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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：
Douglas Postels
金额：
$ 119.42万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
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：
https://reporter.nih.gov/project-details/10458716
关键词：
5 year old Adult Adverse event Affect Africa South of the Sahara African Animal Model Animals Antimalarials Area Biological Markers Blood - brain barrier anatomy Brain Edema Cerebral Malaria Cerebrovascular Circulation Cessation of life Child Childhood Clinical Clinical Trials Coma Communicable Diseases Country Data Diagnosis Disease Dose Double-Blind Method Drug Kinetics Economics Electroencephalogram Enrollment Evaluation Future Glutamine Goals Histopathology Hospitals Human Infection Intervention Intravenous Magnetic Resonance Imaging Malaria Medical Staff Morbidity - disease rate Mouse Strains Mus Neurologic Norleucine Outcome Parasitemia Participant Pathologic Patients Pediatric cohort Persons Phase Physiological Placebo Control Placebos Plasmodium berghei Plasmodium falciparum Population Process Public Health Publishing Randomized Research Risk Factors Safety Serious Adverse Event Supportive care Survivors Syndrome Target Populations Testing Therapeutic Intervention Time Toxic effect Training Vulnerable Populations antagonist anti-cancer base brain magnetic resonance imaging brain volume candidate marker clinical efficacy disability drug discovery efficacy study experience improved improved outcome malaria infection mortality mouse model patient population pre-clinical preclinical study primary outcome radiological imaging safety study scale up tumor

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