Letermovir Phase I Trial

莱特莫韦 I 期试验

基本信息

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
项目类别：
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

项目摘要

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.

该项目是第一阶段适应性、逐步升级的单剂量和多剂量药代动力学和安全性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. Kimberlin，医学博士。先天性巨细胞病毒 (CMV) 感染是导致该病的主要原因。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，影响工业化国家的活产率为 0.5% 至 0.7%，美国每年的出生人口为 380 万。据估计，每年有 19,000 和 26,600 名婴儿出生时患有先天性 CMV 感染。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此外，我们发现患有症状性先天性 CMV 疾病的患者。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记者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反应呈阳性的受者，使其成为第一个新的 CMV 药物莱特莫韦作为一种安全有效的抗病毒药物的可用性已超过二十年。与更昔洛韦不同的作用机制为探索联合治疗提供了机会。然而，我们建议必须对新生儿莱特莫韦的药代动力学和安全性进行表征。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。