As described earlier, memantine has demonstrated benefts in overall ratings of the cognitive, behavioural and functional domains in clinical studies of moderate to severe AD. The results of these studies were analysed further via specifc single-item analyses within each domain, and via analyses of pooled data.

Within the behavioural domain, there have been additional analyses of the prevention of behavioural symptom emergence, and of effcacy of memantine in the population of patients with behavioural disturbances at baseline.

        In a meta-analysis of the six clinical studies detailed earlier, memantine produced a statistically signifcant benefcial effect versus placebo on cognition (ADAS-Cog/SIB) in patients with moderate to severe AD (MMSE <20) (p<0.00001, OC analysis).³⁵

        In an analysis of pooled data from three studies in moderately severe to severe AD (MRZ-9605, MD-01, MD-02), memantine signifcantly improved SIB scores (vs placebo) from Week 4 onwards (p<0.001, OC analysis at endpoint).³⁹

The effects of memantine on specifc single items of cognition were assessed using SIB subscales.

        MRZ-9605: Memantine produced signifcant and favourable results versus placebo (OC analysis) in the subscales of ‘memory’ and ‘visuospatial ability’ (p<0.05), with strong trends in the subscales of ‘language’ (p=0.052) and ‘praxis’ (p=0.059).⁴⁰

        MD-02: In patients receiving stable treatment with donepezil, statistically superior effects of memantine versus placebo were observed in the subscales of ‘language’ and ‘praxis’ (p<0.01) and ‘memory’ (p<0.05) (LOCF analysis).⁴¹ Memantine also produced signifcant benefcial effects versus placebo in the three SIB subscale clusters –‘memory/attention/orientation/orienting to name’, ‘language/social interaction’, and ‘praxis/visuospatial ability/construction’ (Figure 6.8).⁴¹

 

To further assess the validity of these observations, results of the single-item analyses from the three studies in moderately severe to severe AD (MMSE 3/5–14), were pooled. Memantine produced signifcant effects versus placebo in the SIB subscales of ‘language’, ‘orientation’, ‘praxis’, and ‘visuospatial ability’ (LOCF and OC analyses), ‘construction’ (LOCF analysis only) (Figure 6.9), and ‘memory’ (OC analysis only).³⁹

Therefore, memantine’s specifc symptom benefts are observed in individual studies, and these effects are reinforced by pooled data from these studies.

 

        In a meta-analysis of the six clinical studies detailed earlier, memantine produced a statistically signifcant benefcial effect versus placebo on function (p=0.0007, OC analysis) in patients with moderate to severe AD (MMSE <20).³⁵

        In an analysis of pooled data from three studies (MRZ-9605, MD-01, MD-02), memantine signifcantly improved ADCS-ADL₁₉ scores versus placebo from Week 12 onwards (p<0.001, OC analysis at endpoint).⁴²

The effects of memantine on specifc single functional items were assessed using the ADCS-ADL₁₉ scale, which individually rates 19 items of daily living.

        MRZ-9605: Memantine produced signifcant and favourable results versus placebo (OC analysis) in the ADCS-ADL₁₉ items of ‘making conversation’, ‘clear dishes from tables after meal’, and ‘dispose of garbage or litter’ (p<0.05).⁴³ There was also a trend in favour of memantine for the items ‘use a telephone’, and ‘get around outside on his/her own’ (p<0.10).⁴³

        MD-02: In patients receiving stable treatment with donepezil, memantine demonstrated signifcant benefts versus placebo in the ADCS-ADL₁₉ items ‘toileting’, ‘grooming’, ‘watching TV’, and ‘fnding belongings’ (OC analysis) (Figure 6.10).⁴⁴ In addition, in a cluster analysis, memantine-treated patients experience signifcantly less deterioration (vs placebo) in two of the item subgroups: ‘autonomy’, and ‘higher-level functions’ (p≤0.05, OC analysis).⁴⁴

 

The consistency of these observations was further supported by a single-item pooled analysis of results from the three studies (MRZ-9605, MD-01, and MD-02) described above. Memantine produced signifcant benefts versus placebo in the ADCS-ADL₁₉ items of ‘fnding belongings’, ‘conversing’, ‘watching TV’, ‘grooming’, and ‘toileting’, and had a numerical advantage over placebo for the large majority of items (LOCF analysis) (Figure 6.11).⁴² The OC analysis results were consistent with the LOCF results.⁴²

 

The document about Specifc symptom benefts in moderate to severe AD was translated by Huayiwang Mandarin Translation Company.

