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DON in Pediatric Cerebral Malaria: Part 1-Adult Arm

Sponsor
Douglas Postels, MD, MS (Other)
Overall Status
Recruiting
CT.gov ID
NCT05478720
Collaborator
National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
80
Enrollment
1
Location
8
Arms
15.5
Anticipated Duration (Months)
5.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The initial study to be conducted under this IND is a 2-arm dose escalation study. The 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, a second protocol is planned in children with Cerebral Malaria.

Condition or Disease Intervention/Treatment Phase
  • Drug: 6-diazo-5-oxo-L-norleucine (DON)
 Phase 1/Phase 2

Study Design

Study Type:
Interventional
Anticipated Enrollment :
80 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Intervention 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.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.
Masking:
None (Open Label)
Masking Description:
Arms 1 and 2: None (Open Label)
Primary Purpose:
Treatment
Official Title:
DON in Pediatric Cerebral Malaria: A Phase I/IIa Dose-Escalation Safety Study: Part 1-Adult Arm
Actual Study Start Date :
Aug 16, 2022
Anticipated Primary Completion Date :
Dec 1, 2023
Anticipated Study Completion Date :
Dec 1, 2023

Arms and Interventions

Arm Intervention/Treatment
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.

Drug: 6-diazo-5-oxo-L-norleucine (DON)
Single intravenous dose ranging from 0.1-10 mg/kg per dose
Other Names:
  • NSC 7365

    		•
    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.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)
    Single intravenous dose ranging from 0.1-10 mg/kg per dose
    Other Names:
  • NSC 7365

    		•
    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.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)
    Single intravenous dose ranging from 0.1-10 mg/kg per dose
    Other Names:
  • NSC 7365

    		•
    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.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)
    Single intravenous dose ranging from 0.1-10 mg/kg per dose
    Other Names:
  • NSC 7365

    		•
    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.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)
    Single intravenous dose ranging from 0.1-10 mg/kg per dose
    Other Names:
  • NSC 7365

    		•
    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.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)
    Single intravenous dose ranging from 0.1-10 mg/kg per dose
    Other Names:
  • NSC 7365

    		•
    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.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)
    Single intravenous dose ranging from 0.1-10 mg/kg per dose
    Other Names:
  • NSC 7365

    		•
    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.

    Drug: 6-diazo-5-oxo-L-norleucine (DON)
    Single intravenous dose ranging from 0.1-10 mg/kg per dose
    Other Names:
  • NSC 7365

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Incidence of local AEs occurring within 14 days after the administration of DON [14 days]

      Number of AEs

    2. Incidence of systemic AEs occurring within 14 days after the administration of DON [14 days]

      Number of AEs

    Secondary Outcome Measures

    1. PK measurement of DON in sera of recipients measured by half life [Measured through 18 hours post infusion]

      Measurement of half life

    2. PK measurement of DON in sera of recipients measured by volume of distribution [Measured through 18 hours post infusion]

      Measurement of Vd

    3. PK measurement of DON in sera of recipients measure by maximum concentration (Cmax) [Measured through 18 hours post infusion]

      Measurement of Cmax

    4. PK measurement of DON in sera of recipients measure by time of maximal concentration (Tmax) [Measured through 18 hours post infusion]

      Measurement of Tmax

    5. PK measurement of DON in sera of recipients measure by area under the concentrations vs. time curve (AUC) [Measured through 18 hours post infusion]

      Measurement of AUC

    6. PK measurement of DON in sera of recipients measure by clearance [Measured through 18 hours post infusion]

      Clearance measured over time

    7. PK measurement of DON in sera of recipients measure by elimination rate [Measured through 18 hours post infusion]

      Elimination over time

    8. PK measurement of DON in sera of recipients measure by terminal T1/2 [Measured through 18 hours post infusion]

      Measurement of terminal T1/2

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    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

    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Ndirande Research Clinic Blantyre Malawi

    Sponsors and Collaborators

    • Douglas Postels, MD, MS
    • National Institute of Allergy and Infectious Diseases (NIAID)

    Investigators

    • Principal Investigator: Douglas Postels, MD, Children's National Research Institute

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Douglas Postels, Associate Professor of Pediatric Neurology, Children's National Research Institute
    ClinicalTrials.gov Identifier:
    NCT05478720
    Other Study ID Numbers:
    • 21/04/2676
    • 21-0005
    • PAR-18-633
    First Posted:
    Jul 28, 2022
    Last Update Posted:
    Aug 17, 2022
    Last Verified:
    Aug 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Douglas Postels, Associate Professor of Pediatric Neurology, Children's National Research Institute
    malaria
    Plasmodium falciparum
    Additional relevant MeSH terms:
    Malaria
    Malaria, Cerebral
    Diazooxonorleucine

    Study Results

    No Results Posted as of Aug 17, 2022