms only

Secondary Outcome Measures

PK measurement of DON in sera of recipients measured by half life
Measurement of half life
PK measurement of DON in sera of recipients measured by volume of distribution
Measurement of Vd
PK measurement of DON in sera of recipients measure by maximum concentration (Cmax)
Measurement of Cmax
PK measurement of DON in sera of recipients measure by time of maximal concentration (Tmax)
Measurement of Tmax
PK measurement of DON in sera of recipients measure by area under the concentrations vs. time curve (AUC)
Measurement of AUC
PK measurement of DON in sera of recipients measure by clearance
Clearance measured over time
PK measurement of DON in sera of recipients measure by elimination rate
Elimination over time
PK measurement of DON in sera of recipients measure by terminal T1/2
Measurement of terminal T1/2

Full Information

First Posted
July 26, 2022
Last Updated
March 21, 2023
Sponsor
Douglas Postels, MD, MS
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT05478720
Brief Title
DON in Pediatric Cerebral Malaria
Official Title
DON in Pediatric Cerebral Malaria: A Phase I/IIa Dose-Escalation Safety Study
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 16, 2022 (Actual)
Primary Completion Date
December 2025 (Anticipated)
Study Completion Date
December 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Douglas Postels, MD, MS
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The initial study to be conducted under this IND is a 3-arm dose escalation study. The first 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, the third arm 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 a maximum of three years (three malaria seasons, which will be carried out in Study Years 2-4), with a planned interim analysis look at the end of malaria Study Year 3 to determine dosing for malaria Study Year 4. We will first enroll 6 sentinel pediatric patients in malaria season 1 who will receive intravenous artesunate therapy and either adjunctive DON 0.1 mg/kg or placebo randomized 2:1). After review of results by the DSMB, and if approval to move forward is granted, in malaria season 2 (Study Year 3) the next year of pediatric enrollments (n=29, to account for the 6 sentinel subjects) participants will be randomized to receive one of 2 lower doses of adjunctive DON (0.1 mg/kg or 1.0 mg/kg) or placebo (24 subjects will receive DON and 5 will receive placebo) in conjunction with IV artesunate. If DON has a promising risk-benefit profile, the study will continue into a third season of pediatric enrollments (Study Year 4) (n=35) with similar or higher doses of DON (up to 10 mg/kg) or placebo in combination with IV artesunate. pediatric participation in the study will be 6 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria, Cerebral
Keywords
malaria, Plasmodium falciparum

