DON in Pediatric Cerebral Malaria: A Phase I / II Dose-Escalation Safety Study
DON 在小儿脑型疟疾中的应用:I/II 期剂量递增安全性研究
基本信息
- 批准号:10458716
- 负责人:
- 金额:$ 119.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:5 year oldAdultAdverse eventAffectAfrica South of the SaharaAfricanAnimal ModelAnimalsAntimalarialsAreaBiological MarkersBlood - brain barrier anatomyBrain EdemaCerebral MalariaCerebrovascular CirculationCessation of lifeChildChildhoodClinicalClinical TrialsComaCommunicable DiseasesCountryDataDiagnosisDiseaseDoseDouble-Blind MethodDrug KineticsEconomicsElectroencephalogramEnrollmentEvaluationFutureGlutamineGoalsHistopathologyHospitalsHumanInfectionInterventionIntravenousMagnetic Resonance ImagingMalariaMedical StaffMorbidity - disease rateMouse StrainsMusNeurologicNorleucineOutcomeParasitemiaParticipantPathologicPatientsPediatric cohortPersonsPhasePhysiologicalPlacebo ControlPlacebosPlasmodium bergheiPlasmodium falciparumPopulationProcessPublic HealthPublishingRandomizedResearchRisk FactorsSafetySerious Adverse EventSupportive careSurvivorsSyndromeTarget PopulationsTestingTherapeutic InterventionTimeToxic effectTrainingVulnerable Populationsantagonistanti-cancerbasebrain magnetic resonance imagingbrain volumecandidate markerclinical efficacydisabilitydrug discoveryefficacy studyexperienceimprovedimproved outcomemalaria infectionmortalitymouse modelpatient populationpre-clinicalpreclinical studyprimary outcomeradiological imagingsafety studyscale uptumor
项目摘要
Project Summary/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.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Douglas Postels', 18)}}的其他基金
Evaluating EEG as a diagnostic and prognostic biomarker in Malawian children with febrile coma
评估脑电图作为马拉维热昏迷儿童的诊断和预后生物标志物
- 批准号:
10523296 - 财政年份:2023
- 资助金额:
$ 119.42万 - 项目类别:
DON in Pediatric Cerebral Malaria: A Phase I / II Dose-Escalation Safety Study
DON 在小儿脑型疟疾中的应用:I/II 期剂量递增安全性研究
- 批准号:
10248058 - 财政年份:2021
- 资助金额:
$ 119.42万 - 项目类别:
DON in Pediatric Cerebral Malaria: A Phase I / II Dose-Escalation Safety Study
DON 在小儿脑型疟疾中的应用:I/II 期剂量递增安全性研究
- 批准号:
10624265 - 财政年份:2021
- 资助金额:
$ 119.42万 - 项目类别:
Viral Co-Infections in Cerebral Malaria: Preparing for Clinical Trials
脑型疟疾的病毒合并感染:为临床试验做准备
- 批准号:
8617351 - 财政年份:2014
- 资助金额:
$ 119.42万 - 项目类别:
Viral Co-Infections in Cerebral Malaria: Preparing for Clinical Trials
脑型疟疾的病毒合并感染:为临床试验做准备
- 批准号:
8824954 - 财政年份:2014
- 资助金额:
$ 119.42万 - 项目类别:
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