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

Status: Recruiting
Location: See all (2) locations...
Intervention Type: Drug
Study Type: Interventional
Study Phase: Phase 1/Phase 2
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: * Evaluate the safety of a single intravenous dose of DON in healthy adults and adults with uncomplicated malaria ( Part 1) * Determine the safety of a single dose of DON in children 12 months-14 years old with World Health Organization (WHO) clinically defined CM (Part 2 :Cohort 1-4) * Determine the pharmacokinetic (PK) profile of a single dose of DON in healthy adults, adults with uncomplicated malaria and children with CM (Part 1, and Cohorts 1-4 of Part 2) * 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) (Part 2 :Cohort 1-4) * 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) (Part 2 :Cohort 1-4) * 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 (Part 2 :Cohort 1-4) * 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

Eligibility
Participation Requirements
Sex: All
Minimum Age: 1
Healthy Volunteers: t
View:

⁃ For Healthy Adults (Part 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 (Part 1):

• 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 (Part 2):

• 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

Locations
Other Locations
Malawi
Ndirande Research Clinic
COMPLETED
Blantyre
Queen Elizabeth Central Hospital
RECRUITING
Blantyre
Contact Information
Primary
Yamikani Chimalizeni, MD
ychimalizeni@medcol.mw
+265 992 23 32 21
Backup
Alice Liomba
wanguialice@gmail.com
+265 888 36 57 58
Time Frame
Start Date: 2022-08-16
Estimated Completion Date: 2026-12
Participants
Target number of participants: 152
Treatments
Experimental: Dose escalation in healthy Malawian adults - 0.1 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.
Experimental: Dose escalation in healthy Malawian adults - 1.0 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.
Experimental: Dose escalation in healthy Malawian adults - 5.0 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.
Experimental: Dose escalation in healthy Malawian adults - 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.
Experimental: Dose escalation in Malawian adults with uncomplicated malaria - 0.1 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.
Experimental: Dose escalation in Malawian adults with uncomplicated malaria - 1.0 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.
Experimental: Dose escalation in Malawian adults with uncomplicated malaria - 5.0 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.
Experimental: Dose escalation in Malawian adults with uncomplicated malaria - 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.
Experimental: Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 1
After adult doses are shown to be safe. Of the first 6 children with cerebral malaria enrolled, 4 will receive 0.1 mg/kg IV DON, and 2 will receive placebo.
Experimental: Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 2
10 participants will receive 0.1 mg/kg IV DON, and 2 will receive placebo.
Experimental: Dose escalation in Malawian children with cerebral malaria - 1.0 mg/kg IV DON - Cohort 3
14 participants will receive 1.0 mg/kg IV DON, and 4 will receive placebo.
Experimental: Dose escalation in Malawian children with cerebral malaria - 0.1 or 1.0 mg/kg IV DON - Cohort 4
36 participants will receive 0.1 mg/kg IV DON (n=12) or 1.0 mg/kg IV DON (n=12), and 12 will receive placebo.
Placebo_comparator: Dose escalation in Malawian children with cerebral malaria - placebo
Cohort 1 will dose 2 participants to receive placebo Cohort 2 will dose 2 participants to receive placebo Cohort 3 will dose 4 participants to receive placebo Cohort 4 will dose 12 participants to receive placebo
Related Therapeutic Areas
Primary Amebic Meningoencephalitis
Malaria
Sponsors
Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
Leads: Douglas Postels, MD, MS

This content was sourced from clinicaltrials.gov

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