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Model Description
Adult Arms: Healthy (Arm 1) / Uncomplicated Malaria (Arm 2) - 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.
Masking
None (Open Label)
Masking Description
Arms 1 and 2: None (Open Label) Arm 3: Blinded (Participants/ Caregivers, Study Staff
Allocation
Non-Randomized
Enrollment
150 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dose escalation in healthy Malawian adults - 0.1 mg/kg IV DON
Arm Type
Experimental
Arm Description
The first 10 healthy adult participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON the final group will receive 10.0 mg/kg IV DON.
Arm Title
Dose escalation in healthy Malawian adults - 1.0 mg/kg IV DON
Arm Type
Experimental
Arm Description
The first 10 healthy adult participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON the final group will receive 10.0 mg/kg IV DON.
Arm Title
Dose escalation in healthy Malawian adults - 5.0 mg/kg IV DON
Arm Type
Experimental
Arm Description
The first 10 healthy adult participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON the final group will receive 10.0 mg/kg IV DON.
Arm Title
Dose escalation in healthy Malawian adults - 10.0 mg/kg IV DON
Arm Type
Experimental
Arm Description
The first 10 healthy adult participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON the final group will receive 10.0 mg/kg IV DON.
Arm Title
Dose escalation in Malawian adults with uncomplicated malaria - 0.1 mg/kg IV DON
Arm Type
Experimental
Arm Description
The first 10 adults with uncomplicated malaria participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, 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.
Arm Title
Dose escalation in Malawian adults with uncomplicated malaria - 1.0 mg/kg IV DON
Arm Type
Experimental
Arm Description
The first 10 adults with uncomplicated malaria participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, 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.
Arm Title
Dose escalation in Malawian adults with uncomplicated malaria - 5.0 mg/kg IV DON
Arm Type
Experimental
Arm Description
The first 10 adults with uncomplicated malaria participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, 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.
Arm Title
Dose escalation in Malawian adults with uncomplicated malaria - 10.0 mg/kg IV DON
Arm Type
Experimental
Arm Description
The first 10 adults with uncomplicated malaria participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, 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.
Arm Title
Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON
Arm Type
Experimental
Arm Description
During the 2nd year after adult doses are shown to be safe. The first 6 children with cerebral malaria enrolled will receive 0.1 mg/kg IV DON, and 2 will receive placebo. If this dose is proven safe, in the third year, 10 more patients will receive 0.1 mg/kg IV DON, 14 patients will receive 1.0 mg/kg IV DON, and 5 will receive placebo. Should promising risk-benefit ratio profile be shown in year 2 and 3, the study will continue with increased doses of 5.0 mg/kg IV DON, and 10.0 mg/kg IV DON, and 7 placebo patients.
Arm Title
Dose escalation in Malawian children with cerebral malaria - 1.0 mg/kg IV DON
Arm Type
Experimental
Arm Description
During the 2nd year after adult doses are shown to be safe. The first 6 children with cerebral malaria enrolled will receive 0.1 mg/kg IV DON, and 2 will receive placebo. If this dose is proven safe, in the third year, 10 more patients will receive 0.1 mg/kg IV DON, 14 patients will receive 1.0 mg/kg IV DON, and 5 will receive placebo. Should promising risk-benefit ratio profile be shown in year 2 and 3, the study will continue with increased doses of 5.0 mg/kg IV DON, and 10.0 mg/kg IV DON, and 7 placebo patients.
Arm Title
Dose escalation in Malawian children with cerebral malaria - 5.0 mg/kg IV DON
Arm Type
Experimental
Arm Description
During the 2nd year after adult doses are shown to be safe. The first 6 children with cerebral malaria enrolled will receive 0.1 mg/kg IV DON, and 2 will receive placebo. If this dose is proven safe, in the third year, 10 more patients will receive 0.1 mg/kg IV DON, 14 patients will receive 1.0 mg/kg IV DON, and 5 will receive placebo. Should promising risk-benefit ratio profile be shown in year 2 and 3, the study will continue with increased doses of 5.0 mg/kg IV DON, and 10.0 mg/kg IV DON, and 7 placebo patients.
Arm Title
Dose escalation in Malawian children with cerebral malaria - 10.0 mg/kg IV DON
Arm Type
Experimental
Arm Description
During the 2nd year after adult doses are shown to be safe. The first 6 children with cerebral malaria enrolled will receive 0.1 mg/kg IV DON, and 2 will receive placebo. If this dose is proven safe, in the third year, 10 more patients will receive 0.1 mg/kg IV DON, 14 patients will receive 1.0 mg/kg IV DON, and 5 will receive placebo. Should promising risk-benefit ratio profile be shown in year 2 and 3, the study will continue with increased doses of 5.0 mg/kg IV DON, and 10.0 mg/kg IV DON, and 7 placebo patients.
Arm Title
Dose escalation in Malawian children with cerebral malaria - placebo
Arm Type
Placebo Comparator
Arm Description
