DON in pediatric cerebral malaria, a phase I/IIA dose-escalation safety study: study protocol for a clinical trial.
DON in pediatric cerebral malaria, a phase I/IIA dose-escalation safety study: study protocol for a clinical trial.
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尽管使用了高效的抗疟疾药物进行治疗，但在撒哈拉以南非洲，疟疾每年夺去50多万5岁以下儿童的生命。脑型疟疾定义为恶性疟原虫感染并昏迷，是死亡率最高的重症疟疾综合征。在CM小鼠模型中的研究表明，T细胞介导的反应是CM病理的基础，为人类的治疗开辟了新的靶点。本试验旨在确定谷氨酰胺拮抗剂6-重氮-5-氧代-L去甲亮氨酸(DON)的初步安全性。在这项I/IIa期剂量递增临床试验中，单剂量静脉注射DON给三个参与者组--健康成人和患有无并发症疟疾的成人，然后是患有CM的儿科参与者--以初步评估安全性。这项试验的次要目标是评估DON在一定剂量范围内的药代动力学。试验的开放标签成人部分招募了40名健康成年人和40名患有简单疟疾的成年人。由10名参与者组成的队列接受单次静脉注射安非他明，队列之间的剂量从0.1g/kg、1.0g/kg、5.0g mg/kg增加到10g/kg。在随后的安全性审查之后，一项随机、双盲和安慰剂对照的儿科研究招募了72名患有CM的6个月至14岁的参与者。这项研究的儿科部分至少跨越三个疟疾季节，包括计划在50%的儿科登记后进行的中期分析。前一半的儿科参与者服用DON 0.1%mg/kg、1.0%mg/kg或安慰剂。儿科参与者的后半部分的剂量是由先前登记的人的安全性和初步疗效结果来告知的。这项研究的儿科部分具有评估DON初步疗效的探索性结果。疗效是通过对CM结果的诊断预测来评估的：脑电(EEG)、磁共振成像(MRI)和经颅多普勒(TCD)，在服用DON前后进行测量。所有疟疾患者根据当地指南接受标准的抗疟疾药物治疗，无论研究药物剂量组如何。这项初步的安全性和有效性研究评估了DON，一种儿科CM辅助治疗的候选药物。如果结果支持初步的安全性和有效性，将说明后续的II和III期临床试验。这项试验于2022年7月28日在ClinicalTrials.gov上注册(NCT05478720)。
Despite treatment with highly effective antimalarial drugs, malaria annually claims the lives of over half a million children under 5-years of age in sub-Saharan Africa. Cerebral malaria (CM), defined as Plasmodium falciparum infection with coma, is the severe malaria syndrome with the highest mortality. Studies in the CM mouse model suggest that a T cell-mediated response underlies CM pathology, opening a new target for therapy in humans. This trial aims to establish the preliminary safety of one such novel therapy, the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON). In this phase I/IIa dose-escalation clinical trial, a single dose of intravenous (IV) DON is administered to three participants groups—healthy adults and adults with uncomplicated malaria, then pediatric participants with CM—to primarily assess safety. The secondary objective of this trial is to assess pharmacokinetics of DON over a range of doses. The open-label adult portion of the trial enrolls 40 healthy adults concurrently with 40 adults with uncomplicated malaria. Cohorts of 10 participants receive a single IV dose of DON with doses escalating between cohorts from 0.1 mg/kg, 1.0 mg/kg, 5.0 mg/kg, to 10 mg/kg. Following subsequent safety review, a randomized, double-blind, and placebo-controlled pediatric study enrolls 72 participants aged 6 months to 14 years with CM. The pediatric portion of the study minimally spans three malaria seasons including a planned interim analysis after 50% of pediatric enrollments. The first half of pediatric participants receive DON 0.1 mg/kg, 1.0 mg/kg, or placebo. Dosing for the second half of pediatric participants is informed by the safety and preliminary efficacy results of those previously enrolled. The pediatric portion of the study has an exploratory outcome evaluating the preliminary efficacy of DON. Efficacy is assessed by diagnostics predictive of CM outcome: electroencephalography (EEG), magnetic resonance imaging (MRI), and transcranial doppler (TCD), measured before and after DON administration. All participants with malaria receive standard of care antimalarials in accordance with local guidelines, regardless of study drug dose group. This preliminary safety and efficacy study evaluates DON, a candidate adjunctive therapy for pediatric CM. If results support DON preliminary safety and efficacy, follow-up phase II and III clinical trials will be indicated. This trial was registered on ClinicalTrials.gov on 28 July 2022 (NCT05478720).
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DOI：
10.4269/ajtmh.1991.45.608
发表时间：
1991-11-01
影响因子：
3.3
作者：
HEMMER, CJ;KERN, P;DIETRICH, M
通讯作者：
DIETRICH, M
影响因子：
5.2
作者：
Newton, CRJC;Crawley, J;Kirkham, FJ
通讯作者：
Kirkham, FJ
影响因子：
11.8
作者：
Maitland, K;Pamba, A;Levin, M
通讯作者：
Levin, M
影响因子：
5.1
作者：
O'Brien, Nicole Fortier;Taty, Tshimanga Mutatshi;Yotebieng, Marcel
通讯作者：
Yotebieng, Marcel
影响因子：
3
作者：
Namutangula B;Ndeezi G;Byarugaba JS;Tumwine JK
通讯作者：
Tumwine JK