Efficacy of Antiviral Suppression Therapy after Neonatal HSV Infection of the CNS

 描述(申请人提供)：婴儿感染单纯疱疹病毒(HSV)是致命的，幸存者有很高的神经发育障碍风险，包括智力低下和脑瘫。在幸存者中，涉及中枢神经系统的新生儿HSV具有长期神经发育损害的最高风险(70%-86%)。口服阿昔洛韦抑制疗法改善了有中枢神经系统单纯疱疹病毒病史的婴儿的神经发育结果；然而，最有效的抗病毒治疗剂量和持续时间尚不清楚。较高的抗病毒剂量可能是有益的，因为：1)抗病毒血浆和脑脊液水平在儿童人群中变化很大；2)抗病毒脑脊液浓度是血浆水平的50%；3)阿昔洛韦的口服吸收很低。虽然在一项小型随机试验中，6个月的阿昔洛韦治疗被证明优于安慰剂，但更长和更高剂量的阿昔洛韦疗程被证明是安全的，而且可能更有效。万乃洛韦在口服后迅速转化为阿昔洛韦，由于口服吸收的改善和更长的给药间隔，它可能是一种更好的替代品。这项建议的目的是开发一种临床试验方案，比较长期口服万乃洛韦治疗和短期口服阿昔洛韦治疗在改善有中枢神经系统单纯疱疹病史的婴儿神经发育结果方面的有效性。这项建议将利用杜克临床研究所(DCRI)在以下领域的专业知识：1)监管；2)药物计量学；3)生物统计学；以及4)试验操作。史密斯博士将为一项预期的多中心研究制定一项方案，该方案将提交给NIAID，以获得潜在的资金。他预计将招募90名有中枢神经系统病史的婴儿 口服抗病毒药物疗效研究中约60个临床部位的HSV感染 心理治疗。婴儿将被随机分成两组：第一组受试者口服阿昔洛韦，疗程6 2组患者接受万乃洛韦治疗2年。这项研究的主要结果将是在28-32个月龄时测量神经发育障碍。次要终点将包括突破性单纯疱疹病毒感染的数量、死亡率、安全性和阿昔洛韦和万乃洛韦的药代动力学。这项研究将在FDA的监督下进行，研究结果将提交给FDA以更改药品标签。史密斯博士将通过以下方式实现这项建议的目标：1)利用DCRI的专业知识设计和最终确定临床试验的完整方案；2)为知情同意起草模板；3)为拟议的临床试验制定预算；4)从FDA获得方案的研究用新药申请；5)编写试验操作、培训材料和临床试验里程碑的手册；6)开发数据收集表格；以及7)建立数据安全监测委员会。

 DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) infections in infants are deadly, and survivors are at high risk of neurodevelopmental impairment including mental retardation and cerebral palsy. Neonatal HSV involving the central nervous system carries the highest risk of long-term neurodevelopmental impairment (70-86%) among survivors. Oral acyclovir suppressive therapy improves neurodevelopmental outcomes in infants with a history of central nervous system HSV disease; however, the most effective dose and duration of antiviral therapy are unknown. Higher antiviral doses may be beneficial because: 1) antiviral plasma and cerebrospinal fluid (CSF) levels are highly variable in pediatric populations; 2) antiviral CSF concentrations are ≤50% of plasma levels; 3) and oral absorption of acyclovir is low. Although 6 months of acyclovir therapy was shown to be superior to placebo in a small randomized trial, longer and higher dose courses of acyclovir were shown to be safe and potentially more effective. Valacyclovir, which is rapidly converted to acyclovir after oral administration, may be a better alternative due to improved oral absorption and longer dosing intervals. The aim of this proposal is to develop a clinical trial protocol to compare the efficacyof long-term oral valacyclovir therapy with short-term oral acyclovir therapy for improving neurodevelopmental outcomes in infants with a history of central nervous system HSV. This proposal will capitalize on the expertise of the Duke Clinical Research Institute (DCRI) in the following areas: 1) regulatory; 2) pharmacometrics; 3) biostatistics; and 4) trial operations. Dr. Smith will develop a protocol for a prospective multicenter study that will be submitted to NIAID for potential funding. He anticipates enrolling 90 infants with a history of central nervous system HSV infection at approximately 60 clinical sites in an efficacy study of oral antiviral suppressive therapy. Infants will be randomized to 2 groups: group 1 subjects will receive oral acyclovir for 6 months, and group 2 subjects will receive valacyclovir for 2 years. The primary outcome of the study will be neurodevelopmental impairment measured at 28-32 months of age. Secondary end points will include the number of breakthrough HSV infections, mortality, safety, and pharmacokinetics of acyclovir and valacyclovir. This study will be conducted under FDA oversight, and study results will be submitted to the FDA to change the drug labels. Dr. Smith will accomplish the aim of this proposal by: 1) using the expertise at the DCRI to design and finalize a complete protocol for the clinical trial; 2) drafting a template for the informed consen; 3) developing a budget for the proposed clinical trial; 4) obtaining an investigational new drug application for the protocol from the FDA; 5) developing a manual of trial operations, training materials, and clinical trial milestones; 6) developing data collection forms; and 7) establishing data safety monitoring board.