The study included 433 patients (MMSE 10–22) who were on stabilised AChEI treatment for at least 3 months prior to adding memantine (20 mg/day) or placebo to the treatment regimen.

        Memantine was numerically superior to placebo in the measure of cognition (ADAS-Cog), although there were no signi?cant differences between memantine and placebo in the measures of cognition (ADAS-Cog), function (ADCS-ADL₂₃), behaviour (NPI), or global status (CIBIC-Plus).

        There was a smaller than expected decline in the placebo group, and this is likely to have contributed to the lack of signi?cant differences between groups at endpoint.

The study comprised 470 patients (MMSE 11–23) randomised to either memantine monotherapy (20 mg/day) or placebo in a 2:1 ratio. The two treatment groups were well matched at baseline.

Primary ef?cacy assessments of cognition and global status were assessed at baseline and Weeks 4, 12, 18, and 24. Secondary ef?cacy assessments of activities of daily living and behaviour were obtained at baseline and at Weeks 12 and 24. Ef?cacy assessments were made in the TPP patient population.

In total, 15% of patients in the memantine-treated group and 9% of the placebo-treated group withdrew from the study.

        Memantine showed advantages over placebo for the primary ef?cacy measures of cognition and global status (ADAS-Cog and CIBIC-Plus), with signi?cant differences observed at Weeks 12 and 18, and numerical superiority (although not reaching statistical signi?cance) at Week 24 (Figure 6.5). The loss of signi?cance at endpoint could be attributed to the unexpected improvement in the placebo group on ADAS-Cog and CIBIC-Plus towards the end of study. Despite numerous analyses of possible population-based, statistical or drug-related factors, no explanation for the unusual placebo response has been identi?ed.

        Memantine’s effect on ADCS-ADL₂₃ and NPI scores was not signi?cant.

        Responder analysis (responder = patient with marked cognitive improvement, i.e., reduction in ADAS-Cog score of ≥4, and global improvement or stabilisation, i.e., CIBIC-Plus ≤4) was signi?cant for memantine versus placebo at Week 12 (30.1% vs 20.0%; p=0.032) and at Week 18 (30.0% vs 15.7%; p=0.002).

        Large-scale clinical studies indicate that monotherapy with memantine (20 mg/day) produces clinically meaningful bene?ts to patients with moderate to severe AD, by slowing cognitive decline, improving the ability to carry out tasks of daily living, and having a positive impact on global status.

        Furthermore, in patients receiving stable doses of AChEIs, memantine also produced signi?cant and sustained bene?ts in cognition, function, behaviour and global status.

        Consequently, memantine treatment can maximise independence in patients with moderate to severe AD, thereby reducing the burden on carers and the community as a whole.

 

The memantine indication of moderate to severe AD is supported by the individual studies which were previously described, and by ef?cacy data from a meta-analysis of all six Phase III, placebo-controlled, 6-month studies, listed in Table 6.1.

The meta-analysis population comprised the subgroup of patients from these studies (n=1,826) with a baseline MMSE score <20 (i.e., moderate to severe AD).^1,35 Assessments were made in the key domains of global response, function, cognition and behaviour.

        In patients with moderate to severe AD, memantine produced a statistically signi?cant effect versus placebo in the cognitive, functional, global, and behavioural domains.^1,35

        A summary of results is presented in Table 6.4, and is illustrated in more detail, according to individual study in Figure 6.6.

            In the patient population with moderate to severe AD (MMSE <20), meta-analysis shows that memantine provides signi?cant clinical bene?ts across the domains of cognition, function, global status, and behaviour.

 

 

该研究入组了433名在参加该研究前至少3个月接受稳定剂量胆碱酯酶抑制剂治疗的受试者（MMSE 10-22）。

         尽管安慰剂组与美金刚组之间在认知能力（ADAS-Cog），功能（ADCS-ADL₂₃），行为（NPI）或者全身状态CIBIC-Plus）方面无显著统计学差异，但从数字上看，在认知能力（ADAS-Cog）评价方面美金刚优于安慰剂。

         在安慰剂组，受试者的恶化程度较预期低，这可能是导致在观察终点进行评价时，安慰剂组与美金刚组之间缺乏统计学差异的原因。

 

该研究入组了470名受试者（MMSE 11-23），以2:1的比例随机进入美金刚单药组（20毫克/天）或者安慰剂组。两组的基线特征非常相似。

主要有效性评估包括在基线、第4周、第12周、第18周及第24周对认知能力及全身状况进行评价。次要有效性评估包括在基线、第12周及第24周对日常生活活动能力及行为进行评价。采用TPP数据集进行有效性评价。

美金刚组受试者的退出率为15%，安慰剂组受试者的退出率为9%。

         在12周、18周时，美金刚组在认知能力及整体状况（ADAS-Cog and CIBIC-Plus）的主要有效评价方面优于安慰剂组，二者之间有显著统计学差异。在第24周时，美金刚数字上优于安慰剂组（尽管二者之间无显著统计学差异）（图6.5）。在观察终点时二者之间无统计学差异可能是因为安慰剂组在研究结束时ADAS-Cog 及 CIBIC-Plus的非预期改善。尽管对可能的人群因素、统计学或者药物相关因素进行了大量分析，但未能证实存在安慰剂应答。

         美金刚对ADCS-ADL₂₃ 及 NPI 评分无显著影响。

         在第12周及第18周，美金刚组与安慰剂组比较，应答者分析（应答者=显著认知能力改善的患者，也就是说，ADAS-Cog评分减少≥4，并且整体状况改善或者稳定，也就说，CIBIC-Plus ≤4）具有显著统计学意义，第12周（美金刚组应答率30.1%，安慰剂组应答率20.0%；P=0.032），第18周（美金刚组应答率30.0%，安慰剂组应答率15.7%；P=0.002）

        大规模的临床研究表明单用美金刚（20毫克/天）能给中、重度AD患者带来有意义的临床受益，延缓患者认知能力的衰退，改善患者执行日常生活任务的能力，并且对患者整体状况的改善有正面影响。

         而且，对于接受稳定剂量胆碱酯酶抑制剂治疗的患者，美金刚也能给患者在认知能力、功能、行为及全身状态等方面带来显著及持续的受益。

         因此，美金刚可以使中、重度AD患者的独立能力最大化，从而减轻护理者及整个社区的负担。

 

前述的单个研究及列举在表6.1中的六个III期、安慰剂对照、研究周期6个月的Meta分析有效性数据支持使用美金刚治疗中、重度AD患者。

Meta分析的人群包括这些研究中患者的亚组（n=1826），基线MMSE<20(也就是说为中、重度AD) ^1,35。评价的指标包括整体应答、功能、认知能力及行为等关键阈。

         与安慰剂组相比，美金刚能显著改善中、重度AD 患者的认知能力、功能、整体状况及行为^1,35。

         表6.4为Meta分析结果的摘要，图6.6按单个研究进行了更详细的阐述。

            对于中、重度阿尔茨海默病患者（MMSE<20），Meta分析的结果表明美金刚能给患者的认知能力、功能、整体状况及行为等方面带来明显的受益。

 

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