 

如前期所描述的那样，在中、重度AD临床研究中，已证实美金刚可以使处于认知能力、行为及功能域的各个分级阶段的患者受益。

在行为方面，进行了防止行为症状出现及美金刚治疗基线期行为障碍患者有效性的额外分析，

          在前述的6个临床研究Meta分析中，对中、重度AD患者（MMSE<20），与安慰剂组相比，美金刚对患者认知能力(ADAS-Cog/SIB)具有显著的统计学受益（p<0.00001， OC 分析）³⁵。

         对三个中重度至重度AD患者临床研究（MRZ-9605, MD-01, MD-02）汇总数据的分析表明，美金刚自第四周开始可极大地改善患者SIB评分（p<0.001，观察终点进行 OC 分析）³⁹。

采用SIB次级量表评价美金刚对特异性单项认知能力的影响。

         MRZ-9605:与安慰剂组相比（OC分析），美金刚组在次级量表的“记忆”及“视觉空间能力”方面具有显著的临床受益（P<0.05），在次级量表的“语言”（p=0.052）及“实践”方面（p=0.059）具有强烈的受益倾向⁴⁰。

         MD-02 接受稳定剂量多奈哌齐治疗的患者被随机分配至美金刚组及安慰剂组，统计学结果表明美金刚组的患者在“语言”和“实践”（p<0.01）以及“记忆”（p<0.05）(LOCF分析)等次级量表方面优于安慰剂组⁴¹。同时，在美金刚组在三个SIB次级量表组合“记忆/注意力/定位/名称定位”、“语言/社会相互影响”及“实践/视觉空间能力/构建”方面也明显优于安慰剂组（图6.8）⁴¹。

 

为了进一步评价这些观察结果的有效性，汇总了上述三个中、重度阿尔茨海默病（MMSE 3/5-14）研究的单项分析结果。在SIB次级量表“语言”、“定位”、“实践”及“视觉空间”能力（LOCF分析及OC分析）、构建（仅仅进行LOCF分析）（图6.9）、及记忆（仅仅进行OC分析）等方面，美金刚组与安慰剂组相比具有明显的统计学差异。³⁹

因此，在单个研究中观察到美金刚特异性症状受益，通过从这些研究中汇总数据，进一步应证了这些效用。

 

         在前面详述的六个临床研究Meta分析中，与安慰剂组相比，美金刚对中、重度（MMSE<20）阿尔茨海默病患者的功能具有明显的统计学受益，（p=0.0007，OC分析）³⁵。

         对MRZ-9605、 MD-01及MD-02三个研究的数据汇总分析，与安慰剂组相比，自第12周开始，美金刚可以明显改善患者ADCS-ADL₁₉评分（p<0.001，观察终点时OC分析）⁴²

采用ADCS-ADL₁₉量表（该量表将日常生活能力分成19个单项）评价美金刚对特异性单个功能项的效应。

          MRZ-9605:与安慰剂组相比，美金刚组患者在ADCS-ADL₁₉量表“交流”、“饭后从桌子上清盘子”以及“垃圾处理”方面明显的受益（OC分析）(p<0.05)⁴³。同时，在“使用电话”、“独自在外面走动”方面，美金刚组也表现出一种受益的倾向（p<0.10）⁴³。

         MD-02: 接受稳定剂量多奈哌齐治疗的患者被随机分配至美金刚组及安慰剂组，美金刚组的患者在ADCS-ADL₁₉ 次级量表“上厕所”、“梳理”、“看电视”及“寻找随身物品”（OC分析）（图6.10）方面明显优于安慰剂组⁴⁴。此外，在组合分析中，美金刚组患者在“自主性”及“稍高难度功能”两个亚组方面恶化程度明显低于安慰剂组（p≤0.05，OC 分析）⁴⁴。

 

上述MRZ-9605、 MD-01及MD-02三个研究单项数据汇总分析的结果进一步应证了这些观察结果的一致性。在ADCS-ADL₁₉量表“寻找随身物品”、“交谈”、“看电视”、“梳理”及“上厕所”等方面美金刚组明显优于安慰剂组。对一些大的、主要项目美金刚组较安慰剂组具有数字优势（LOCF分析）（图6.11）⁴²。OC分析的结果与LOCF分析的结果一致⁴²。

 

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