Clinical effcacy of memantine
Indication
Memantine is indicated for the treatment of patients with moderate to severe AD (MMSE <20).1
The ef?cacy and safety of memantine in this indication has been supported by data from six large-scale, placebo-controlled clinical studies. The design and results of these studies are presented later in this section, after a description of some of the main ef?cacy measures used in these assessments (below).
Assessment measures
Various scales and ef?cacy measures have been employed to assess the in?uence of memantine on AD in terms of disease severity and progression, as well as in the key domains of global status, function, cognition and behaviour. The statistical techniques of meta-analysis and data pooling have also been employed to reinforce and interpret an increasing quantity of memantine clinical data.
Disease severity measures
Measures used to assess disease severity in memantine clinical studies include:
Mini-Mental State Examination (MMSE)
Global Deterioration Scale (GDS)
Functional Assessment Staging (FAST).
The Mini-Mental State Examination (MMSE) is often used to describe or determine the range of disease severity included in AD clinical studies. The scale comprises two sections – verbal score and performance score.2 The overall maximum score is 30 points, and a score below 24 points indicates probable cognitive impairment.2,5 In spite of lack of sensitivity with recognised ‘?ooring’ and ‘ceiling’ effects, the MMSE is widely used to monitor treatment effect on cognition in clinical practice.
The stage of AD at baseline can also be established using the Global Deterioration Scale (GDS)3 or the Functional Assessment Staging instrument (FAST).4 The GDS assesses both cognitive and functional capacity in patients with dementia.3 It comprises seven stages, from stage 1 (normal) to stage 7 (severe dementia), and is scored on the basis of subjective complaints of loss of memory and performance, and on the clinician’s assessment of the patient’s functional capabilities.
The FAST instrument can be used to characterise patients’ disease status, and to assess the progressive functional decline associated with AD by evaluating the performance of daily activities.4 The scale is divided into seven major stages – normal (stage 1) to severe dementia (stage 7) – and stages 6 and 7 are further subdivided into 11 sub-categories (stages 6a to 6e and 7a to 7f).
Ef?cacy measures
There are no speci?c guidelines for investigating the ef?cacy of treatments in moderate to severe AD. While many instruments are available for evaluating global change, cognition, function, and behaviour in AD, most of them have been used to assess mild-to-moderate AD. Some of the memantine studies presented in the following section are the ?rst clinical registration studies in this patient population.
Instruments to be used to assess the ef?cacy of treatment in AD must be validated, reliable, and sensitive to change over a time span corresponding to the duration of the study.
Global change
In the memantine studies, global change in AD has been measured by:
Clinician’s Interview-Based Impression of Change plus caregiver input score (CIBIC-Plus; New York University version)
Clinical Global Impression of Change (CGI-C).
Both of these scales are based on patient interviews by clinicians and both use 7-point scales to evaluate the patient’s clinical change (1=very much improved, 4=no change, 7=very much worse). The CIBIC-Plus also includes observations from the patient’s main carer.
美金刚的临床有效性
适应症
美金刚用于治疗中、重度阿尔茨海默病患者（简易精神状态量表<20）。
六个大规模的安慰剂对照的临床研究研究对美金刚治疗中、重度阿尔茨海默病的有效性及安全性进行了评价。在下面的这些评价方法中，描述一些主要的有效性评价方法后，将在随后部分对这些研究的设计及结果进行阐述。
评价方法
根据患者疾病的严重程度、疾病进展情况以及全身状况、功能、认知能力及行为等方面的关键领域，采用各种量表及有效性评价方法评价美金刚对阿尔茨海默病的影响。采用Meta分析及数据汇总的统计方法增加美金刚临床试验的数据，以对结果进行补充，并解释。
疾病严重程度评价方法
在美金刚临床试验中评价疾病严重程度的方法包括：
简易精神状态量表（MMSE）
整体恶化评分量表
生活功能分期量表
在阿尔茨海默病临床研究中简易精神状态量表通常用于描述或者判断疾病严重程度的范围。量表由两部分构成 ― 语言能力评分及行为能力评分。2总分最高为30分，评分低于24分表明可能存在认知损害2,5。尽管MMSE缺乏敏感性，具有“天花板”效应及“地板”效应，但在临床实践中MMSE还是被广泛用于监测对认知能力的治疗效应。
阿尔茨海姆病在基线的分期也可以通过整体恶化评分量表（GDS）3或者生活功能分期量表(FAST)进行评价。4GDS可评价痴呆患者的认知能力及功能状态。3该量表可分为7级，从1级（正常）至7级（严重痴呆），以主诉记忆丧失、行为能力丧失以及临床医生对患者的功能评价为基础进行评分。
生活功能分期量表（FAST）可用于描述患者的疾病状态，并通过评价患者日常活动能力评估患者阿尔茨海默病相关的进行性功能减退。4该量表分为7个主要级别 ― 正常(1级)至严重痴呆(7级) ― 6级和7级被进一步分为11个亚类(即6a-6e及7a-7f) 。
有效性评价方法
尚无研究美金刚治疗中、重度阿尔茨海默病有效性的特异性指南。尽管有许多方法可以评价阿尔茨海默病患者整体状态变化、认知能力、功能及行为等，但大部分被用于评价轻、重度阿尔茨海默病患者。在下面部分所介绍的一些美金刚研究为首个阿尔茨海默病患者临床注册研究。
用于评价治疗阿尔茨海默病有效性的方法必须得到确证，方法可靠，在研究期间内对患者病情变化敏感。
整体状况变化
在美金刚研究中，阿尔茨海默病患者整体状况变化通过以下方法测量：
基于临床医生访谈的印象变化量表（CIBIC-Plus；纽约大学版）
临床总体状态变化(CGI-C).
所有的这些量表均基于临床医生对患者患者的访谈，并且均采用7级评分制评价患者的临床改变（1=改善非常好，4=无改变，7=非常差）。CIBIC-Plus也包括患者主要照顾者的观察。
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