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| ID | Type | Description | Link |
|---|---|---|---|
| PAR-18-633 | Other Grant/Funding Number | DMID | |
| PAR-25-305 | Other Grant/Funding Number | DMID | |
| 21-0005 | Other Identifier | DMID |
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| Name | Class |
|---|---|
| National Institute of Allergy and Infectious Diseases (NIAID) | NIH |
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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 12 months-14 years old with clinically defined Cerebral Malaria. The main objectives are:
Healthy adult participants will receive:
Adults with uncomplicated malaria will receive:
Pediatric participants will receive:
The initial study to be conducted under this IND is a 2-part dose escalation study. The first part (Adults) 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 (pediatric) of the study will be a randomized, placebo-controlled, dose-escalation study in children ages 12 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-artemether 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-artemether 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-artemether therapy, and either adjunctive DON 1.0 mg/kg or placebo randomized 7:1.
Cohort 4 will enroll 36 participants who will receive intravenous artesunate therapy, enteral lumefantrine-artemether therapy, and either adjunctive DON 0.1 mg/kg, DON 1.0 mg/kg or placebo randomized 1:1:1. Pediatric participation in the study will be 6 months.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dose escalation in healthy Malawian adults - 0.1 mg/kg IV DON | Experimental | 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. |
|
| Dose escalation in healthy Malawian adults - 1.0 mg/kg IV DON | Experimental | 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. |
|
| Dose escalation in healthy Malawian adults - 5.0 mg/kg IV DON | Experimental | 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. |
|
| Dose escalation in healthy Malawian adults - 10.0 mg/kg IV DON | Experimental | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 6-diazo-5-oxo-L-norleucine (DON) | Drug | Single intravenous dose ranging from 0.1-10 mg/kg per dose |
|
| 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 |
| Assessment of Blantyre Coma Score | Time to Blantyre Coma Score of 5 | 14 days |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Pediatric participants: Number of minutes of electrographic seizures within the first 12 hours after DON administration |
Inclusion Criteria:
For Healthy Adults (Part 1):
For Adults with Uncomplicated Malaria (Part 1):
For Children with Cerebral Malaria (Part 2):
Exclusion Criteria (All Participants):
Additional Exclusion Criteria for Children with Cerebral Malaria (Part 2):
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Yamikani Chimalizeni, MD | Contact | +265 992 23 32 21 | ychimalizeni@medcol.mw | |
| Alice Liomba | Contact | +265 888 36 57 58 | wanguialice@gmail.com |
| Name | Affiliation | Role |
|---|---|---|
| Douglas Postels, MD | Children's National Research Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ndirande Research Clinic | Completed | Blantyre | Malawi | |||
| Queen Elizabeth Central Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41748157 | Result | Riggle BA, Chamzas A, Gopalakrishnan M, Nyirenda OM, Nampota-Nkomba N, Mallewa JE, Masonga R, Manyozo C, Zuze K, Liomba AM, Alt J, Rais R, Slusher B, Moodley N, Miller LH, Pierce SK, O'Brien NF, Laurens MB, Postels DG. Safety, Tolerability, and Pharmacokinetics of 6-Diazo-5-Oxo-L-Norleucine in Malawian Adults With and Without Malaria: A Phase 1 Dose-Escalation Clinical Trial. J Infect Dis. 2026 May 15;233(5):e1226-e1237. doi: 10.1093/infdis/jiag121. | |
| 38279124 |
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| ID | Term |
|---|---|
| D016779 | Malaria, Cerebral |
| D008288 | Malaria |
| D016778 | Malaria, Falciparum |
| ID | Term |
|---|---|
| D020808 | Central Nervous System Protozoal Infections |
| D020807 | Central Nervous System Parasitic Infections |
| D002494 | Central Nervous System Infections |
| D007239 | Infections |
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| ID | Term |
|---|---|
| D003980 | Diazooxonorleucine |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D001391 | Azo Compounds |
| D009930 | Organic Chemicals |
| D009646 | Norleucine |
| D000614 | Aminocaproates |
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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.
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Part 1: None (Open Label) Part 2: Blinded (Participants/ Caregivers, Study Staff)
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|
| Dose escalation in Malawian adults with uncomplicated malaria - 0.1 mg/kg IV DON | Experimental | 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. |
|
| Dose escalation in Malawian adults with uncomplicated malaria - 1.0 mg/kg IV DON | Experimental | 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. |
|
| Dose escalation in Malawian adults with uncomplicated malaria - 5.0 mg/kg IV DON | Experimental | 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. |
|
| Dose escalation in Malawian adults with uncomplicated malaria - 10.0 mg/kg IV DON | Experimental | 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. |
|
| Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 1 | Experimental | 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. |
|
| Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 2 | Experimental | 10 participants will receive 0.1 mg/kg IV DON, and 2 will receive placebo. |
|
| Dose escalation in Malawian children with cerebral malaria - 1.0 mg/kg IV DON - Cohort 3 | Experimental | 14 participants will receive 1.0 mg/kg IV DON, and 4 will receive placebo. |
|
| Dose escalation in Malawian children with cerebral malaria - 0.1 or 1.0 mg/kg IV DON - Cohort 4 | Experimental | 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. |
|
| Dose escalation in Malawian children with cerebral malaria - placebo | Placebo Comparator | 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 |
|
|
| Placebo | Drug | Single intravenous dose of saline |
|
|
| 6-diazo-5-oxo-L-norleucine (DON) | Drug | Single intravenous dose ranging from 0.1-1.0 mg/kg per dose |
|
|
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 |
Detected by continuous EEG monitoring |
| Measured through 12 hours post infusion |
| 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 |
| 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 |
| 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 |
| Pediatric participants: Transcranial Doppler (TCD) phenotype flow velocities | Detected by TCD at 4H and 24H post infusion | Measured through 24 hours post infusion |
| Pediatric participants: Cerebrospinal Fluid Metabolic Profile | Detected by LP at baseline and 4H (+ or - 2H) post DON infusion | Measured through 4 hours post infusion |
| Recruiting |
| Blantyre |
| Malawi |
|
| Derived |
| Nampota-Nkomba N, Nyirenda OM, Mallewa J, Chimalizeni Y, Dzabala N, Fay MP, Gopalakrishnan M, Laurens MB, O'Brien NF, Miller LH, Pierce SK, Riggle BA, Postels DG. DON in pediatric cerebral malaria, a phase I/IIA dose-escalation safety study: study protocol for a clinical trial. Trials. 2024 Jan 26;25(1):87. doi: 10.1186/s13063-023-07808-w. |
| D010272 | Parasitic Diseases |
| D011528 | Protozoan Infections |
| D000096724 | Mosquito-Borne Diseases |
| D000079426 | Vector Borne Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D000596 |
| Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |