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期自适应，单剂量和多剂量药代动力学和安全性的升级 对有症状的先天性巨细胞病毒病的婴儿的letermovir评估，由David领导 W. Kimberlin，医学博士。先天性巨细胞病毒（CMV）感染是主要的非遗传原因 感官听力损失（SNHL）和最常见的智力病毒原因，影响 工业化国家的活产活性为0.5％至0.7％。美国每年有380万的美国出生队列 据估计，每年有19,000和26,600名婴儿出生于先天性CMV感染。百分之十 先天感染的新生儿在分娩时患有症状性疾病，其中35％的SNHL最高可 三分之二的神经功能缺陷，在新生儿时期死亡4％。 SNHL的发生率较低 90％的先天性感染的新生儿在分娩时是不对称的，但是有更多的新生儿 无症状的新生儿比有症状的新生儿大多数由CMV引起的SNHL病例发生在此中 无症状组。 针对CMV活性的抗病毒药物的数量很少，只有三个主动部分批准 美国食品和药物管理局（FDA）：Foscarnet（1991年批准），Ganciclovir（1994年批准），， 和Cidofovir（1996年批准）。 valganciclovir，Ganciclovir的L-缬氨酸酯，因此相同 部分作为Ganciclovir，于2001年获得批准。迄今为止，所有有关先天性CMV疾病的研究 已经使用了Ganciclovir或Valganciclovir，并记录了听力和 发展结果。此外，我们发现有症状先天性CMV疾病的患者 在治疗的第14天之前，将病毒抑制至≤2.5log，然后在接下来的4个月内维持。 从统计学上讲，在整个生命的头两年中，更有可能改善听力。 2017年11月，FDA批准了成人CMV-的CMV感染和疾病预防的Lettermovir 同种异体造血干细胞移植的血清胶质接受者，使其成为第一个新的CMV药物 超过二十年。 Letermovir作为一种安全有效的抗病毒药物的可用性 Ganciclovir的不同作用机制为探索组合疗法提供了机会。第一的， 但是，必须对新生儿中Leteromovir的药代动力学和安全性进行表征。我们建议 进行I期自适应，多中心的单剂量和多剂量评估 在患有先天性CMV疾病的婴儿中静脉注射液体的静脉注销以开发安全 有症状先天性CMV疾病的新生儿和年轻婴儿的给药方案。