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
• 负责人: Douglas Postels
• 金额: $ 108.83万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 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/10248058
• 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; Brain Edema; Cerebral Malaria; Cerebrovascular Circulation; Cessation of life; Child; Childhood; Clinical; Clinical Trials; Coma; Communicable Diseases; Country; Data; Diagnosis; Diagnostic radiologic examination; 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; Phase; Physiological; 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; anti-cancer; base; 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; safety study; scale up; tumor

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.

项目摘要/摘要 脑疟疾（CM）定义为恶性疟原虫患者的原本无法解释的昏迷 寄生虫。这种情况很常见，主要影响不到五年的非洲儿童，并且有一个 大型公共卫生对内在地区的影响。在每年被诊断出广告的约35万名儿童中，有15％死亡 出院时，有30％的表面有神经异常。主要的中流tay 治疗是静脉内抗疟药和支持性护理。以前没有辅助疗法 被证明有效地降低了这种情况下的高死亡率和发病率。我们的长期目标是 建立可行的疗法，以降低该脆弱人群的死亡和残疾率。 我们将研究谷氨酰胺拮抗剂6-二氧二氧二氧化碳-5-氧 小儿CM的治疗。我们通过合理的药物发现过程确定了Don并测试了其有效性 在几项临床前研究中。具有实验CM的小鼠具有射线学和病理异常 类似于人类小儿CM中看到的那些；对严重临床不良救援的小鼠施用 动物在临床上，射线照相上并逆转异常的组织病理学。我们将测试Don的安全 人小儿CM的初步效率。为此，我们将首先对DON进行剂量升级研究 健康的马拉维成年人和具有简单疟疾的成年人，评估安全性。审查后，我们将 进行随机安慰剂对照的双盲安全性和辅助性DON的初步有效性研究 在有70名厘米的马拉维儿童中。第一个儿科队列的参与者（n = 35）将获得较低剂量的 辅助唐或安慰剂。给予第二个小儿队列的辅助剂剂量 参与者（n = 35）将通过以前收集的药代动力学和安全数据告知 注册。我们的主要结果是参加任何3级或严重不良事件的参与者的比例 （SAE）。同时，随着安全性研究，DON的小儿CM初步效率将使用 大脑磁共振成像（MRI），脑电图（EEG）和经颅多普勒（TCD）。我们 假设接受辅助DON的CM的马拉维儿童不会增加死亡率或 与接受安慰剂的参与者相比，SAE的比率。我们假设CM接收的孩子 辅助DON将具有与改善结果相关的生物标志物变化（MRI，EEG，TCD）。 总而言之，这项研究很重要，因为辅助疗法当在鼠模型中使用 CM逆转大脑肿胀，这是CM儿童死亡最重要的危险因素。如果成功 随后的人类临床试验，这将是第一次对 减少该患者人群的死亡或残疾。我们预计会随着宽度的传播 这种可扩展的干预措施，这种毁灭性传染病的公共卫生影响最终将 减少。