Memantine clinical studies in AD
The efficacy and safety of memantine has been investigated in six large-scale, Phase III, placebo-controlled clinical studies – three in moderate to severe AD and three in mild to moderate AD. These trials are discussed below.
Design overview
All six outpatient studies shared the following design features:
6-month study duration, including a 4-week titration period
placebo-controlled
randomised
double-blind
multicentre
parallel-group
fixed maintenance dose: 20 mg/day
patient population aged at least 50 years, with a probable diagnosis of AD.
Although the designs of these six studies share many similarities, four of the studies focus on memantine as monotherapy, while two (MD-02 and MD-12) comprise patients already receiving stable therapy with an approved acetylcholinesterase inhibitor (AChEI).
The studies discussed in this section formed the basis of the clinical part of the memantine regulatory dossier.
A summary of the variations in these study designs is shown in Table 6.1, followed by a brief description of the key findings from the individual studies.
Individual study results
MRZ-9605 (Reisberg et al, 2003)10
Study MRZ-9605 evaluated the ef?cacy and safety of memantine (20 mg/day) as monotherapy in patients with moderate to severe AD (MMSE 3–14).
The study comprised 252 patients with moderate to severe AD, who were based in a community setting. In addition to MMSE criteria (3–14), patients were required to be at FAST stage 6a or above, and some patients had substantially advanced disease, having reached stage 7a. Eligible patients were in GDS stages 5 or 6. Baseline characteristics were similar between the memantine and placebo groups, and the study population had a mean baseline MMSE score of 7.9.
Patients (ITT population) were assessed at Weeks 4, 12 and 28 (endpoint), or at early termination. The withdrawal rate from the study was lower in the memantine group than in the placebo group (23%, 29 patients vs 33%, 42 patients), generating a bias in favour of placebo in the LOCF analysis.
Results
Memantine signi?cantly reduced patient decline in the three core domains of global status, function, and cognition, when compared with placebo (Table 6.2). The percentage of patients in CIBIC-Plus global change categories at Week 28 is illustrated in Figure 6.1.
In the SIB measure of cognition, the bene?t of memantine was already signi?cant at Week 12 (p=0.0003, OC), and was maintained throughout the study.31
In the assessment of behaviour (NPI), the bene?t of memantine was signi?cant at Week 12 (p=0.022, OC), and in favour of memantine (although not reaching signi?cance) throughout the rest of the study (including Week 28).31
RUD analysis showed that carers of patients receiving memantine spent an average of 52 hours less per month on caregiving tasks than carers of patients in the placebo group (p=0.02, TPP).32
Further analysis indicated an advantage for memantine patients in terms of residential status and delayed institutionalisation.32
美金刚治疗AD的临床研究
已经可开展了六个大规模的、III期、安慰剂对照的评价美金刚治疗AD的有效性及安全性的临床研究， ― 三个针对中、重度AD，另三个针对轻、重度AD。将在下面对这些临床试验进行讨论。
试验设计概述
六个AD门诊患者研究具有以下的设计特点：
6个月的研究周期，包括4周的滴定期
安慰剂对照
随机
双盲
多中心
平行设计
固定的维持剂量：20毫克/天
患者年龄至少50岁，可能性诊断为AD。
尽管这六个研究的设计具有许多相似性，其中的四个研究关注美金刚单一治疗的效果，而另两个研究(MD-02 及MD-12)所纳入的患者正在接受稳定剂量的、已上市的胆碱酯酶抑制剂(AChEI)治疗。
在该部分所讨论的这些研究构成了美金刚注册档案临床部分的基础。
在表6.1中对这些研究设计的差异进行了简要概括，随后对单个研究的关键结果进行了简要描述。
单个研究的结果
MRZ-9605 （Reisberg 等，2003）10
研究MRZ9605评价美金刚单药（20毫克/天）治疗中、重度阿尔茨海默病患者（MMSE3-14）的有效性及安全性。
该研究入组了252名来自社区的中、重度阿尔茨海默病患者。除了MMSE评分标准（3-14分）外，患者FAST分级在6a或者以上，一些患者处于疾病的晚期阶段，FAST分级达到7a。合格的受试者GDS分级为5或者6。美金刚组及安慰剂组的基线特征相似，研究人群基线平均MMSE评分为7.9。
在第4周、12周及28周（研究终点）或者早期终止时对受试者（ITT数据集）进行评价，美金刚组受试者的退出率较安慰剂组低（美金刚组：23%，29名受试者；安慰剂组33%，42名受试者），这在LOCF分析中就产生了一种疗效偏向于安慰剂组的偏倚。
结果
与安慰剂组比较，美金刚极大地延缓了受试者整体状态、功能及认知能力三大核心域的衰退（表6.2）。图6.1列举了28周时受试者按CIBIC-Plus整体改变分类的百分比。
用于评价患者认知功能的SIB方面，在第12周时美金刚对受试者的收益已经非常明显（p=0.0003，OC），并且一直维持到整个研究结束31。
在评价患者行为的NPI方面，在第12周时美金刚对受试者的收益已经非常明显（p=0.022, OC），并且在12周后的剩余研究阶段（包括28周）也显示美金刚对患者有益（尽管没达到显著意义）31。
RUD分析显示服用美金刚患者的护理者每个月执行照顾患者任务的平均时间为52小时，少于照顾安慰剂组患者的时间（p=0.02, TPP）32。
进一步的分析表明：根据残留的状态及患者延迟在养老院或者医院的时间，美金刚能让患者受益。32 原件下载： 
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