DON in Pediatric Cerebral Malaria: A Phase I / II Dose-Escalation Safety Study

项目概要/摘要 脑型疟疾（CM）是指恶性疟原虫感染者发生的原因不明的昏迷 寄生虫血症这种情况很常见，主要影响不到五岁的非洲儿童， 对流行地区的公共卫生产生重大影响。在每年诊断出的约350，000名CM儿童中，15%死亡 30%的幸存者在出院时有神经系统异常。的中流砥柱 治疗是静脉注射抗疟药物和支持性护理。以前没有治疗方法， 已被证明有效降低这种情况下的高死亡率和发病率。我们的长期目标是 建立可行的治疗方法，降低这一弱势群体的死亡率和残疾率。 我们将研究谷氨酰胺拮抗剂6-重氮-5-氧代-L-正亮氨酸（DON）作为候选药物， 治疗小儿CM。我们通过合理的药物发现过程确定了DON并测试了其疗效 在几个临床前研究中。实验性CM小鼠的影像学和病理学异常 类似于在人类儿科CM中观察到的那些; DON给予严重临床疾病抢救的小鼠 动物临床上，放射学，并逆转异常的组织病理学。我们将测试唐的安全性， 在人类儿科CM中的初步疗效。为此，我们将首先进行DON的剂量递增研究， 健康的马拉维成年人和患有单纯性疟疾的成年人，评估安全性。经过审查，我们将 进行一项随机安慰剂对照的双盲安全性和初步疗效研究 在70名马拉维儿童CM。第一个儿科队列的参与者（n=35）将接受较低剂量的 DON或安慰剂。给予第二组儿童的抗DON剂量 参与者（n=35）将被告知从先前研究中收集的药代动力学和安全性数据。 注册了我们的主要结局是发生任何3级或严重不良事件的受试者比例 （SAE）。与安全性研究同时进行的是，DON在儿科CM中的初步疗效将使用以下方法进行评估： 脑磁共振成像（MRI）、脑电图（EEG）和经颅多普勒（TCD）。我们 假设马拉维CM儿童接受预防性DON治疗后死亡率不会增加， 与接受安慰剂的受试者相比的SAE发生率。我们假设接受CM治疗的儿童 持续性DON将具有与改善的结果相关的生物标志物变化（MRI、EEG、TCD）。 总之，这项研究是有意义的，因为连续治疗，DON，当用于小鼠模型， 逆转脑肿胀，脑肿胀是CM儿童死亡的最重要危险因素。如果成功， 在随后的人体临床试验中，这将是第一个对人类具有明显效果的连续疗法。 降低该患者群体的死亡或残疾。我们预计，随着广泛传播 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。

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.