During the 2nd year after adult doses are shown to be safe. The first 6 children with cerebral malaria enrolled will receive 0.1 mg/kg IV DON, and 2 will receive placebo. If this dose is proven safe, in the third year, 10 more patients will receive 0.1 mg/kg IV DON, 14 patients will receive 1.0 mg/kg IV DON, and 5 will receive placebo. Should promising risk-benefit ratio profile be shown in year 2 and 3, the study will continue with increased doses of 5.0 mg/kg IV DON, and 10.0 mg/kg IV DON, and 7 placebo patients.
Intervention Type
Drug
Intervention Name(s)
6-diazo-5-oxo-L-norleucine (DON)
Other Intervention Name(s)
NSC 7365
Intervention Description
Single intravenous dose ranging from 0.1-10 mg/kg per dose
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Saline
Intervention Description
Single intravenous dose of saline
Primary Outcome Measure Information:
Title
Incidence of local AEs occurring within 14 days after the administration of DON
Description
Number of AEs
Time Frame
14 days
Title
Incidence of systemic AEs occurring within 14 days after the administration of DON
Description
Number of AEs
Time Frame
14 days
Title
Incidence of systemic SAEs occurring within 14 days after the administration of DON
Description
Number of SAEs - pediatric arms only
Time Frame
14 days
Secondary Outcome Measure Information:
Title
PK measurement of DON in sera of recipients measured by half life
Description
Measurement of half life
Time Frame
Measured through 18 hours post infusion
Title
PK measurement of DON in sera of recipients measured by volume of distribution
Description
Measurement of Vd
Time Frame
Measured through 18 hours post infusion
Title
PK measurement of DON in sera of recipients measure by maximum concentration (Cmax)
Description
Measurement of Cmax
Time Frame
Measured through 18 hours post infusion
Title
PK measurement of DON in sera of recipients measure by time of maximal concentration (Tmax)
Description
Measurement of Tmax
Time Frame
Measured through 18 hours post infusion
Title
PK measurement of DON in sera of recipients measure by area under the concentrations vs. time curve (AUC)
Description
Measurement of AUC
Time Frame
Measured through 18 hours post infusion
Title
PK measurement of DON in sera of recipients measure by clearance
Description
Clearance measured over time
Time Frame
Measured through 18 hours post infusion
Title
PK measurement of DON in sera of recipients measure by elimination rate
Description
Elimination over time
Time Frame
Measured through 18 hours post infusion
Title
PK measurement of DON in sera of recipients measure by terminal T1/2
Description
Measurement of terminal T1/2
Time Frame
Measured through 18 hours post infusion
Other Pre-specified Outcome Measures:
Title
Pediatric participants: Brain volume score on MRI at admission and 24 hours (+/- 6 hours) post-randomization, if MRI is available
Description
Detected by MRI
Time Frame
Measured at baseline and 24 hours post randomization
Title
Pediatric participants: 2. Number of minutes of electrographic seizures within the first 12 hours after DON administration
Description
Detected by continuous EEG monitoring
Time Frame
Measured through 12 hours post infusion
Title
Pediatric participants: EEG power analysis
Description
Detected by 30 minute EEG samples analyzing power at baseline and 3, 6, and 12 hours post infusion
Time Frame
Measured at baseline and through 12 hours post infusion
Title
Pediatric participants: EEG amplitude analysis
Description
Detected by 30 minute EEG samples analyzing amplitude at baseline and 3, 6, and 12 hours post infusion
Time Frame
Measured at baseline and through 12 hours post infusion
Title
Pediatric participants: EEG frequency analysis
Description
Detected by 30 minute EEG samples analyzing frequency at baseline and 3, 6, and 12 hours post infusion
Time Frame
Measured at baseline and through 12 hours post infusion
Title
Pediatric participants: Transcranial Doppler (TCD) phenotype flow velocities
Description
Detected by TCD at 4H and 24H post infusion
Time Frame
Measured through 24 hours post infusion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jane Mallewa, MD
Phone
+265 993 71 12 74
Email
jmallewa@medcol.mw
First Name & Middle Initial & Last Name or Official Title & Degree
Yamikani Chimalizeni, MD
Phone
+265 992 23 32 21
Email
ychimalizeni@medcol.mw
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Douglas Postels, MD
Organizational Affiliation
Children's National Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ndirande Research Clinic
City
Blantyre
Country
Malawi
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Douglas Postels, MD
Phone
+265 995 83 32 73
Email
dpostels@childrensnational.org
First Name & Middle Initial & Last Name & Degree
Jane Mallewa, MD
Phone
+265 993 71 12 74
Facility Name
Queen Elizabeth Central Hospital
City
Blantyre
Country
Malawi
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yamikani Chimalizeni, MD
Phone
+265 992 23 32 21
Email
ychimalizeni@medcol.mw
First Name & Middle Initial & Last Name & Degree
Douglas Postels, MD
Phone
+265 995 83 32 73
Email
dpostels@childrensnational.org

12. IPD Sharing Statement

Plan to Share IPD
No

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DON in Pediatric Cerebral Malaria

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