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

项目摘要/摘要 脑型疟疾(CM)被定义为恶性疟原虫患者的一种无法解释的昏迷 寄生虫血症。这种情况很常见，主要影响五岁以下的非洲儿童，并有一种 对流行区的公共卫生影响很大。在每年约350,000名确诊为CM的儿童中，15%的人死亡 30%的幸存者在出院时有神经异常。的中流砥柱 治疗方法是静脉注射抗疟疾药物和支持性护理。以前没有任何辅助疗法是 事实证明，在降低这种情况下的高死亡率和发病率方面是有效的。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致残率。 我们将考察谷氨酰胺拮抗剂6-重氮-5-氧代-L去甲亮氨酸(DON)作为候选辅助剂 儿童CM的治疗。我们通过合理的药物发现过程确定了DON，并测试了它的有效性 在几项临床前研究中。实验性心肌炎小鼠有放射学和病理学异常 与人类儿科CM相似；DON用于临床上病情严重的小鼠的抢救 动物的临床、放射学检查，并逆转异常组织病理学。我们将测试唐的安全性和 在人类儿童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简单疟疾的成年人，评估安全性。经过审查，我们将 辅助性DON的随机、安慰剂对照、双盲、安全性和初步疗效研究 在70名患有CM的马拉维儿童中。第一个儿科队列(n=35)的参与者将获得较低剂量的 辅助性DON或安慰剂。辅助性DON给药的第二个儿科队列 参与者(n=35)将从先前收集的药代动力学和安全性数据中获得信息 已注册。我们的主要结果是有3级或严重不良事件的参与者的比例 (SAE)。在安全性研究的同时，DON在儿童CM中的初步疗效将通过以下方法进行评估 脑磁共振成像(MRI)、脑电(EEG)和经颅多普勒(TCD)。我们 假设接受辅助性DON治疗的马拉维CM儿童的死亡率或 与接受安慰剂的参与者相比，SAE的发生率。我们假设患有CM的儿童会收到 辅助性DON的生物标志物改变(MRI、EEG、TCD)与改善预后相关。 总之，这项研究是有意义的，因为辅助疗法DON，当用于小鼠的模型时， Cm，逆转脑肿胀，脑肿胀是CM儿童死亡的最重要风险因素。如果在 随后的人体临床试验，这将是第一个具有明显疗效的辅助疗法 减少这一患者群体中的死亡或残疾。我们预计，随着广泛传播 这种可扩展的干预措施，最终将对这种毁灭性传染病的公共卫生影响 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.