MMM 300 (France; Orgogozo et al, 2002)70
Patients entering the study (n=321) had 6 months’ disease prior to study inclusion, and a modi?ed ischaemic score (MIS) of ≥5.
At Week 28, memantine produced statistically signi?cant improvements, versus placebo (ITT, LOCF), in scores of:
cognition – ADAS-Cog (p=0.01) (Figure 6.24);31 MMSE (p=0.003)
intellectual function – GBS subscore (p=0.04).
In addition, numerical (but non-signi?cant) superiority was observed for memantine versus placebo in the measures of:
global status – CIBIC-Plus (60% vs 52%; p=0.227); CGI-C investigator ratings (80% vs 70%; p=0.118)
disturbing behaviour – NOSGER scale item (p=0.07).
Memantine was also well tolerated, with a frequency of reported AEs comparable to that of placebo (76% vs 74%).
MMM 500 (UK; Wilcock et al, 2002)69
Patients entering the study (n=579) had 12 months’ disease prior to study inclusion, and a HIS of ≥4. The study included outpatients only.
Memantine produced statistically signi?cant bene?ts in measures of:
cognition – ADAS-Cog (p=0.0005; ITT, LOCF)
memory – NOSGER scale item (p=0.02; TPP analysis).
The effect on global status (CGI-C), was not statistically signi?cant (p=0.292; ITT).
Memantine was well tolerated, with an overall AE rate that was comparable to placebo (77% vs 75%). The distribution of AEs classed as mild, moderate or severe, was also similar between the groups.
Pooled analysis
Analysis by cognitive severity71
Pooled data from the MMM 300 and MMM 500 studies included 710 patients (ITT subset) with mild to moderate VaD.
A post-hoc assessment of this pooled data set presented ADAS-Cog scores for three patient subgroups, with mild (MMSE 20–22; n=215), moderate (MMSE 15–19; n=354), or moderately severe (MMSE 10–14; n=141) cognitive incapacity, at baseline.
Memantine produced an improvement over placebo in ADAS-Cog score for all three subgroups, reaching statistical signi?cance for the most severe subgroup (MMSE 10–14; p=0.008), as well as for the group as a whole (p=0.0003) (Figure 6.25).
Analysis by radiological classi?cation72
In a second analysis of pooled data from the MMM 300 and MMM 500 studies, screening CT or MRI scans were used to categorise patients as having ‘large vessel disease’, or ‘small vessel disease’ (de?ned as white matter lesions and/or lacunes), or ‘other diagnosis’.
Memantine treatment resulted in mean ADAS-Cog total scores that were superior to placebo, across all of the radiological subgroups. There were greater differences observed within the subset of patients with ‘small vessel disease’ (difference of 2.0 points; p=0.002), than in those with ‘large vessel disease’ (difference of 0.93 points; p=0.62). The difference was mainly driven by the cognitive decline in placebo-treated patients, which was faster in patients with ‘small vessel disease’ than in those with ‘large vessel disease’.
Long-term data73
At the end of the 28-week double-blind, placebo-controlled study period of MMM 500, 464 patients opted to enter the 24-week open-label extension phase, receiving memantine 20 mg/day. Patients were assessed for ef?cacy and safety (MMM 300 assessed safety only).
Over the whole 12-month study period, patients receiving memantine in both phases showed a slightly smaller decline from baseline in mean ADAS-Cog score (2.00 points), as compared with patients receiving placebo followed by memantine (3.15 points) (ITT, OC; Figure 6.26).
The rate of decline of the memantine–memantine group over the 12-month period remained lower than in the group receiving placebo during the double-blind period.
Memantine was safe and well tolerated in both phases of the study, with the spectrum and frequency of AEs observed in the open-label phase consistent with those recorded in the double-blind phase. The overall withdrawal rate was low (14%), and the proportion of patients withdrawing due to AEs in the open-label phase was similar between the memantine–memantine and placebo–memantine groups (8% vs 9%).
As shown in two independent clinical trials, memantine is able to signi?cantly improve cognition in patients with mild to moderate VaD. Memantine is also well tolerated in this patient population.
The subgroup of patients with small vessel VaD were particularly responsive to memantine therapy.
In mild to moderate VaD, the positive cognitive effects of memantine were maintained for a period of up to 12 months. Patients receiving memantine in the initial double-blind phase showed an advantage over patients initially receiving placebo. Memantine treatment was safe and well tolerated over a 12-month period.
