DON in pediatric cerebral malaria: a phase i / II dose-escalation safety study
Active Cooperative Agreement Awarded Last action
- Award ID
- U01AI155300
- Recipient
-
Children's Research Institute UEI M3KHEEYRM1S6 Part of Children's National Medical Center
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $14,619,631
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 90% complete
- Originally
- Funding
-
- $13,531,315.00 Federal
- $1,088,316.00 Non-federal
- Place of performance
- Washington, DC 20010, USA
Award details come from USAspending.gov.
Description
- Abstract
- Cerebral malaria (CM) is defined as an otherwise unexplained coma in a patient with plasmodium falciparum parasitemia. The condition is common, primarily affects african children less than five years old, and has a large public health impact in endemic areas. Of the ~350,000 children diagnosed annually with CM, 15% DIE and 30% of survivors have neurological abnormalities at the time of hospital discharge. The mainstay of treatment is intravenous antimalarial drugs and supportive care. No adjunctive therapy has previously been proven effective in decreasing the high rates of mortality and morbidity in this condition. Our long-term goal is to establish feasible therapies that decrease death and disability rates in this vulnerable population. We will investigate 6-diazo-5-OXO-l-norleucine (DON), a glutamine antagonist, as a candidate adjunctive therapy for pediatric CM. We identified DON through a rational drug discovery process and tested its efficacy in several pre-clinical studies. Mice with experimental CM have radiographic and pathological abnormalities similar to those seen in human pediatric CM; DON administered to mice that are severely clinically ILL rescues animals clinically, radiographically, and reverses abnormal histopathology. We will test DON's safety and preliminary efficacy in human pediatric CM. To do so, we will first perform a dose escalation study of DON in healthy malawian adults and adults with uncomplicated malaria, evaluating safety. After review, we will perform a randomized placebo-controlled double-blind safety and preliminary efficacy study of adjunctive DON in 70 malawian children with CM. Participants in the first pediatric cohort (n=35) will receive lower doses of adjunctive DON or placebo. Doses of adjunctive DON administered to the second cohort of pediatric participants (n=35) will be informed by pharmacokinetic and safety data gathered from those previously enrolled. Our primary outcome is the proportion of participants with any grade 3 or severe adverse events (saes). Concurrently with safety studies, DON's preliminary efficacy in pediatric CM will be evaluated using brain magnetic resonance imaging (MRI), electroencephalogram (EEG), and transcranial doppler (TCD). We hypothesize that malawian children with CM who receive adjunctive DON will have no increase in mortality or rates of saes compared to participants receiving placebo. We hypothesize that children with CM receiving adjunctive DON will have biomarker changes (MRI, EEG, TCD) associated with improved outcome. In summary, this research is significant because the adjunctive therapy, DON, when used in a murine model of CM, reverses brain swelling, the most important risk factor for death in children with CM. If successful in subsequent human clinical trials, this would be the first adjunctive therapy with a demonstrable effect on decreasing death or disability in this patient population. We anticipate that with widespread dissemination of such a scalable intervention, the public health impact of this devastating infectious disease would finally decrease.
Transactions
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| Amendment | $1,088,316 | $0 | |
| Original award | $1,088,316 | $1,088,316 |
Show all 29
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Kamuzu University Of Health Sciences | $318,321 | |
| The Washington University | $90,140 | |
| The Children's Hospital Of Philadelphia | $62,505 | |
| Georgetown University | $66,568 | |
| University Of Malawi College Of Medicine | $1,473,304 | |
| University Of Maryland, Baltimore | $402,492 | |
| Research Institute At Nationwide Children's Hospital | $362,796 |
Quick answers
Who received award U01AI155300?
U01AI155300 was awarded to Children's Research Institute by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on August 1, 2021.
How much is award U01AI155300 worth?
$14,619,631 has been obligated on U01AI155300: $13,531,315 in federal funding and $1,088,316 in non-federal funding.
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