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

 描述（由申请人提供）：婴儿单纯疱疹病毒（HSV）感染是致命的，幸存者有神经发育障碍的高风险，包括智力迟钝和脑瘫。在幸存者中，累及中枢神经系统的新生儿单纯疱疹病毒造成长期神经发育障碍的风险最高（70-86%）。口服阿昔洛韦抑制治疗可改善有中枢神经系统HSV疾病史的婴儿的神经发育结局;然而，抗病毒治疗的最有效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（CSF）水平在儿科人群中高度可变; 2）抗病毒CSF浓度≤血浆水平的50%; 3）阿昔洛韦的口服吸收较低。虽然在一项小型随机试验中，6个月的阿昔洛韦治疗上级安慰剂，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。伐昔洛韦口服后迅速转化为无环鸟苷，由于口服吸收改善和给药间隔更长，可能是更好的替代方案。本提案的目的是制定一项临床试验方案，以比较长期口服伐昔洛韦治疗与短期口服阿昔洛韦治疗对改善有中枢神经系统HSV病史的婴儿神经发育结局的疗效。本提案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; 4）试验操作。Smith博士将为一项前瞻性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 口服抗病毒抑制剂的疗效研究中约60个临床部位的HSV感染 疗法婴儿将被随机分为2组：第1组受试者将接受口服阿昔洛韦， 组2受试者将接受伐昔洛韦治疗2年。研究的主要结局是在28-32个月龄时测量的神经发育障碍。次要终点将包括突破性HSV感染的数量、死亡率、安全性和阿昔洛韦和伐昔洛韦的药代动力学。本研究将在FDA监督下进行，研究结果将提交给FDA以更改药物标签。Smith博士将通过以下方式实现本提案的目标：1）利用DCRI的专业知识设计并最终确定临床试验的完整方案; 2）起草知情同意书的模板; 3）制定拟议临床试验的预算; 4）从FDA获得方案的研究新药申请; 5）制定试验操作手册、培训材料和临床试验里程碑; 6）制定数据收集表; 7）建立数据安全性监查委员会。

 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.