In the meta-analysis of six clinical studies detailed earlier, memantine showed a signi?cant effect versus placebo on NPI score in moderate to severe AD (p=0.03, OC analysis).³⁵

        In an analysis of pooled data from the six 6-month studies in patients with moderate to severe AD (MMSE <20), memantine-treated patients had signi?cantly less deterioration from baseline in NPI scores, versus placebo-treated patients from Week 12 onwards (p=0.035, OC analysis at endpoint).⁴⁵

Speci?c effects on behaviour were analysed using the 12 individual items of the NPI scale.

        MRZ-9605: The bene?t of memantine over placebo reached statistical signi?cance for the NPI items of ‘agitation/aggression’ (p=0.008), and ‘delusions’ (p=0.04) (LOCF analysis), although it was noted that the memantine group had a signi?cantly higher prevalence of delusions at baseline versus placebo.⁴⁶ Furthermore, memantine patients with ‘agitation/aggression’ at baseline showed a signi?cant improvement in this item versus placebo patients (p<0.05).⁴⁶

        MD-02: In patients receiving stable treatment with donepezil, there were statistically signi?cant differences for memantine over placebo in the NPI items of ‘agitation/aggression’, ‘irritability/lability’, and ‘appetite/eating change’ (LOCF analysis) (Figure 6.12).³³ No behaviours worsened signi?cantly on memantine compared with placebo, and memantine patients with agitation/aggression at baseline showed signi?cant improvement, compared with placebo-treated patients (p=0.021).³³

 

These observations were further supported by a single-item analysis of pooled data from the six Phase III 6-month studies, including patients with MMSE <20. Memantine produced signi?cant bene?ts versus placebo in the NPI items of ‘delusions’ (p=0.007), ‘hallucinations’ (p=0.037), ‘agitation/aggression’ (p=0.001) at Week 12; and ‘delusions’, ‘agitation/aggression’, and ‘irritability/lability’ at Week 24 (Figure 6.13).⁴⁵

In patients who were symptomatic for the NPI items at baseline, statistically signi?cantly more memantine-treated patients than placebo-treated patients showed improvement at Week 24 on ‘delusions’, ‘agitation/aggression’, and ‘disinhibition’.⁴⁵ At Week 12, 68% of patients treated with memantine showed improvement on ‘hallucinations’ versus 49% of patients treated with placebo (p=0.003), LOCF analysis.⁴⁵

 

Further post hoc analyses in studies MRZ-9605 and MD-02, and in pooled data from the six Phase III 6-month studies (MMSE <20 subgroup), investigated the emergence of behavioural symptoms in patients without those specific symptoms at baseline.^33,46

        MRZ-9605: There was signi?cantly less emergence of ‘agitation/aggression’ in the memantine group, compared with the placebo group (p=0.003) (LOCF analysis).⁴⁶

        MD-02: At Week 12, there was signi?cantly less emergence of ‘delusions’ (p=0.011), and ‘agitation/aggression’ (p=0.032) (LOCF analysis).³³ At Week 24, there was signi?cantly less emergence of ‘agitation/aggression’ (p=0.016), ‘irritability/lability’ (p=0.041), and ‘night-time behaviour’ (p=0.027), in the memantine group, compared with the placebo group (LOCF analysis).³³

            Pooled data: At Week 24, memantine prevented the emergence of behavioural symptoms (‘agitation/aggression’, ‘irritability/lability’, and ‘night-time behaviour’) in statistically signi?cantly more patients than placebo (Figure 6.14).⁴⁵

 

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         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、重度阿尔茨海默病患者的NPI评分具有明显的统计学受益，（p=0.03，OC分析）³⁵。

          从六个为期6个月的中、重度阿尔茨海默病患者（MMSE<20）研究中汇总的数据分析表明：在NPI评分方面，自第12周开始，与基线比较，美金刚组较安慰剂组恶化程度更低（P=0.035，观察终点时OC分析）⁴⁵。

采用12个NPI量表独立单项评价美金刚对行为的特异性效应。

          MRZ-9605:在NPI单项“焦虑/攻击”（P=0.008）及“幻觉”（p=0.04）（LOCF分析）方面，美金刚组与安慰剂组相比具有显著统计学意义，美金刚可使患者受益。尽管在基线期，美金刚组患者幻觉的发生率明显高于安慰剂组⁴⁶。而且，与安慰剂组相比，在基线具有“焦虑/攻击”表现的美金刚组患者在这些方面出现了明显改善（P<0.05）⁴⁶。

         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NPI次级量表“焦虑/攻击”、“易怒/情绪不稳定”及“胃口/食欲改变”等方面与安慰剂组比较具有明显的统计学差异（LOCF分析）（图6.12）³³。与安慰剂组相比，美金刚组患者无明显的行为恶化，在基线具有“焦虑/攻击”表现的美金刚组患者在这些方面出现了明显改善（P<0.021）³³。

 

从六个为期6个月的中、重度阿尔茨海默病患者（MMSE<20）研究中汇总的单项数据分析进一步应证了这些观察结果。第12周时，与安慰剂组相比，在NPI“妄想”（p=0.007）、“幻觉”（p=0.037）、“焦虑/攻击”（p=0.001）等方面美金刚可使患者产生明显受益。在24周时，美金刚在“妄想”、“焦虑/攻击”及“易怒/情绪不稳定”等方面可以使患者受益（图6.13）⁴⁵。

在基线具有NPI单项症状的患者，24周时，美金刚组与安慰剂组相比，在“妄想”、“焦虑/攻击”及“去抑制”等方面具有显著统计学差异⁴⁵。第12周时，68%的美金刚组患者在“幻觉”方面出现改善，而安慰剂组为“49%”(p=0.003)，LOCF分析⁴⁵。

 

对研究MRZ-9605 、MD-02以及六个为期6个月的III期研究（MMSE<20）的汇总数据进行进一步的析因分析，研究在基线期无那些特异性症状患者的行为症状的出现^33,46。

         MRZ-9605:在美金刚组，出现“焦虑/攻击”症状的患者明显少于安慰剂组（p=0.003）（LOCF分析）⁴⁶。

         MD-02:在第12周，美金刚组出现“妄想”（p=0.011）及“焦虑/攻击”（p=0.032）（LOCF分析）症状的患者明显少于安慰剂组³³。在第24周，美金刚组出现“焦虑/攻击”（p=0.016）、“易怒/情绪不稳定”（p=0.041）及“夜间行为”（p=0.027）的患者明显少于安慰剂组（LOCF分析）³³。

          汇总数据：在第24周，与安慰剂组相比，美金刚可防止行为症状的出现（“焦虑/攻击”、“易怒/情绪不稳定”及“夜间行为”）（图6.14）⁴⁵

 

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