Letermovir Phase I Trial

莱特莫韦 I 期试验

• 批准号: 10248360
• 负责人: DAVID W KIMBERLIN
• 金额: $ 19.16万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10248360
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Adverse event; Affect; African American; Age; Age-Months; Allogenic; Antiviral Agents; Antiviral Therapy; Asian Americans; Birth; Childhood; Cidofovir; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Cytomegalovirus; Cytomegalovirus Infections; Data; Developed Countries; Development; Disease; Dose; Drug Interactions; Drug Kinetics; Enrollment; Esters; Evaluation; Foscarnet; Funding; Future; Ganciclovir; Growth; HIV; Hearing; Hematopoietic Stem Cell Transplantation; Hepatitis C; Infant; Infection; Life; Live Birth; Mental Retardation; Neurologic Deficit; Newborn Infant; Oral; Outcome; Patients; Perinatal Infection; Pharmaceutical Preparations; Phase; Physicians; Prophylactic treatment; Rare Diseases; Regimen; Safety; Secure; Sensorineural Hearing Loss; Serious Adverse Event; Toxic effect; United States Food and Drug Administration; United States National Institutes of Health; Valganciclovir; Valine; Viral; base; cohort; congenital cytomegalovirus; congenital infection; efficacy study; experience; improved; in utero; intravenous administration; neonatal infection; neonate; non-genetic; novel; phase I trial; safety assessment; seropositive; standard of care; symptom treatment; treatment duration; trial readiness

This project, A Phase I Adaptive, Escalating Single-Dose and Multiple-Dose Pharmacokinetic and Safety Assessment of Letermovir in Infants with Symptomatic Congenital Cytomegalovirus Disease, is led by David W. Kimberlin, MD. Congenital cytomegalovirus (CMV) infection is the leading non-genetic cause of sensorineural hearing loss (SNHL) and the most frequent known viral cause of mental retardation, affecting 0.5% to 0.7% of live births in industrialized countries. With a U.S. birth cohort of 3.8 million annually, between 19,000 and 26,600 babies are estimated to be born each year with congenital CMV infection. Ten percent of congenitally infected neonates have symptomatic disease at delivery, of whom 35% have SNHL, up to two- thirds have neurologic deficits, and 4% die in the newborn period. SNHL occurs at a lower rate among the 90% of congenitally infected neonates who are asymptomatic at delivery, but because there are so many more asymptomatic neonates than symptomatic ones the majority of cases of SNHL caused by CMV occurs in this asymptomatic group. The number of antiviral drugs with activity against CMV is very small, with only three active moieties approved by the U.S Food and Drug Administration (FDA): foscarnet (approved in 1991), ganciclovir (approved in 1994), and cidofovir (approved in 1996). Valganciclovir, the L-valine ester of ganciclovir and therefore the same moiety as ganciclovir, was approved in 2001. To date, all studies of the treatment of congenital CMV disease have utilized ganciclovir or valganciclovir, and have documented a modest benefit of treatment on hearing and developmental outcomes. In addition, we have found that patients with symptomatic congenital CMV disease who achieve viral suppression to ≤ 2.5 log by day 14 of therapy and then maintain it over the next 4 months are statistically more likely to have improved hearing across the first two years of life. In November 2017, the FDA approved letermovir for prophylaxis of CMV infection and disease in adult CMV- seropositive recipients of an allogeneic hematopoietic stem cell transplant, making it the first new CMV drug in over two decades. The availability of letermovir as a safe and effective antiviral drug with a completely different mechanism of action from ganciclovir offers the opportunity to explore combination therapy. First, though, the pharmacokinetics and safety of letermovir in neonates must be characterized. We propose to perform a Phase I adaptive, multi-center, dose-escalation evaluation of single-dose and multiple-dose administration of intravenous letermovir in infants with symptomatic congenital CMV disease to develop a safe dosing regimen for neonates and young infants with symptomatic congenital CMV disease.

该项目是一项I期适应性、递增单次给药和多次给药药的药代动力学和安全性研究， 莱特莫韦在有症状的先天性巨细胞病毒病婴儿中的评估，由大卫领导 W. Kimberlin，MD.先天性巨细胞病毒（CMV）感染是导致先天性巨细胞病毒感染的主要非遗传原因。 感音神经性听力损失（SNHL）和最常见的已知病毒性精神发育迟滞的原因， 工业化国家活产的0.5%至0.7%。美国每年有380万人出生， 估计每年有19，000和26，600名婴儿出生时患有先天性CMV感染。的百分之十 先天性感染的新生儿在分娩时有症状性疾病，其中35%患有SNHL，最多2- 三分之一有神经缺陷，4%在新生儿期死亡。SNHL的发生率较低， 90%的先天性感染新生儿在分娩时无症状，但因为有这么多 无症状的新生儿比有症状的，大多数由CMV引起的SNHL病例发生在这 无症状组。 具有抗CMV活性的抗病毒药物的数量非常少，只有三个活性部分被批准 美国食品和药物管理局（FDA）：膦甲酸（1991年批准），更昔洛韦（1994年批准）， 和西多福韦（1996年批准）。缬更昔洛韦，更昔洛韦的L-缬氨酸酯，因此其 2001年批准了更昔洛韦。迄今为止，所有关于先天性CMV疾病治疗的研究 使用更昔洛韦或缬更昔洛韦，并记录了治疗对听力的适度益处， 发展成果。此外，我们发现有症状的先天性CMV病患者 在治疗第14天达到病毒抑制≤ 2.5 log，然后在接下来的4个月内维持该水平的患者是 在统计学上，在生命的头两年更有可能改善听力。 2017年11月，FDA批准莱特莫韦用于预防成人CMV感染和疾病。 异基因造血干细胞移植的血清阳性接受者，使其成为第一个新的CMV药物， 超过二十年。莱特莫韦作为一种安全有效的抗病毒药物， 与更昔洛韦不同的作用机制为探索联合治疗提供了机会。第一、 然而，必须表征莱特莫韦在新生儿中的药代动力学和安全性。我们建议 对单次给药和多次给药进行I期自适应、多中心、剂量递增评价 在患有症状性先天性CMV疾病的婴儿中静脉内施用莱特莫韦以开发安全的 用于患有症状性先天性CMV疾病的新生儿和小婴儿的给药方案。