MMM300(法国；Orgogozo等，2007)70
受试者在参加该研究前已发病6个月（n=321），修正的缺血指数（MIS）≥5
在28周时，与安慰剂组相比，美金刚组出现显著的统计学改善（ITT，LOCF），各项评分如下：
认知能力 ―ADAS-Cog（P=0.01）(图6.24)31；MMSE（p=0.003）
智力功能 ― GBS次级量表(p=0.04)
另外，与安慰剂组相比，美金刚在以下方面表现出数字上的改善（但无显著统计学意义）：
整体状况 ―CIBIC-Plus（美金刚组：60%，安慰剂组：52%；p=0.227）；CGI-C研究者评级（美金刚组：80%，安慰剂组：70%；p=0.118）
滋扰行为 ― NOSGER （p=0.07）
同时，美金刚具有较好的耐受性，所报告的不良事件发生频率与安慰剂组相当（美金刚组：76%，安慰剂组：74%）。
MMM500（美国；Wilcock等，2002）69
在参加该研究前，患者已发病12个月（n=579），HIS≥4，该研究仅入组门诊患者。
美金刚组在以下方面表现出明显的统计学受益：
认知能力 ― ADAS-Cog（P=0.0005;ITT，LOCF）
记忆 ―NOSGER（p=0.02；TPP分析）
美金刚对整体状况（CGI-C）的影响无显著统计学意义（p=0.292；ITT）
美金刚具有很好的耐受性，总的不良事件发生率与安慰剂组相当（美金刚组：77%，安慰剂组75%）。两组之间不良事件严重程度（轻度、中度或者重度）的分布也相似。
汇总分析
认知能力丧失严重程度分析71
从MMM300及MMM500研究中汇总的数据包括710名轻、中度血管性痴呆受试者（ITT数据集）。
受试者在基线被分成3个亚组：轻度认知能力丧失（MMSE 20-22；n=215），中度认知能力丧失（MMSE 15-19；n=354），中等偏重认知能力丧失（MMSE10-14；n=141），对汇总数据采用析因分析对三个亚组患者ADAS-Cog评分进行分析。
与安慰剂组相比，三个亚组的患者服用美金刚后ADAS-Cog评分出现改善，在最严重的亚组具有显著统计学意义（MMSE10-14；P=0.008），对整组也有显著统计学意义（p=0.0003）（图6.25）。
放射学分类分析72
对MMM300及MMM500汇总的数据进行二次分析，筛选期CT或者MRI结果被作为患者分类的依据，患者被分为“大血管疾病”、“小血管疾病”（定义为脑白质变性和/或腔隙）或者“其他诊断”。
经美金刚治疗后，所有放射学分类的亚组平均ADAS-Cog总分优于安慰剂组。在“小血管疾病”亚组，美金刚组与安慰剂组之间差异更大（差异2.0分；P=0.002），“大血管疾病”亚组差异稍小（差异0.93分；P=0.62）。 差异主要源于安慰剂组认知能力的下降，在安慰剂组，“小血管疾病”亚组较“大血管疾病”亚组认知能力下降更快。
长期数据73
在MMM 500为期28周、双盲、安慰剂对照研究结束时，464名受试者选择进入24周开放的拓展研究，接受美金刚治疗，20mg/天。对受试者进行有效性及安全性评价（MMM300仅进行安全性评价）。
在整个12个月的研究中，自基线开始，与先接受安慰剂治疗，然后接受美金刚治疗的患者相比（3.15分），在两个研究相均接受美金刚治疗的患者平均ADAS-Cog评分（2.0分）恶化更为轻微（ITT，OC，图6.26）。
在12个月的研究期间，美金刚-美金刚组恶化的速度慢于在双盲研究中接受安慰剂治疗的组。
在研究的双盲相及开放相，美金刚安全性良好，具有较好的耐受性，在开放相所观察到的不良事件发生种类及频率与双盲相所记录的一致。总退出率低（14%），在开放相，美金刚-美金刚组与安慰剂-美金刚组之间患者由于不良事件退出的比例相似（美金刚-美金刚组：8%，安慰剂-美金刚组：9%）。
正如两个独立的临床试验所证实的那样，美金刚能极大地改善轻、中度血管性痴呆患者的认知能力。同时，这些患者对美金刚具有良好的耐受性。
小血管血管性痴呆患者亚组对美金刚能产生更好的应答。
对轻、中度血管性痴呆患者，美金刚阳性认知能力效应可维持12个月以上。在双盲期即接受美金刚治疗的患者治疗效果优于在双盲期接受安慰剂治疗的患者。在12个月的研究期内，美金刚安全性及耐受性良好。
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