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：
10624265
负责人：
Douglas Postels
金额：
$ 120.14万
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/10624265
关键词：
5 year old Adult Adverse event Affect Africa South of the Sahara African Animal Model Animals Antimalarials Antineoplastic Agents Area Biological Markers Blood - brain barrier anatomy Brain Edema Cephalic 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 Electroencephalography 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 Predisposition 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 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 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.

项目概要/摘要脑型疟疾 (CM) 被定义为恶性疟原虫患者出现无法解释的昏迷这种疾病很常见，主要影响五岁以下的非洲儿童，并且具有传染性。每年诊断出患有 CM 的约 350,000 名儿童中，有 15% 死亡。 30% 的幸存者在出院时出现神经系统异常。治疗方法是静脉注射抗疟药物和支持治疗，以前没有进行过辅助治疗。事实证明，可以有效降低这种情况下的高死亡率和发病率。建立可行的疗法，降低这一弱势群体的死亡率和残疾率。我们将研究 6-diazo-5-oxo-L-norleucine (DON)（一种谷氨酰胺拮抗剂）作为候选辅助剂我们通过合理的药物发现过程确定了 DON 并测试了其疗效。在一些临床前研究中，患有实验性 CM 的小鼠存在放射学和病理学异常。与人类儿童 CM 中观察到的类似，对患有严重临床疾病的小鼠进行 DON 治疗；我们将测试 DON 的安全性和逆转异常的组织病理学。为此，我们将首先对 DON 进行剂量递增研究。健康的马拉维成年人和患有无并发症疟疾的成年人，在审查后评估安全性。进行一项辅助 DON 的随机安慰剂对照双盲安全性和初步疗效研究第一个儿科队列的 70 名马拉维儿童 (n=35) 将接受较低剂量的治疗。给予第二组儿科的辅助 DON 或安慰剂剂量。参与者 (n=35) 将了解从之前收集的药代动力学和安全性数据我们的主要结果是发生任何 3 级或严重不良事件的参与者的比例。 (SAE) 与安全性研究同时，将使用 DON 在儿科 CM 中的初步疗效进行评估。脑磁共振成像 (MRI)、脑电图 (EEG) 和经颅多普勒 (TCD)。坚持认为接受辅助 DON 治疗的马拉维患有 CM 的儿童不会增加死亡率或与接受安慰剂的参与者相比，我们跟踪了患有 CM 的儿童的 SAE 发生率。辅助 DON 会产生与改善预后相关的生物标志物变化（MRI、EEG、TCD）。总之，这项研究意义重大，因为辅助疗法 DON 用于小鼠模型时 CM，逆转脑肿胀，这是 CM 儿童死亡的最重要的危险因素。随后的人体临床试验中，这将是第一个对患者有明显效果的辅助疗法我们预计随着病毒的广泛传播，该患者群体的死亡或残疾将会减少。如此可扩展的干预措施，这种毁灭性传染病对公共卫生的影响最终将减少。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

DON in pediatric cerebral malaria, a phase I/IIA dose-escalation safety study: study protocol for a clinical trial.

DON 在小儿脑型疟疾中的应用，I/IIA 期剂量递增安全性研究：临床试验的研究方案。

DOI：
发表时间：
2024-01-26
期刊：
影响因子：
2.5
作者：
Nampota;Nyirenda, Osward M;Mallewa, Jane;Chimalizeni, Yamikani;Dzabala, Nettie;Fay, Michael P;Gopalakrishnan, Mathangi;Laurens, Matthew B;O'Brien, Nicole F;Miller, Louis H;Pierce, Susan K;Riggle, Brittany A;Postels, Douglas G
通讯作者：
Postels, Douglas G