DON in Pediatric Cerebral Malaria

Study Overview
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Brief Summary
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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

Detailed Description
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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.

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

Conditions
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Malaria, Cerebral

Intervention / Treatment
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* Drug: 6-diazo-5-oxo-L-norleucine (DON)
* Drug: Placebo
* Drug: 6-diazo-5-oxo-L-norleucine (DON)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 6 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation in healthy Malawian adults - 0.1 mg/kg IV DON<br>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)<br>* Single intravenous dose ranging from 0.1-10 mg/kg per dose<br>* Other names: NSC 7365;|
| Experimental: Dose escalation in healthy Malawian adults - 1.0 mg/kg IV DON<br>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)<br>* Single intravenous dose ranging from 0.1-10 mg/kg per dose<br>* Other names: NSC 7365;|
| Experimental: Dose escalation in healthy Malawian adults - 5.0 mg/kg IV DON<br>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)<br>* Single intravenous dose ranging from 0.1-10 mg/kg per dose<br>* Other names: NSC 7365;|
| Experimental: Dose escalation in healthy Malawian adults - 10.0 mg/kg IV DON<br>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)<br>* Single intravenous dose ranging from 0.1-10 mg/kg per dose<br>* Other names: NSC 7365;|
| Experimental: Dose escalation in Malawian adults with uncomplicated malaria - 0.1 mg/kg IV DON<br>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)<br>* Single intravenous dose ranging from 0.1-10 mg/kg per dose<br>* Other names: NSC 7365;|
| Experimental: Dose escalation in Malawian adults with uncomplicated malaria - 1.0 mg/kg IV DON<br>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)<br>* Single intravenous dose ranging from 0.1-10 mg/kg per dose<br>* Other names: NSC 7365;|
| Experimental: Dose escalation in Malawian adults with uncomplicated malaria - 5.0 mg/kg IV DON<br>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)<br>* Single intravenous dose ranging from 0.1-10 mg/kg per dose<br>* Other names: NSC 7365;|
| Experimental: Dose escalation in Malawian adults with uncomplicated malaria - 10.0 mg/kg IV DON<br>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)<br>* Single intravenous dose ranging from 0.1-10 mg/kg per dose<br>* Other names: NSC 7365;|
| Experimental: Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 1<br>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. | Drug: 6-diazo-5-oxo-L-norleucine (DON)<br>* Single intravenous dose ranging from 0.1-1.0 mg/kg per dose<br>* Other names: NSC 7365;|
| Experimental: Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 2<br>10 participants will receive 0.1 mg/kg IV DON, and 2 will receive placebo. | Drug: 6-diazo-5-oxo-L-norleucine (DON)<br>* Single intravenous dose ranging from 0.1-1.0 mg/kg per dose<br>* Other names: NSC 7365;|
| Experimental: Dose escalation in Malawian children with cerebral malaria - 1.0 mg/kg IV DON - Cohort 3<br>14 participants will receive 0.1 mg/kg IV DON, and 4 will receive placebo. | Drug: 6-diazo-5-oxo-L-norleucine (DON)<br>* Single intravenous dose ranging from 0.1-1.0 mg/kg per dose<br>* Other names: NSC 7365;|
| Experimental: Dose escalation in Malawian children with cerebral malaria - 1.0 mg/kg IV DON - Cohort 4<br>28 participants will receive 0.1 mg/kg IV DON or1.0 mg/kg IV DON (n=TBD), and 8 will receive placebo. | Drug: 6-diazo-5-oxo-L-norleucine (DON)<br>* Single intravenous dose ranging from 0.1-1.0 mg/kg per dose<br>* Other names: NSC 7365;|
| Placebo Comparator: Dose escalation in Malawian children with cerebral malaria - placebo<br>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 8 participants to receive placebo | Drug: Placebo<br>* Single intravenous dose of saline<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of local AEs occurring within 14 days after the administration of DON | Number of AEs | 14 days | 
| Incidence of systemic AEs occurring within 14 days after the administration of DON | Number of AEs | 14 days | 
| Incidence of systemic SAEs occurring within 14 days after the administration of DON | Number of SAEs - pediatric arms only | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK measurement of DON in sera of recipients measured by half life | Measurement of half life | Measured through 18 hours post infusion | 
| PK measurement of DON in sera of recipients measured by volume of distribution | Measurement of Vd | Measured through 18 hours post infusion | 
| PK measurement of DON in sera of recipients measure by maximum concentration (Cmax) | Measurement of Cmax | Measured through 18 hours post infusion | 
| PK measurement of DON in sera of recipients measure by time of maximal concentration (Tmax) | Measurement of Tmax | Measured through 18 hours post infusion | 
| 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 | 
| PK measurement of DON in sera of recipients measure by clearance | Clearance measured over time | Measured through 18 hours post infusion | 
| PK measurement of DON in sera of recipients measure by elimination rate | Elimination over time | Measured through 18 hours post infusion | 
| PK measurement of DON in sera of recipients measure by terminal T1/2 | Measurement of terminal T1/2 | Measured through 18 hours post infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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malaria, Plasmodium falciparum