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 I 期适应性、逐步升级的单剂量和多剂量药代动力学和安全性项目 莱特莫韦对患有症状性先天性巨细胞病毒病婴儿的评估由 David 领导 W.金伯林，医学博士。先天性巨细胞病毒（CMV）感染是导致该病的主要非遗传原因 感音神经性听力损失 (SNHL) 是导致智力低下的最常见的已知病毒原因，影响 工业化国家活产婴儿的 0.5% 至 0.7%。美国每年出生人口为 380 万， 据估计，每年有 19,000 名和 26,600 名婴儿出生时患有先天性 CMV 感染。百分之十的 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，最多可达 2- 三分之一的人患有神经系统缺陷，4% 的人在新生儿期死亡。 SNHL 的发生率较低 90%的先天性感染新生儿在分娩时没有症状，但因为还有更多 无症状新生儿多于有症状新生儿 CMV 引起的 SNHL 病例大多数发生在 无症状群体。 具有抗 CMV 活性的抗病毒药物数量很少，仅批准了三个活性部分 美国食品和药物管理局（FDA）批准：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，因此相同 更昔洛韦 (ganciclovir) 于 2001 年获得批准。迄今为止，所有治疗先天性 CMV 疾病的研究 已使用更昔洛韦或缬更昔洛韦，并记录了治疗对听力和听力有一定的益处 发展成果。此外，我们发现有症状的先天性巨细胞病毒病患者 在治疗第 14 天实现病毒抑制≤ 2.5 log 并在接下来的 4 个月内维持该水平的人 据统计，在生命的头两年里听力得到改善的可能性更大。 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反应呈阳性的受者，使其成为第一个新的 CMV 药物 二十多年来。莱特莫韦作为一种安全有效的抗病毒药物的可用性 与更昔洛韦不同的作用机制为探索联合治疗提供了机会。第一的， 然而，必须确定莱特莫韦在新生儿中的药代动力学和安全性。我们建议 对单剂量和多剂量进行 I 期适应性、多中心、剂量递增评估 对有症状的先天性 CMV 疾病婴儿静脉注射莱特莫韦，以开发安全的 患有症状性先天性 CMV 疾病的新生儿和小婴儿的给药方案。