抗病毒治疗：伐昔洛韦治疗阿尔茨海默病（VALAD）试验：一项随机、双盲、安慰剂对照治疗试验的方案。
Antiviral therapy: Valacyclovir Treatment of Alzheimer's Disease (VALAD) Trial: protocol for a randomised, double-blind,placebo-controlled, treatment trial.
机构信息
Department of Psychiatry, Columbia University, New York, New York, USA
Division of Geriatric Psychiatry, New York State Psychiatric Institute, New York, New York, USA.
出版信息
BMJ Open. 2020 Feb 6;10(2):e032112. doi: 10.1136/bmjopen-2019-032112.
INTRODUCTION
After infection, herpes simplex virus-1 (HSV1) becomes latent in the trigeminal ganglion and can enter the brain via retrograde axonal transport. Recurrent reactivation of HSV1 may lead to neurodegeneration and Alzheimer's disease (AD) pathology. HSV1 (oral herpes) and HSV2 (genital herpes) can trigger amyloid beta-protein (Aβ) aggregation and HSV1 DNA is common in amyloid plaques. Anti-HSV drugs reduce Aβ and phosphorylated tau accumulation in cell-culture models. Cognitive impairment is greater in patients with HSV seropositive, and antiviral drugs show robust efficacy against peripheral HSV infection. Recent studies of electronic health records databases demonstrate that HSV infections increase dementia risk, and that antiviral medication treatment reduces this risk. The generic antiviral drug valacyclovir was superior to placebo in improving memory in a schizophrenia pilot trial but has not been tested in AD.
METHODS AND ANALYSIS
In patients with mild AD who test positive for HSV1 or HSV2 serum antibodies, valacyclovir, repurposed as an anti-AD drug, will be compared with placebo (lactose pills) in 130 patients (65 valacyclovir and 65 placebo) in a randomised, double-blind, 78-week phase II proof-of-concept trial. Patients on valacyclovir, dose-titrated from 2 g to a targeted oral dose of 4 g daily, compared with placebo, are hypothesised to show smaller cognitive and functional decline, and, using F-Florbetapir positron emission tomography (PET) and F-MK-6240 PET imaging, to show less amyloid and tau accumulation, respectively. In the lumbar puncture subsample, cerebrospinal fluid acyclovir will be assayed to assess central nervous system valacyclovir penetration.
ETHICS AND DISSEMINATION
The trial is being overseen by the New York State Psychiatric Institute Institutional Review Board (protocol 7537), the National Institute on Ageing, and the Data Safety Monitoring Board. Written informed consent is obtained for all subjects. Results will be disseminated via publication, clinicaltrials.gov, media and conferences.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov identifier (NCT03282916) Pre-results.
简介
感染后，单纯疱疹病毒 1（HSV1）潜伏在三叉神经节中，并可通过逆行轴突运输进入大脑。HSV1 的复发性再激活可能导致神经退行性变和阿尔茨海默病（AD）病理。HSV1（口腔疱疹）和 HSV2（生殖器疱疹）可引发淀粉样β蛋白（Aβ）聚集，HSV1 DNA 常见于淀粉样斑块中。抗 HSV 药物可减少细胞培养模型中 Aβ和磷酸化 tau 的积累。HSV 血清阳性患者的认知障碍更严重，抗病毒药物对周围 HSV 感染具有强大的疗效。电子健康记录数据库的最近研究表明，HSV 感染会增加痴呆风险，抗病毒药物治疗可降低这种风险。通用抗病毒药物伐昔洛韦在精神分裂症的一项先导试验中优于安慰剂，改善了记忆，但尚未在 AD 中进行测试。
方法和分析
在 HSV1 或 HSV2 血清抗体检测呈阳性的轻度 AD 患者中，将伐昔洛韦（重新用于抗 AD 药物）与安慰剂（乳糖丸）在 130 例患者（伐昔洛韦 65 例，安慰剂 65 例）中进行随机、双盲、78 周 2 期概念验证试验比较。与安慰剂相比，接受伐昔洛韦（从 2g 滴定剂量至每日 4g 的目标口服剂量）治疗的患者，预计认知和功能下降幅度较小，并且使用 F-Florbetapir 正电子发射断层扫描（PET）和 F-MK-6240 PET 成像，分别显示出较少的淀粉样蛋白和 tau 积累。在腰椎穿刺子样本中，将测定脑脊液阿昔洛韦以评估中枢神经系统伐昔洛韦穿透。
伦理和传播
该试验由纽约州精神病学研究所机构审查委员会（协议 7537）、美国国立老化研究所和数据安全监测委员会监督。所有受试者均获得书面知情同意。结果将通过发表、clinicaltrials.gov、媒体和会议进行传播。
试验注册号
ClinicalTrials.gov 标识符（NCT03282916）预结果。
Zotero 插件