This 12-week study comprised 167 dementia patients in a nursing home setting, 79 of whom had a con?rmed diagnosis of AD (prospectively de?ned).³⁰ Eligible patients had to have an MMSE score <10 (mean baseline score = 6.3), and be in GDS stage 5, 6 or 7. Other eligibility criteria included an age of between 60 and 80 years, a diagnosis of dementia according to DSM-III-R criteria, and a Hachinski Ischemic Scale (HIS) total score <5 points for the AD subgroup. Baseline characteristics were similar between the memantine and placebo patient groups.

Study assessments took place at Weeks 1, 4, 8, and 12 (endpoint), or at dropout. Ef?cacy analysis was performed on the ITT population of all patients, and a separate analysis was carried out in the AD subgroup.³⁰

In the moderately-severe to severe dementia population, memantine produced improvements in:

·            global status (CGI-C) – improvements were statistically signi?cant versus placebo from Week 4 onwards. A positive response (de?ned as any degree of improvement) at Week 12 (endpoint) in favour of memantine was seen in 73% vs 45% of patients (p<0.001, LOCF analysis) (Figure 6.23)

·            function, in terms of care dependency (BGP subscale) – improvements were statistically signi?cant versus placebo at Week 12 (endpoint) (p=0.016, LOCF analysis)

·            function and behaviour (BGP total score) – statistically signi?cant bene?t for memantine versus placebo (-7.2 points vs -4.6 points; p=0.015, LOCF analysis).

 

In the AD subgroup, memantine produced significant benefits in the three main domains of global status (CGI-C), function (BGP care dependency subscale) and cognition (BGP cognition subscale).

 

Although memantine is currently indicated for the treatment of AD, its mode of action gives rise to the possibility that it may be useful in other neurodegenerative diseases, with many studies currently ongoing regarding its use in other indications.

No drugs are currently licensed to treat VaD, and therefore its treatment is limited to secondary prevention via the control of known vascular risk factors. However, the neurotoxicity that is caused by glutamate-induced tonic stimulation of the NMDA receptor that occurs in AD, can also be induced by ischaemia.⁶⁸ Therefore, it might be expected that, via its ability to block the NMDA receptor, memantine could protect against further cortical neurodegeneration in VaD.

In addition to the mixed population (AD/VaD) observed in study MRZ-9403,¹⁵ two clinical studies (MMM 300 and MMM 500) have speci?cally investigated the use of memantine in patients with VaD.^69,70 Both VaD trials were multicentre, randomised, double-blind, placebo-controlled studies in patients with probable mild to moderate VaD (MMSE 12–20).^69,70 Patients with other types of dementia were excluded.^69,70

The studies were 28 weeks in duration, with an additional open-label extension period of 24 weeks.^69,70 Patients received a ?xed-dose of memantine 20 mg/day (10 mg bid) as monotherapy, and primary endpoints were global status (CIBIC-Plus; CGI-C) and cognition (ADAS-Cog).^69,70

 

Huayiwang Chinese Translation Company has translated many professional documents about Clinical studies in VaD.

 

这项为期12周的研究入组了167名护理院的痴呆患者，79名患者已确证为AD（前瞻性定义）³⁰ 。合格的受试者必须满足以下条件：MMSE<10（基线评价分=6.3），GDS分级为5、6或7。其他的入组标准包括年龄60-80岁；根据DSM-III-R标准诊断为痴呆；AD患者组Hachinski缺血指数量表（HIS）总分<5分。美金刚组及安慰剂组基线特征相似。

在第1周、第4周、第8周、第12周（观察终点）或者受试者脱落时，进行研究评价。对所有患者的ITT数据集进行有效性分析，同时对AD亚组进行单独分析³⁰。

 

在中-重度及重度痴呆患者中，经美金刚治疗后在以下方面出现改善：

·         整体状况（CGI-C） ― 自第4周开始，与安慰剂组比较，美金刚组的改善情况具有显著统计学意义。在第12周时（观察终点），美金刚组阳性应答（定义为任何程度的改善）为73%，而安慰剂组为45%（p<0.001，LOCF分析）（图6.23）

·         功能，根据护理依赖情况进行评价（BGP次级量表） ― 在第12周时（观察终点），与安慰剂组比较，改善情况具有显著统计学意义（p=0.016，LOCF分析）

·         功能及行为（BGP总分）― 与安慰剂组比较，美金刚组具有明显的统计学受益（美金刚组：-7.2分，安慰剂组：-4.6分；p=0.015，LOCF分析）。

 

在AD亚组，在整体状况（CGI-C）、功能（BGP护理依赖次级量表）及认知能力（BGP认知能力次级量表）等三个主要域方面，美金刚可以使患者明显受益³⁰。

尽管美金刚当前的适应症为治疗AD，美金刚的作用方式提出了这种可能：即美金刚可被用于治疗其他神经变性疾病。当前许多研究正在开展美金刚其他适应症方面的研究。

当前尚无药物被批准用于治疗血管性痴呆，因而血管性痴呆饿治疗仅限于通过控制已知的血管风险因素进行二级预防。然而，在AD中，由谷氨酸盐诱导的NMDA受体紧张性刺激所导致的神经毒性也可由缺血诱导⁶⁸。因此，期望通过美金刚阻断NMDA受体，从而阻止血管性痴呆患者大脑皮质的进一步神经退行性变。

除了MRZ-9403研究中观察的混合人群（AD/VaD）外¹⁵，另两个临床研究（MMM 300 及MMM 500）特异性地探讨美金刚在血管性痴呆患者中的应用^69,70。两个血管性痴呆试验均为多中心、随机、双盲、安慰剂对照研究，入组的受试者为轻、中度血管性痴呆患者（MMSE 12-20）^69,70。其他类型的痴呆患者排除在外^69,70。

这两项研究的研究周期为28周，并另外进行了为期24周的开放性扩展研究^69,70。受试者接受固定剂量的单一美金刚治疗（20mg/天，10mg一次，一天两次），主要的观察终点为整体状况（CIBIC-Plus；CGI-C）及认知能力（ADAS-Cog）^69,70。

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